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Pancreas: Anatomy, diseases and health implications
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Chapter
PANCREAS: ANATOMY, DISEASES

AND HEALTH IMPLICATIONS
Eliete Dalla Corte Frantz, Vanessa de Souza-Mello

and Carlos Alberto Mandarim-de-Lacerda*
Laboratory of Morphometry, Metabolism and Cardiovascular Disease,
Biomedical Center, Institute of Biology, Department of Anatomy and Cell Biology,
State University of Rio de Janeiro, Brazil
ABSTRACT
The pancreas consists of two organs in one: exocrine and endocrine glands. The
exocrine gland secretes enzymes into the digestive tract, whereas the endocrine gland
secretes hormones into the bloodstream. The endocrine cells are mainly grouped into the
pancreatic islets (of Langerhans), including five types of cells: the alpha cells are
responsible for producing glucagon; the beta cells produce insulin; the delta cells produce
somatostatin; the PP cells produce the pancreatic polypeptide, and the epsilon cells
produce ghrelin. All these products are involved in the maintenance of glucose
homeostasis. The human pancreas is a retroperitoneal organ anatomically divided into
head, neck, body and tail of the pancreas. At its origin, the pancreas has two buds
developing on the dorsal and the ventral sides of the final foregut, both endocrine and
exocrine cells arise from the same endodermal rudiment. As the stomach and the
duodenum rotate, the ventral and dorsal pancreatic buds fuse, resulting in the formation
of the main pancreatic duct. Vascularization begins to invade these immature endocrine
cell clusters, which coexpress several pancreatic hormones and will become the islets -
isletogenesis. The outcomes of the individual pancreatic cells are determined by the
expression of a series of transcription factors (Pdx1, Neurogenin3, Pax6, Isl1…). The
fastest expansion of the cell mass occurs in the late gestational period with further
additional remodeling and maturation. Signaling factors from inside and outside the
pancreas, modulate the secretory functions of the islet cells. The inappropriate activation
or inactivation of the pathways mediating the regulatory mechanisms of the pancreas has
considerable impacts upon health and disease. The whole pancreas can be isolated and
*
E-mail address: Professor and Head of the Department, mandarim@uerj.br, www.lmmc.uerj.br, [+55 21] 2868-
8316.
2 Eliete Dalla Corte Frantz, Vanessa de Souza-Mello et al.
cultured under suitable conditions, a technique which is commonly used in researches

targeting at studying the pancreas development and its responses to insults. The use of
animal models in the development of the novel therapeutic strategies is welcome.
Therefore, the creation of experimental models is currently a major issue. Various animal
models are normally employed in contemporary research of Type 1 and Type 2 diabetes
mellitus, pancreatitis, pancreatic cancer, cell isolation and islet transplantation.
Commonly employed experimental techniques for pancreatic research include, but are
not limited to, molecular and functional studies: techniques ex vivo (for example, glucose
stimulated insulin secretion), in vivo (for example, hyperinsulinemic, euglycemic clamp),
and in vitro (for example, gene level -PCR and protein level – Western blot and
immunohistochemistry).
ABBREVIATIONS LIST
Ach – Acetylcholine
Akt - Protein kinase B
ATP - Adenosine triphosphate
bHLH - Basic helix-loop-helix
Brn - Brain-specific homeobox
CCK - Cholecystokinin
Co A - Acetyl coenzyme A
DM - Diabetes mellitus
DPP-IV – Dipeptidyl peptidase 4
ELISA - Enzyme-linked immunosorbent assay
FFA - Free fatty acids
FGF - Fibroblast growth factors
Foxa - Forkhead box protein
FOXO - Forkhead box
GHSR - Growth hormone secretagogue receptor
GIP - Glucose-dependent insulinotropic peptide
GLP- 1 - Glucagon like peptide-1
GLUT – Glucose transporter
Hes1 - Hairy and enhancer of split-1
HF- High fat diet
HOMA - Homeostatic Model Assessment index
IGF- Insulin-like growth factor
IGTT - Intraperitoneal glucose tolerance test
IR - Insulin receptor
IRS - Insulin receptor substrate
Isl - Insulin gene enhancer protein
Ki - Insulin sensitivity index
Mist1 - basic helix-loop-helix (bHLH) transcription factor
NaCl – Sodium chloride
NAFPD - Fatty pancreatic disease
NASP - Non alcoholic steatopancreatitis
Ngn3 - Neurogenin3
Pancreas: Anatomy, Diseases and Health Implications 3
Nkx - Homeobox protein

OGTT - Oral glucose tolerance test
Pax - Paired box gene
PCR - Polymerase chain reaction
PDA - Pancreatic ductal adenocarcinoma
Pdx1 - Pancreatic-duodenal homeobox 1
pH - Hydrogenionic potential
PI3K - Phosphatidylinositol 3-kinase
PP - Pancreatic polypeptide
PPAR-gamma - Peroxisome proliferator-activated receptors
PSCs - Pancreatic stellate cells
Ptf1a - Pancreas-specific transcription factor 1a subunit
PTPases - Protein tyrosine phosphatase
QUICKI - Quantitative insulin sensitivity check index
RER - Rough endoplasmic reticulum
SC – Standard chow diet
TGF-beta - Transforming growth factor beta
VEGF - Vascular endothelial growth factor
VIP - Vasoactive intestinal polypeptide
ZG – Zymogen granules
INTRODUCTION
In antiquity, the pancreas was ignored as much as an organ as the seat of disease. The
first description of the pancreas is attributed to Herophilus (335-280 BC). The word
"pancreas” was build in 1570s, from Gk. pankreas "sweetbread (pancreas as food), pancreas,"
from pan- "all" + kreas "flesh", probably on notion of homogeneous substance of the organ. It
was in the 17th century that the main duct of the organ was described, and, in 19th century
Claude Bernard discovered the function of the pancreas relative to digestion, but not the
association with diabetes. In 1889, Reginald Fitz has established the pancreatitis as a disease
entity. In 1922, Banting and Best have obtained isletin and have demonstrated the capacity of
the substance to recover a dog from diabetic coma. In 1927, the first case of hyperinsulinism
due to a tumor of the pancreas islet cells was reported and, in 1955, Zollinger and Ellison
described two patients with severe peptic ulcer disease due to noninsulin-secreting tumors of
the pancreatic islets. Subsequently, gastrin was isolated as the hormone responsible for this
syndrome. In March 1940, Dr. O. Whipple performed the first documented surgery of one-
stage pancreaticoduodenectomy [1].
The human pancreas extends from the duodenum to the spleen in the upper abdomen (at
the 2nd lumbar vertebral level), behind the stomach. The pancreas, anatomically, has four
parts: head (with the process uncinate that embraces the superior mesenteric vessels), neck,
body, and tail. The head of the pancreas is surrounded by the duodenum. The common bile
duct traverses through the head of the pancreas and joins with the pancreatic duct at the
ampulla of Vater to empty bile into the second or descending part of the duodenum. The tail
of the pancreas lies in the splenorenal ligament and enters the hilum of the spleen (only the
tail is covered by peritoneum, the remainder of the pancreas should be considered in adults as
retroperitoneal). The blood supply of the pancreas originates from the superior and inferior
pancreaticoduodenal artery. These two vessels arise from the gastroduodenal (which comes
from the celiac artery) and superior mesenteric artery, respectively. The splenic artery gives
three important arterial branches to the pancreas: dorsal pancreatic artery, pancreatica magna
(midportion of body) and the caudal pancreatic artery (tail).
In rodents, an animal model often used to study the structure, function and dysfunction of
the pancreas, the anatomy of the pancreas is less well defined and it is immersed in the fatty
tissue that fills the space behind the stomach.
Structurally, the pancreas in the mammals is formed by acini connected to ducts. The
acinar cells are darker and belong to the exocrine pancreas. These cells secrete digestive
enzymes into the duodenum via a system of ducts. Distributed into the pancreatic tissue there
are clusters of paler cells, called islets (of Langerhans – described by Paul Langerhans, 1847
- 1888, German pathologist and biologist), which produce hormones that underlie the
endocrine functions of the pancreas.
The genetic and molecular researches have pointed out numerous possibilities to better
understand the pancreas function and dysfunction. Therefore, one may expect new medical
approaches to diagnosis and treatment of the pancreas diseases. This is pivotal in the modern
World that shows an increasing prevalence of the metabolic diseases, mainly diabetes
mellitus and associated diseases as dyslipidemia, arterial hypertension, obesity, with
increased risk of cardiovascular disease and general morbidity. The significance of these
studies is still greater when one think that these diseases have an actual potential of be
transmitted to the offspring, as one will see in this review.
PANCREAS DEVELOPMENT
Early Stages of Pancreatic Development
The mature pancreas is a bifunctional organ primarily consisting of exocrine tissue

organized in acini that secrete zymogens for digestive purposes and the ductal scaffold that
drains the fluid from the acinar compartment. The pancreatic duct cells also serve an exocrine
function as they secrete bicarbonate for neutralization of stomach acid in the duodenum. The
pancreatic islets, which harbor the different endocrine cell types, can be found embedded
within the exocrine tissue [1].
During gastrulation, the pancreas is formed from clumps of cells that bud from the dorsal
and ventral aspects of the gut endoderm near the foregut/midgut junction [2]. Pancreas
development begins with a pool of common progenitor cells (multipotent endodermal
progenitors) that will give rise to duct, endocrine, or acinar cell lineages (Fig. 1). The
pancreas develops from evaginations of the gut epithelium, and both exocrine and endocrine
cells are differentiated from the common epithelial matrix of the developing pancreatic
anlagen [3]. Early morphological events of pancreas formation appear to be phylogenetically
conserved among mammals [2]. In humans, this process of budding is observed as early as
ten-weeks into gestation [4].
In mice, the developmental process begins when the endoderm is specified to “the
pancreatic state” and these protodifferentiated cells expand to form the pancreatic anlagen [2].
The final size of the pancreas is determined by the original number of progenitor cells already
present at this early stage [5]. In this sequence of events, apparent since four-week gestation
in humans, pancreas organogenesis includes the formation of two pancreatic buds (ventral
and dorsal), which are derivatives of the primitive gut endoderm at the level of the future
duodenum [6].
The dorsal pancreatic bud develops near to the notochord, while the ventral bud develops
in close association with the liver and under the control of signals from the overlying
cardiogenic mesenchyme (Fig. 1). The dorsal bud grows more rapidly than the ventral one,
and extends into the dorsal mesentery around six-week gestation. As the stomach and the
duodenum rotate, the ventral and dorsal pancreatic buds fuse with the ventral bud, giving rise
to the posterior part of the head and the dorsal bud, thereby forming the remainder of the
organ. This fusion occurs during the seventh-week gestation in humans and around 11-11.5
days in mice (stages 13 and 14) [4, 7]. The regulation of this rotation is not well understood,
but perturbations lead to malformations in humans, including annular pancreas, wherein a part
of the ventral pancreas is mislocalized and can constrict the adjacent duodenum [8].
Epithelial cells branch into the surrounding mesenchyme to form an elaborate duct
system that allows transport of exocrine enzymes into the duodenum. Distal cells of the
branching epithelium differentiate into acinar cells that are connected to the duct system via
centroacinar cells [9]. The fusion of the ventral duct with the dorsal duct results in the
formation of the main pancreatic duct (of Wirsung), which runs through the entire pancreas.
The proximal end of the dorsal duct usually does not communicate with the main duct, but
rather forms the accessory pancreatic duct [10]. The terms head, neck, body and tail are used
to designate regions of the organ from proximal to distal in humans, while in rodents it is
rather less well defined [1].
Acinar cells are organized as small glands that produce a variety of digestive enzymes,
including carboxypeptidases, amylase, chymotrypsin, trypsin, ribonucleases, and lipases,
which are responsible for the hydrolytic degradation of carbohydrates, nucleic acids, proteins,
and fatty acids in the digestive tract [11]. The mature exocrine marker amylase is first
detected in mice at day 11 of gestation. The human equivalents of these transitions have not
been described, though a marked transition of the exocrine genes has been observed at 11-
week gestation. The pancreatic acini and the first zymogen granules appear at 12-week
gestation [12].
Transcription Factors
Hormone secretion is controlled at least in part by the nervous system; the sympathetic,
parasympathetic and sensory neurons that innervate the islet are derived from cells that
migrate from the neural crest into the pancreas just as the two buds fuse [13]. Studies of
pancreatic gene expression have identified a large number of pancreatic markers, which are
primarily transcription factors used to define pancreatic cells at different stages of
development [14], their regulation determines the initial budding of the organ as well as cell
fates towards the endocrine or exocrine lineage. However, this transcription factor network is
complicated because several factors are expressed more than once during the differentiation
process, and the factors play more than one role in development [3].
Pancreas generation from the gut endoderm is controlled by signals generated in the
adjacent notochord, a mesodermal structure known to regulate organogenesis and cell
differentiation in adjacent structures [9]. Notch signaling operates in the developing pancreas
and controls the choice between differentiated endocrine and progenitor cell fates in the
developing pancreas. This mechanism explains the initially scattered distribution of endocrine
cells within the pancreatic epithelium [14].
Patterning of the dorsal foregut by the notochord and dorsal aorta is mediated at least in
part by secreted members of the FGF and transforming growth factor beta (TGF-beta)
signaling pathways. A critical aspect of their activity involves repression of the expression of
Sonic Hedgehog, a member of Hedgehog signaling pathway within the pancreas anlagen [15].
Increased Hedgehog signaling at the onset of pancreas formation results in pancreas agenesis;
by contrast, a low level of Hedgehog signaling is detected throughout pancreas organogenesis
and in mature islets, indicating this pathway is essential for proper organ formation [9]. As
discussed, TGF-beta, FGF, Notch and Hedgehog signaling pathways coordinate initiation of
embryonic pancreas formation (Fig. 1). Conflicting data exist about the role of Wnt signaling
during early pancreas development, but several members of the canonical Wnt signaling
pathway are expressed in the developing pancreas [15].
The pancreas-specific transcription factor 1a subunit Ptf1a(p48) is an important bHLH
factor, functioning in the regulation of exocrine gene transcription [16]. The Ptf1a-expressing
precursor was initially found to be essential for exocrine pancreatic development, so much so
that deficient mice in Ptf1a failed to form an exocrine pancreas. The Ptf1a is co-expressed
with Pdx1 in both dorsal and ventral pancreas epithelia from day 9 of gestation in mice (Fig.
1), several days before the onset of exocrine development and suggestive of a role of Ptf1a
beyond that of exocrine specification. The contribution of Ptf1a-expressing cells extended to
both endocrine and ductal cell types, but endocrine or ductal development does not seem to
rely on specific absence of Ptf1a expression [17]. At 10.5 days in mice, Mist1 expression is
observed only in the peripheral epithelial regions most likely destined to develop as exocrine
cells and absent in ducts. Mist1 is the only one completely restricted to exocrine cells, and it
can be hypothesized that Mist1 may be autoregulated to stabilize the exocrine state [3].
Loss-of-function of various Notch pathway genes leads to the upregulation of
Neurogenin3 and increased endocrine formation. Therefore, one of the major targets of the
Notch pathways is Neurogenin3 (Ngn3), a bHLH transcription factor expressed in pancreatic
endocrine progenitor cells that is required for endocrine differentiation, which has been
demonstrated by the complete lack of all pancreatic cell types in Neurogenin3-deficient mice
[18]. Expression of Neurogenin3 begins in mice at nine-day embryo, peaks at 12-days
embryo during the major wave of endocrine cell genesis and is greatly diminished at birth,
with little or no expression being in the adult pancreas [19, 20].
Once Neurogenin3 is expressed in an appropriate progenitor, that cell is destined to
become an islet cell. But the decision as to which of the islet cell types it will become
apparently is controlled by other factors (Fig. 1), including: Foxa2 (to regulate Pdx1 promoter
activity), Isl1, Hes1 (inhibits expression of Ngn3), also, are involved transient expression of
Nkx2.2, Nkx6.1, Pax4 and Pdx1 drives Ngn3-positive cells towards a beta cell phenotype;
meanwhile expression of Brn4, Nkx6.2 and Pax6 direct cells towards an alpha cell phenotype
[21, 22]. Any alteration in the expression of these regulatory genes will disrupt the balance of
pancreatic hormone-expressing cells developed. Figure 1 summarizes a raft of proposed

transcription factors that play important roles in governing the differentiation and
development of the pancreatic exocrine and endocrine cells in the pancreas.
Pdx1/IPF-1 (pancreatic-duodenal homeobox 1/islet promoter factor 1) is a key
transcription factor that is recognized as the earliest and most specific gene expressed in the
primordial pancreas, and it is expressed at numerous stages of pancreatic development and
beta cell differentiation. Pdx1 deficiency, in mice and humans, results in arrested growth of
the pancreatic primordia at a very early stage, leading to complete pancreas agenesis at birth
[23, 24]. Expression of Pdx1 appears during E8.5 in the dorsal and ventral endoderm distal to
the stomach and duodenal epithelium when the endoderm is still closely associated with the
notochord [20].
Figure 1. Schematic view of early stages in the development of the pancreas in rodents. After
gastrulation, with three germ layers known as the ectoderm (Ect), mesoderm (Mes) and endoderm
(End), structures such as the notochord (Not) and the neural tube (NT) are noted. The specification of
the future dorsal and ventral pancreatic buds, the exo-endocrine specification, leading to the duct and
acinar fate, and the endocrine cell differentiation are controlled by the successive expression of
transcription factors, some steps being represented on the figure.
Subsequently, Pdx1 expression becomes progressively restricted to the beta cell lineage.
Later in development, as well as in the adult pancreas, Pdx1 regulates the transcriptional
expression of insulin, somatostatin genes, and glucokinase promoters [25]. Furthermore, the
inactivation of Pdx1 in late gestational beta cells leads to a decrease in the proliferation of
insulin-producing cells concomitant with an augmentation of the proliferation of glucagon-
producing cells, suggesting that Pdx1 function is necessary for the genesis and maintenance
of beta cells and late gestational regulation of correct endocrine cell numbers [26]. Of note,
ectopic expression specifically in adult pancreatic Pdx1-positive cells resulted in

hypoinsulinemia followed by diabetes [9].
We know that the cancer progression and organ development are similar phenomena,
both involve rapid bursts of proliferation, angiogenesis, tissue remodeling, and cell migration.
Therefore, it is not surprising that both processes utilize similar signaling machinery. In fact,
many recent studies have suggested that cancer is a disease triggered by the erroneous re-
activation of signaling pathways that are typically downregulated after the completion of
embryonic development. Our evolving understanding of pancreatic adenocarcinoma is an
excellent example of this relationship between development and cancer with indicated
important roles for two major developmental signaling pathways in pancreatic cancer: Notch
and Hedgehog [27].
Later Stage of Pancreatic Development
The endocrine region of the pancreas consists of five different cell types, each of which is
characterized by the distinctive expression of a specific peptide hormone. For example,
glucagon is expressed in alpha cells; insulin is expressed in beta cells; somatostatin is present
in delta cells; pancreatic polypeptide is expressed in PP cells; and ghrelin is expressed in
epsilon cells [1]. In human, discrete islets can be observed at 12 weeks, and 1 week later,
large primitive islet structures expressing all four pancreatic hormones are formed [28]. In
mice, the first endocrine cells detected in the pancreas express glucagon at nine-day embryo,
subsequently, the cells co-express glucagon and insulin, but they are most likely not
precursors of beta and alpha cells. Later (11.5 days embryo in mice), beta cells are generated
in large numbers after extensive growth and branching of the pancreas. Some endocrine cells
are also scattered among small aggregates of cells, which suggests that the endocrine cluster
is enlarged by the fusion of several small endocrine clusters that originated from different
regions of the pancreatic endoderm. This cell cluster is composed primarily of glucagon-
expressing cells, with a few randomly distributed insulin-expressing cells [29, 30].
Figure 2. Typical mantle-core arrangement with a “ribbon-like” organization of endocrine cells: a core
of beta cells (red) surrounded by a mantle of alpha cells (green).
This aggregation process, termed “isletogenesis”, occurs with a “ribbon-like”

organization of endocrine cells being observed in the central core of the pancreas. This
primary phase of islet development occurs during the second trimester, although remodeling
occurs throughout late gestation and early childhood [4]. Proper islet formation appears to
occur through an ensnaring process, which involves the growth of exocrine tissue and leads to
a separation of the islets of the “ribbon” to form a “pearls on a string” structure (Fig. 2) [3].
Vascular endothelial growth factor (VEGF) is expressed in the developing pancreas or
neighboring tissues and promotes beta cell expansion [14] (Fig. 2). Endothelial cells in blood
vessels are known to provide inductive signals that promote the development of the pancreas,
and in the embryo, endocrine pancreatic beta cells require endothelial signals for their
differentiation and functioning [30]. Mesenchymal tissue rich in a complex capillary network
penetrates these immature endocrine cell clusters, which become the islets at 14 weeks
gestation [28]. The concept of a “vascular niche", which is a microenvironment generated by
endothelial cells that affects the behavior of adjacent cells, has been applied to beta cells [31].
Because of intimate interactions between endocrine cells and blood vessels, islets have a
highly specialized vasculature with a fenestrated endothelium [10].
The number of endocrine cell clusters increases and the beta cells take place in the islet
periphery [32]. Due to a relatively rapid increase of mature beta cells, their clusters fuse
together to form central cores within the endocrine region, and the mature alpha cell mass
then spreads to form a thin mantle layer partially covering the mature beta cell cores. The
arrangement of these endocrine cells within the islet is described as a mantle core, in which a
core of beta cells is surrounded by a mantle of non-beta cells with a thickness of one to three
cells. This typical arrangement becomes evident in mice at approximately 14-days old
embryos (stages 18–21) (Fig. 2) [29, 33]. The formation of islet-like structures occurs earlier
in humans (28% of gestation) and sheep (22% of gestation) compared to rodents, in which
islets do not form until 70% of gestation has taken place [34].
Postnatal Pancreas
At the end of embryogenesis and the early postnatal period, high rates of beta cell
proliferation result in the doubling of the number of beta cells every day in association with
vascular growth [31]. Additionally, during isletogenesis, the pancreas will positively stain for
both Pdx1 and glucagon [3]. In the human fetus, beta cells exhibit robust insulin secretion in
response to insulin secretagogues [35]. However, in rodents, beta cells begin to become
responsive near term, but the response is not robust until a week after birth [36]. At birth, the
arrangement of endocrine cells in the islets appears to be the same as in the adult animal,
while their total population sizes continue to increase. For beta and alpha cell populations, an
additional period of accelerated growth occurs between postnatal days 4 to 10, and growth
continues through day 28 due to increased physiological demands of insulin production, most
of the islet cells develop within the tail of the pancreas and in the dorsal pancreas [6, 37].
In addition to proliferation, apoptosis is a major process that modulates the development
of the endocrine pancreas. Beta cell apoptosis is rare during embryogenesis, although a wave
of apoptosis has been described in early postnatal stages, which is thought to be associated
with islet remodeling and/or changes in beta cell maturation [38]. The frequency of apoptotic
beta cells in the adult rat is approximately 0.5% and declines progressively until 6 months
postnatal [38]. The mitochondria play a prominent role associated with apoptosis in
protecting the islets from oxidative stress to prevent apoptosis. Another growth factor that
prevents the apoptosis of beta cells is insulin-like growth factor (IGF)-II, which is a survival
factor that potentiates beta cell growth, maturation and functioning and is expressed in beta
cells during the early life of rodents [39].
The total mass of beta cells is a critical factor in the regulation of glucose homeostasis
and islet morphology [40] and results from a balance between the dynamic changes of new
cell growth and old cell loss [41]. Beta cell mass expansion in adult continues; however, their
regenerative ability decreases with age [42]. Beta cell regeneration has been postulated to be
carried out through three possible mechanisms: proliferation of pre-existing beta cells,
neogenesis from undefined adult progenitor or stem cells and transdifferentiation from
terminally differentiated cells, particularly in association with conditions such as obesity and
pregnancy, although variations in insulin demand due to physiological and pathological states
leads to increased insulin requirements of the body [43]. Beta cell hypertrophy in response to
increased demand can also contribute to increased beta cell mass [41].
However, even if the mechanisms regulating the maintenance of the beta cell mass in
physiologic conditions are the same in humans, monkeys and rodents, we cannot exclude that
during pathological conditions different pathways, species-specific and injury-specific (for
type and magnitude), might be activated. Through intense research over the last several years,
a hierarchy of transcription factors regulating pancreas development has emerged. Identifying
and manipulating master regulatory molecules to generate functional pancreatic cells has
become the focus of regenerative medicine aimed new insights into the causes of disease and
new strategies for intervening.
FUNCTIONAL STRUCTURE OF THE PANCREAS

Our understanding regarding pancreas structure at molecular level and pancreatic
remodeling is mainly based on the murine model. The developmental stages are well
conserved comparing humans and mice; therefore, mice represent a suitable model to
understand pancreatic functioning as well as some impairment due to eventual diseases.
The functional structure of the pancreas is comparable with two organs in one: an
exocrine gland, made up of acinar cells aimed at secreting digestive enzymes and sodium
bicarbonate, and an endocrine pancreas, made up of five different kinds of secretory islet cells
and secrete hormones targeting at glucose homeostasis. In brief, the exocrine pancreas is
related to normal digestion and absorption of daily meals, whereas the endocrine pancreas is
finely regulated by neuroendocrine, endocrine, paracrine and intracrine pathways to maintain
glucose homeostasis [44].
Even though endocrine and exocrine pancreas exhibit distinct functions, they are
physiologically interrelated. The pancreas can be considered having four structurally
independent components: the exocrine pancreas, made up of acinar cells and duct cells;
endocrine pancreas, with its characteristic islet cells, blood vessels and the extracellular
space. Exocrine pancreas accounts for at least 80% of the volume of the organ, being the most
expressive part [45]. It is characterized by blind-ended ductal system, reminding a massive
bunch of grapes. Each acinus is equivalent to a grape, bounded by other acinar cells that
secrete digestive enzymes into tubules. Acini are grouped into lobules with branched network
of tubules. Each acinus is composed by pyramidal acinar cells, whose apical membranes is
responsible for intercellular canaliculus formation and basolateral membranes are found at the
periphery. Duct cells are found all the way along the canaliculi and secrete sodium
bicarbonate. Narrow ducts from acini converge to form interlobular ducts, which converge to
form extralobular ducts and then main collecting duct. The latter joins with common bile duct
before pancreatic juice enters duodenum [46].
Conversely, endocrine pancreas encompasses a cluster of cells, called Langerhans islets,
which secrete different hormones aiming at reaching and maintaining glucose homeostasis.
Islets have got spherical shape and account for 1-2% of total volume of the organ. There are
five different major cells: alpha cells (α-cells), beta cells (β-cells), delta cells (δ-cells), PP
cells (also known as F-cells) and the epsilon cells (ε-cells), which are responsible for
producing glucagon, insulin, somatostatin, pancreatic polypeptide, and ghrelin, respectively.
Despite being controlled by signaling factors from pancreas and other tissues,
intercommunication of these cells is important and influences one another’s secretion [47,
48].
Exocrine Pancreas and Insulin-Acinar Axis
Pancreatic cells from exocrine and endocrine pancreas are also interrelated given that
they lack basal membranes. Peri-insular acini possess larger number of zymogen granules
than acini removed from islets. The presence of insulin nearby also impacts the morphology
of peri-insular acini. Not only does diabetes mellitus (DM) alter endocrine pancreas, but it
also impairs exocrine pancreas functioning [48, 49]. These observations have put forward the
concept of insulin-acinar axis, which suggests the regulation of acinar cells functioning by
islet peptides. Peri-insular acini are exposed to high concentrations of islets hormones due to
protrusion of efferent vessels stemmed from islets into surrounding exocrine pancreas. Some
peptides secreted by endocrine pancreas regulate synthesis, transport, secretion and growth of
acinar cells [45].
Acinar cells present abundant free ribosomes, rough endoplasmic reticulum and
mitochondria, besides a well organized golgi apparatus. This configuration enables the cell to
produce granules called zymogen (ZG), which contains countless enzymes and are located at
the apical side of the cell. ZG protease precursors include trypsinogen, chymoytypsinogen
and procarboxypeptidases, which mix with NaCl from duct cells to form pancreatic juice.
These enzymes are activated by cleavage into duodenum in order to prevent pancreas auto-
digestion, which would lead to pancreatitis. Apart from proteases, acinar secretion also
contains active enzymes such as lipase, nuclease and amylase [50, 51].
The presence of food into digestive system is the first stimulus for exocrine pancreas
secretory function, but hormonal and neural systems play a central role when it comes to
regulation of exocrine secretion. The major regulators include the neurocrine molecule
acetylcholine (ACh) and the endocrine molecule cholecystokinin (CCK), whose action relies
on interaction with muscarinic receptors and is independent of calcium stores. On the other
hand, other regulators such as secretin, vasoactive intestinal polypeptide (VIP) and
angiotensin II depends on intracellular calcium concentrations to suffer exocytose from their
granules [52, 53]. However, given that the pancreatic acinar cell is not electrically excitable,
though, it cannot rely on the extracellular Ca2+ influx to stimulate enzyme secretion. The
Ca2+ concentration required can be achieved from intracellular stores. Major regulators are
important for the release of less important regulators as low concentrations of ACh or CCK
induce weak local Ca2+ signals near the secretory pole of the acinar cells. In contrast, a high
concentration of secretagogue produces a global Ca2+ wave that spreads over the entire cell
[54, 55].
Despite representing the minority of cells in exocrine pancreas, duct cells are
indispensible for normal functioning of digestive enzymes and integrity of intestinal mucosa.
The secretion of sodium bicarbonate by duct cells is essential for neutralize gastric chyme and
allow gastric empty into duodenum. Sodium bicarbonate provides an optimal pH for
pancreatic digestive enzyme activity but physiology of duct cells is poorly understood in
comparison with acinar cells [56, 57].
It represents 10% of total number of cells from pancreas and 5% of pancreas volume.
These ducts are lined with principal cells that possess small amounts of rough endoplasmic
reticulum, Golgi apparatus and secretory vesicles. Great number of mitochondria is found in
the principal cells, linked with the huge energy demands of the secretory duct cells. The
apical membranes of the principal cells possess microvilli while the basal membranes of the
principal cells are rich in tight junctions or adherent junctions. Being the largest branches of
the network, the interlobular duct cells become columnar in shape and intermingle with goblet
cells, which are responsible for mucous production. Sodium bicarbonate concentrations are
usually 120-140 mmol/L, getting higher immediately after food consumption. The main
stimulus is the presence of secretin, peptide that is produced by endocrine D cells in response
to the presence of acid chyme into duodenum. The presence of bile salts or fat rich meal into
duodenum also triggers secretin secretion as well as CCK does. Neurohormonal regulation is
suggestive of the complexity of ductal secretion control [58, 59].
Apart from secretory function, pancreatic ductal cells have been proposed as a source of
progenitor cells or stem cells. It has been described that these cells possess capacity of
proliferative neogenesis of duct cells and pancreatic islets as well. Co-expression of Pdx1 in
rodents, a specific development cell marker, confirms this hypothesis. However, lack of
pancreatic markers specific for ductal cells made this discovery inconclusive [60]. Exocrine
pancreas functioning is summarized at table 1.
Table 1. Exocrine pancreas: cells and function
Type of cell Secretion Function

Acinus Zymogens (trypsinogen, chymoytypsinogen and Digestion of protein,
procarboxypeptidases), lipase, nuclease and lipids and
amylase carbohydrate
Ductal cell Sodium bicarbonate Neutralize chyme
Endocrine Pancreas
On the contrary of exocrine pancreas, endocrine pancreas represents only 2% of total

volume of the organ. Beta cells constitute 80% of the total number of islets and normally in
rodents they are found in the centre of the islet, surrounded by alpha and delta cells in islet
periphery. Blood flows from centre to periphery, leading to a paracrine interaction among the
islet cells and hence alpha cells and delta cells are exposed to high concentrations of insulin in
order to finely regulate glucagon and somatostatin release. On the other hand, in humans beta
cells are not restricted to the core of the islet a well as alpha cells are not restricted to
periphery, being important this difference when it comes to studies interpretations [44, 61].
Pancreatic beta cells are responsible for insulin synthesis. Insulin is an anabolic hormone,
which is synthesized from pre(pro)insulin. It is cleaved into proinsulin at endoplasmic
reticulum, where proinsulin is cleaved by an endopeptidase known as prohormone convertase
to originate mature insulin. Removal of c-peptide allows insulin to interact with its own
receptor. Free c-peptide and mature insulin are packed in the golgi apparatus and under
maximal stimulation only 5% of the granules are released [44, 61]. Beta cell release insulin in
response to amino acid, fatty acids and, mainly, glucose. Regarding glucose-stimulated
insulin secretion, glucose enters beta cell through GLUT2 facilitative diffusion. Glucokinase
promotes the phosphorilation of imported glucose during glysolysis, leading to citric acid
cycle with the resulting production of acetyl coenzyme A (Co A) and adenosine triphosphate
(ATP). ATP concentrations inhibit ATP sensitive potassium channel and reduce potassium
efflux, leading to membrane depolarization. This event open voltage gate calcium channel
and promotes calcium influx, which stimulates exocytosis of insulin granules. Insulin release
is a biphasic event. The first phase is rapid and can be accounted for stores presynthesized
insulin, whereas the slow second phase is related to new insulin biosynthesis. It is worthwhile
to mention that amylin is produced by beta cells in a ratio of one to one with insulin and
regulates gastric motility, renal reabsorption and metabolic actions. Amyloid deposit within
beta cells reduces insulin production, representing a key factor when it comes to diabetes
pathogenesis [61, 62].
Alpha cells are responsible for glucagon synthesis, which antagonize insulin action. It is a
catabolic hormone that stimulates de novo synthesis of hepatic glucose via gluconeogenesis,
being activated at hypoglycemic states and inhibited by hyperglycemic states. High plasma
levels of amino acids, epinephrine and vagal activation stimulate glucagon release, whereas
somatostatin inhibits [44, 63]. Glucagon can counteract the effect of insulin on glucose
homeostasis through its binding to the Gs protein coupled glucagon receptor. Interestingly,
alpha cells can produce a ligand of the growth hormone secretagogue receptor (GHSR),
which stimulates the release of growth hormone from the anterior pituitary through a G-
protein coupled GHSR [63-65].
Somatostatin is secreted by delta cells and is associated with inhibition of growth
hormone release from pituitary gland. It also exerts a wide range of secretory and motor
functions upon organs from digestive system. Somatostatin is a profound inhibitor of insulin
and glucagon secretion, reducing glycemia, besides inhibition of exocrine secretion,
particulary CCK and secretin [63].
Pancreatic peptide (PP) is produced by PP cells or F cells (less than 1% os islet
population). PP is a 36-amino acid peptide with a distinctive C-terminal tyrosine amide
residue which belongs to the neuropeptide Y and peptide YY family. Food intake increases its
secretion as well as cholinergic stimulation and hypoglycemia. On the other hand, the
presence of glucose inhibits its production. The release of PP is dependent upon cholinergic
stimulation, even though some nutrients may trigger this event. PP physiological functions
remain obscure, but diverse effects upon digestive secretion and motility have been described.
These effects include acid secretion and relaxation of gallbladder [66, 67].
Finally, ghrelin was first identified in the stomach. It stimulates appetite and food intake,
while enhancing fat mass deposition and weight gain via through influences upon the central
nervous and gastro-intestinal systems. Recently, epsilon cells are identified in the developing
and adult human pancreas, indicating that epsilon cells are ontogenetically and
morphogenetically distinct from alpha cells and beta cells. In the pancreas, ghrelin acts direct
upon islet cell insulin secretion and acinar enzyme secretion from the endocrine and exocrine
pancreas, respectively. In this regard, a locally expressed ghrelin system has been identified
within acinar cells so as to regulate acinar cell function. Hence, the acinar cell ghrelin system
is subjected to regulation by physiological and pathophysiological stimuli such as gastric acid
inhibition, acute pancreatitis, and starvation, suggesting that it is involved in exocrine
pancreatic function and dysfunction [68-70]. Table 2 offers an overview of pancreatic
endocrine cells and secretion.
Table 2. Endocrine pancreas: cells and secretion
Type of cell Secretion Function

Alpha cell Glucagon Raises blood glucose levels
Beta cell Insulin Lowers blood glucose levels
Delta cell Somatostatin Inhibits growth hormone release
from pituitary
PP cell Pancreatic peptide Regulate digestive secretion and
motility
Epsilon cell Ghrelin Orexigenic
PANCREAS REMODELING
Pancreatic Lipotoxicity
Pancreas remodeling includes all features derived from abnormal functioning of

pancreatic beta cell. In the presence of insulin resistance, excessive free fatty acids (FFA) due
to high rates of lipolysis in adipose tissue is also deviated to pancreas [71]. In the exocrine
pancreas, pancreatic fat (interlobular, intralobular, and perilobular) density; pancreatic
vascularization; amyloid deposition; acinar and duct volume; the number, volume, and size of
zymogen granules in pancreatic acinar cells can be evaluated. The ectopic fat accumulation in
pancreatic tissue is named nonalcoholic fatty pancreatic disease (NAFPD) [71]. It is
characterized by increased pancreatic mass and fat (especially triglycerides and free fatty
acids), and increased cytokines as well. This NAFPD is related with pancreatitis, another
disease compromising normal pancreatic function, although its pathogenesis is not yet fully
understood. However, there is pathological significance in extreme fat infiltration in the
pancreas, as it diminishes exocrine function substantially, resulting in malabsorption [72].
Pancreatic steatosis precedes DM2, and therefore, any kind of intervention that reduces lipid
overload to the pancreas might be feasible to avoid fat accumulation within the pancreas and
the progression to diabetes [73].
The first correlation between pancreatic mass and body mass was made in 1926 [74]. In
1933, a study described 9% of pancreatic fat in lean individuals and 17% in obese individuals
[75]. In the 60 and 70 associations between the presence of excessive pancreatic fat and
obesity began to be made [76, 77] and, more recently, experimental studies have confirmed
this tendency of increase in pancreatic mass due to overweight [78] and foung pancreatic
steatosis in animals fed with high-fat high sucrose diet [72].
In a similar way to what is observed in liver, there is a strong association between
pancreatic cancer and obesity [73]. Another finding that is correlated with obesity is
pancreatitis because obese individuals present severe forms of this disease [79, 80].
Pancreatitis can be defined as a condition where occur autodigestion of the gland through a
mechanism not well defined. Digestive enzymes are activated within pancreas, which lead
disruption of cell membrane, causing edema, interstitial hemorrhage and activation of pro-
enzymes and destruction of pancreatic acini [81].
Excessive fatty acids in pancreatic tissue interfere with insulin secretion, leading to
hypersecretion and hypertrophy of pancreatic islets, causing dysfunction and loss of
pancreatic beta cell through apoptosis. This phenomenon is known as lipotocixity [82, 83].
Maintenance of these conditions yields pancreatic exhaustion [84]. Regarding NAFPD
progression, studies have identified activated stellate cells, suggesting that inflammation and
enhanced oxidative stress are crucial to NAFPD evolution to non alcoholic steatopancreatitis
(NASP) [73, 85]. All the conditions described above lead to modifications in pancreatic cell
machinery, morphology, volume and functional capacity and can be evaluated through many
different techniques.
Light Microscopy
Through analysis of light microscopy can be estimated volume density of steatosis in

exocrine pancreas, besides morphometric and stereological quantities in the endocrine
pancreas: area of a pancreatic islet; major and minor diameters; islet number; islet and beta
cell volume density; islet, beta and alpha cell mass; irregularly shaped islets [86]. In this
regard, chronic intake of high-fat diet by adult mice resulted in increased cell diameter
concomitant with higher islet mass, beta cell mass and alpha cell mass in comparison with
control group, implying islet hypertrophy, which was confirmed by immunofluorescence
[86]. Immunolabeling revealed important disarrangement of islets cells distribution after
double labeling for glucagon and insulin in diet-induced insulin resistance in mice. These
alterations comprises infiltration of alpha cells into islet core, characterizing
hyperglucagonemia, besides higher immunodensity for insulin, confirming greater beta cell
mass in high-fat fed animals when compared to their counterparts [86]. As for pancreatic
steatosis, a recent work has revealed a seven-fold increase in pancreatic fat deposits after the
intake of a high-fat high-sucrose diet during 12 weeks, these overweighed animals also
exhibited increased pancreas mass, islet hypertrophy and increased immunodensity for insulin
and GLUT2 [72]. Pancreatic steatosis is illustrated in figure 3, whereas distribution of alpha
cell and beta cell through immunofluorescence is depicted in figure 4.
Figure 3. (a and b) Pancreatic tissue illustrating interlobular and intralobular pancreatic steatosis (open
arrows). Hematoxylin-eosin, same magnification.
Figure 4. Immunofluorescence double labeling for glucagon (green) and insulin (red) in pancretic islets
from mice. (a) Normal islet cell distribution in lean mice, with alpha cells restricted to periphery and
beta cells within islet core. (b) Adverse remodeling due to insulin resistance, with alpha cell infiltration
into islet core (open arrow) and islet hypertrophy, characterizing hyperinsulinemia. Same
magnification.
Transmission Electron Microscopy
Also by electron microscopy analysis can be evaluated organization of mitochondria,

endoplasmic reticulum, secretory granules and pancreatic stellate cells, cytoarchitecture of the
beta and alpha cell islets, fat globules within the pancreas [86]. In the pancreas, alterations in
the architecture at the cellular level can compromise the proper functioning of the endocrine
and exocrine pancreas, and this level of organization can only be viewed by electron
microscopy.
These conditions were evaluated recently through electron microscopy and after the
chronic intake of high-fat diet (during 16 weeks) electronmicrography showed scarce
mitochondria, which when observed were swollen with fragmented cristae. However, a rough
endoplasmic reticulum (RER) was well developed, suggesting intense protein synthesis. This
observation agrees with the large number of secretory granules observed within the pancreatic
acinar cells of these animals. Another interesting observation was the presence of activated
pancreatic stellate cells (PSCs), indicating a progression to nonalcoholic steatopancreatitis in
the HF group. Regarding endocrine pancreas, innumerous insulin granules were identified in
the untreated HF animals, besides a larger number of mitochondria. However, RER was less
developed than in the SC or treated group [86]. Pancreatic ultrastructure is illustrated in figure
5.
Figure 5. Exocrine pancreas ultrastructure. (a) Normal sized mitochondria (arrow), well developed
rough endoplasmic reticulum (open arrow) and numerous secretion granules in lean mice. (b)
Hypertrophied mitochondria (arrow), less secretion granules, hypertrophied rough endoplasmic
reticulum (open arrow) and some lipid droplets characterizing pancreatic steatosis (asterisk) in exocrine
pancreas from obese mice. Transmission electron microscopy.
THE GLUCOSE HOMEOSTASIS AND THE PANCREAS

After the discovery of insulin, in 1920, understanding of DM as a metabolic disease
evolved considerably [87, 88]. By definition, DM is characterized whenever fasting blood
glucose exceeds 7 mM/L. Insulin targets at maintaining blood glucose levels between 3.8 and
6.1 mM/L during fasting state in healthy individuals, being considered normal rise to about
10 mM at postprandial phase and decline to 3.3 mM during prolonged fast [89].
It is known that blood glucose concentrations are determined by the balance or unbalance
between velocity of glucose influx into and removal from bloodstream. Circulating glucose is
stemmed from intestinal absorption, glycogenolysis or neoglucogenesis [88].
Insulin Signaling
Blood glucose concentrations drive the insulin biosynthesis and secretion, activating
complex glucose sensing and control machinery. Even though ketones, some amino acids,
gastrointestinal peptides and neurotransmitter are also able to triggers insulin secretion, blood
glucose level is the key regulator of insulin secretion by pancreatic beta cell [90, 91]. Glucose
levels above 3.9 mmol/L (70 mg/dL) stimulate protein translation and processing, enhancing
insulin synthesis and release. The first event is the transportation of glucose into the cell
through a facilitative glucose transporter (GLUT). It is followed by glucose phosphorylation
by glucokinase, which is a rate limiting step when it comes to insulin secretion regulated by
glucose [92].
Moreover, ATP is generated by the metabolism of glucose-6-phosphate via glycolysis,
which leads to the inhibition of the ATP sensitive K+ channel. This channel consists of two
different domains, one binds to certain kinds of oral hypoglycemic such as sulfonylureas,
whereas the other is an inwardly rectifying K+ channel protein. The inhibition of these
channels leads to beta cell membrane depolarization, opening voltage-dependent calcium
channels, whose calcium influx stimulates insulin secretion by pancreatic beta cell [93, 94].
Insulin unravels a pulsatile pattern of hormone release, with small bursts of releasing every 10
minutes and oscillations of about 80-150 min. Beta cells are best known for producing insulin
in response to changes in plasma levels of major nutrients, particularly glucose, amino acids,
and fatty acids. Insulin secretion is also increased by a number of gut hormones such as
insulin, glucagon like peptide-1 (GLP-1), gastric inhibitory peptide (or called glucose-
dependent insulinotropic peptide, GIP), secretin and CCK, as well as by vagal and β-
adrenergic stimulation. On the other hand, beta cell secretion is decreased by fasting, exercise
and somatostatin as well as by enhanced α-adrenergic activity. Beta cells take up and
metabolize glucose, galactose and mannose, and each can provoke insulin secretion by the
islet [92, 95].
Apart from neurohormonal stimulli, endocrine pancreas is also influenced by exocrine
pancreas and this interaction is called insulo-acinar axis. In this regard, the regulation of
pancreatic exocrine secretion depends on the peptide hormone insulin released by the
pancreatic islet beta cells. It is known that infusion of glucose into perfused rat pancreas has
been shown to induce release of endogenous insulin, and thereby enhance pancreatic exocrine
secretion in response to the peptide hormone CCK [45]. A significant increase in pancreatic
secretion was also observed in the presence of exogenous insulin. Pancreatic secretion is
stimulated by vagal cholinergic activation, which is evoked by hypoglycemia. Exogenous
insulin has also been reported to inhibit pancreatic exocrine bicarbonate secretion stimulated
by secretin in dogs [96, 97].
At about 50% of insulin secreted into portal venous system is removed and degraded by
the liver. The remaining enters systemic circulation by targeting to specific sites with receptor
to this hormone. When binding to its receptor, insulin triggers intrinsic tyrosine kinase
activity, resulting in receptor autophosphorylation, which recruits intracellular signaling
molecules named insulin receptor substrate (IRS)[98, 99].
Insulin is a hypoglycemiant hormone. It controls postprandial glucose levels, signaling
for enhanced uptake of glucose by insulin sensitive tissues. Other effects include stimulation
of glycogenesis, keeping stored glucose for fasting periods; inhibition of glucagon synthesis
by pancreatic alpha cells, resulting in interruption of hepatic production of glucose through
glycogenolysis and neoglucogenesis [100, 101].
During the first hours of fasting, glycogenolysis is the main mechanism to maintain
glucose available as energy source. The presence of glucagon and the reduction of
insulinemia are crucial factors to increase blood glucose concentrations. After long periods of
fasting, neoglucogenesis is responsible for maintaining adequate glycemia. This event occurs
mainly in liver and has got rise in glucagon levels and fall in insulin levels as stimuli. Thus,
insulin and glucagon are antagonic and potents regulators of glucose metabolism [91, 102].
Under normal physiological conditions, insulin stimulates the translocation of glucose
transporter (GLUT) from an intercellular storage to cell membrane. Translocation of GLUT is
a complex process that involves the release of GLUT from its storage, intracellular transit,
recognition and fusion with cell membrane. Consequently, there are many steps that can be
compromised in insulin resistant states [47, 90].
Figure 6. Schematic insulin signaling in hepatocytes. At postprandial state, insulin binds to its receptor,
leading to phosphorylation of its internal subunit. A phosphorylated tyrosine residue activates IRS-1,
leading to Akt phosphorylation. Akt mediates GLUT-2 translocation to membrane and glucose
internalization to aerobic metabolism and GSK-3 phosphorylation to produce glycogen. In fasting state,
Akt leads to FOXO-1 phosphorylation, triggering gluconeogenesis. Abbreviations: IR (insulin
receptor), GLUT2 (glucose transporter 2), IRS1 (insulin receptor substrate 1), phosphoenolpyruvate
carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), Phosphoinositide 3-kinase (PI3K), Protein
kinase B (Akt), Forkhead box protein O1 (FOXO1), p (phosphate), pThr (phosphorylated tyrosine
residue).
Insulin plays its role in target organs by phosphorylation of a transmembrane insulin

receptor (IR). Binding of insulin to alpha subunit (extracellular) of IR activates tyrosine
residues present at beta subunit (transmembrane), leading to receptor autophosphorilation.
This event activates intrinsic tyrosine kinase, which catalyses phosphorylation of the IRS
(insulin receptor substrate) present in the tissue. IRS 1 and IRS 2 are broadly expressed in
mammalian tissues, being IRS 4 largely restricted to hypothalamus. IRS proteins are adapters
molecules that link the IR to common downstream signaling cascade. IRS 1 usually interacts
with 1A phosphatidylinositol 3-kinase (PI3K), which stimulates the recruitment of the main
effector of the cascade: protein kinase B (Akt). The later is a serine/treonine kinase that
promotes glucose uptake through GLUT translocation and distribution to cell membrane [90,
103, 104]. Different tissues express diverse subtypes of GLUT, being GLUT 4 related to
adipose tissue and skeletal muscle and GLUT 2 related to pancreas and liver [105]. These
events are depicted at figure 6.
Glucose Homeostasis and Incretins
Glucose homeostasis is determined by a balance between hepatic glucose production,

uptake and utilization of glucose by the peripheral tissues. Insulin is the most important
regulator of this metabolic equilibrium. However, other hormones, such as glucagon and
incretins, neural inputs and metabolic signals are also important and results in a complex
integrated control of glucose supply and utilization [95, 106]. In fasting state, insulin levels
are low, which stimulate glucose production through gluconeogenesis, via forkhead
transcription factor FOXO1, and glycogenolysis by the liver, while reduce glucose uptake by
skeletal muscle and adipose tissue. As a result, a mobilization of alternative fuels such as
amino acids and FFA through lipolysis occurs [107]. Conversely, glucagon is secreted by
alpha cells whenever blood glucose or insulin levels are low. This catabolic hormone is
crucial to stimulate glycogenolysis and gluconeogenesis by the liver and renal medulla. At
postprandial state, the glucose load elicts a rise in insulin and fall in glucagon, reversing the
processes. Insulin, an anabolic hormone, promotes the storage of carbohydrate, fat and protein
synthesis when glucose is available. The majority of postprandial glucose is utilized by
skeletal muscle by and insulin-stimulated glucose uptake. On the other hand, the brain uses
glucose in an insulin-independent fashion [108]. Table 3 summarizes main events during
fasting and postprandial states.
Incretins (GLP-1 and GIP) are intestine derived peptides, intimately related with
increasing insulin sensitivity after nutrient intake. Oral stimulation is indispensable to their
synthesis [109, 110]. Incretins act together with insulin and glucagon to regulate postprandial
glucose homeostasis and turned DM into a multihormonal disease [111]. Endocrine cells
along small and large intestine contribute to energy homeostasis by the secretion of hormones
targeting at satiety, intestinal motility and pancreatic islets function [112]. Enteroinsular axis
can be defined as a link between intestinal tract and endocrine pancreas, characterized after
repeated observations that administration of oral glucose provokes in bigger stimulus for
insulin secretion than endovenous administration [95]. This difference between oral
stimulated insulin secretion and a similar intravenous stimulus is called incretin effect [110].
Nowadays, only two incretins are widely known and are responsible for 50% of postprandial
insulin secretion, whose 70% is accounted for GLP-1 [109, 113].
Table 3. Metabolic events during fast and postprandial phases
Period Glucagon Insulin Stimulation Inhibition

Gluconeogenesis and
Fasting state High Low Glycogenesis and lipogenesis
ketosis
Glucose utilization as
Postprandial energy fuel, Gluconeogenesis,
Low High
state glycogenesis and glycogenolysis and lipolysis
lipogenesis
GLP-1 levels are low at fasting state and the intake of meal rich in carbohydrates and
lipids triggers its secretion by L cells from ileum and colon [114]. When GLP-1 levels are
high, there is suppression of glucagon levels and reduction of gastric emptiness at
postprandial period. It is worth mentioning that reduction of glucagon levels as a direct effect
of elevated GLP-1 in the postprandial state does not compromise the action of glucagon in
maintaining glycemia at fasting periods. Furthermore, reduced gastric emptiness has direct
relationship with reduction of postprandial glycemia. [115]. GLP-1 was proved to preserve or
even enhance beta cell mass by inducing islets neogenesis or inhibiting apoptosis when used
as a therapy for DM2 [116]. The stimulus of insulin secretion by GLP-1 occurs in a glucose
dependent fashion. GLP-1 has got a specific receptor in pancreas, which is related to glucose
uptake and metabolization. These mechanisms avoid hypoglycemia [109, 117].
GIP is secreted by luminal stimulus from K cells at the first parts of small intestine [114].
Intake of high-fat diets elevates GIP secretion, increasing intestinal absorption of glucose and
insulin release, both of which promote accumulation of fatty acids within adipocytes,
resulting in obesity. [111]. GIP acts likewise GLP-1 by increasing the transcription of the
gene implicated into insulin biosynthesis as well as the expression of components of sensing
glucose in pancreatic beta cell levels [109, 110]. Resistance to GIP and elevation in its level
are alterations of DM2.
Other hormones also exert influence upon insulin and exocrine pancreatic secretion. In
this regard, many works have shown that endogenous somatostatin secreted by the pancreatic
delta cells inhibits secretin and CCK release thus pancreatic exocrine secretion [46]. Since
somatostatin is present in both the intestinal mucosa and the pancreas, it is hypothesized that
mucosal somatostatin may play a role in the regulation of gut hormones, which influence
insulin release. Meanwhile, pancreatic somatostatin regulates pancreatic exocrine secretion
directly, in the form of paracrine messengers. Somatostatin and PP also have suppressive
roles in the insulo-acinar axis [45, 46, 63]. In contrast, the effect of glucagon on the exocrine
secretion remains rather controversial. Intravenous injection of glucagon transiently can
activate then suppress secretin and CCK-stimulated somatostatin, followed by an increase in
circulating somatostatin in dogs, suggesting that glucagon-mediated regulation of exocrine
secretion may occur indirectly [118].
Insulin Resistance and Metabolic Outcomes
Radioimmunoassay technique allowed the verification that in some cases patients with
DM presented elevated levels of insulin, instead of absence of this hormone in bloodstream,
which brought the concept of insulin resistance [87, 88]. Insulin resistance combines genetic
background with environmental factors, being a multifactorial finding. By definition, it
represents a state with reduced response to normal levels of insulin and therefore supranormal
levels of circulating insulin are required to maintain normal plasma glucose levels [119].
Insulin is the greatest anabolic hormone, whose action is crucial to development and growth
of tissues and glucose homeostasis [120]. Insulin normally regulates the glucose homeostasis
in different tissues, reducing hepatic production of glucose, stimulating glucose uptake by
peripheral tissues and suppressing lipolysis [48, 121].
Under insulin resistant state, insulin dose-response curve exhibit a rightward shift,
indicating reduced sensitivity and overall decrease in maximum glucose utilization. Insulin
resistance impairs glucose utilization by peripheral tissues and increases hepatic glucose
output, resulting in hyperglycemia in the long term. Reduced utilization of glucose by
peripheral tissues leads to postprandial hyperglycemia, while increased production of glucose
by the liver results in fasting hyperglycemia [122].
Insulin resistance is crucial to the understanding of DM2, but recent studies showed that
other hormones also play important roles upon glucoregulation, contributing to glucose
homeostase. Among those hormones, it should be highlighted glucagon, which is the most
important stimulator of hepatic glucose production and that is why DM was considered
initially as a bihormonal disease [100]. More recently, the concept that DM was a bihormonal
disease is not up to date [123]. Other hormones, such as incretines are equally important and
have been exhaustively studied, allowing DM to be characterized as a multihormonal disease.
Insulin resistance seems to be an early lesion, being detected even ten years before DM2
onset [124]. Islets hypertrophy and insulin hypersecretion usually appear as an attempt to
compensate the resistance to insulin and to promote normal values of plasma glucose.
Nevertheless, excessive functioning leads to progressive deterioration of islets, being 50% of
pancreatic islets compromised at the moment when DM2 is diagnosed and when oral glucose
intolerance is present [125, 126]. Islet hypertrophy is depicted in figure 7.
Figure 7. Pancreatic tissue. (a) Normal sized islet from a lean mice. (b) Hypertrophied islet from mice
fed onto high fat diet chronically. Hematoxylin-eosin, same magnification.
Insulin resistant state is characterized by a combination of factors that include resistance

to insulin in liver, muscle and adipose tissue, progressive decline in mass and function of
pancreatic beta cells and defect in the suppression of glucagon levels, causing increased
hepatic glucose production [101, 127].
Insulin secretion and sensitivity are interrelated. In DM2, insulin secretion initially
increases in response to decreased sensitivity. The response of insulin to other secretagogues,
such as arginine, is preserved. Abnormalities in proinsulin processing are reflected by
increased secretion of proinsulin in DM2. Eventually, insulin secretory defect progresses to a
state of inadequate insulin secretion [108, 128]. The reason for the decline in insulin secretory
capacity in DM2 is unclear. Some events such as the amyloid fibrillar deposit found in the
islets of individuals with long standing DM2 might be involved into this decline [129, 130].
Metabolic environment also impacts negatively islet function. Chronic hyperglycemia impairs
islet function (glucotoxicity), as well as elevated free fatty acids levels (lipotoxicity). Thus,
dietary fat may worsen islet function [82].
In this context, the increased deposits of adipose tissue in obese individuals concomitant
with high rates of lipolysis results in excessive influx of circulating FFA to the liver, pancreas
and skeletal muscle. Concomitantly, at insulin resistant state, the fat oxidation is impaired
within these tissues, resulting in abnormal deposits of fat [131]. This ectopic accumulation of
lipids is involved in the pathogenesis of insulin resistance and in the impairment of pancreatic
beta cell function, effect known as lipotocixity [132].
Fatty acids competes with glucose as substrate to oxidation in cardiac muscle and smooth
muscle of rodents, which led to the notion that fatty acid oxidation is responsible for insulin
resistance in cases of overweight [133]. However, recently, it was unraveled that elevated
levels of circulating FFA reduce intramuscular levels of glucose-6-phosphate. This
observation suggests that the rise in plasma FFA levels provoke insulin resistance by
inhibition of glucose internalization by the cell or hexokinase II activity, yielding reduced
synthesis of muscular glycogen and glucose oxidation secondary events. Taking into account
that intracellular glucose is an intermediate metabolite between glucose transportation and
hexokinase II action, the reduction in intracellular glucose indicates a defect into glucose
transportation, while the accumulation of this metabolite suggests a defect in hexokinase II
[134, 135]. Studies in vivo reveal that humans with insulin resistance due to lipotocixity
present reduction of intracellular glucose concentrations in the presence of elevated levels of
FFA in bloodstream, confirming a defect in glucose transportation [136, 137].
When it comes to insulin resistance, defects of IR could be related with inadequate
binding with insulin or reduction of available number of receptors. However, more often
defects at post-receptor insulin signaling are described [47, 103]. In this context, inadequate
phosphorylation of IR after insulin binding to its extracellular subunit was found in skeletal
muscle form non-obese individuals with DM2 [138], in adipose tissue of obese with or
without DM2 [139] and in the liver from obese patients with the diagnose of DM2 [140]. All
these observations serve to highlight that defect in phosporilation of IR and IRS-1 and
impairment of PI3K activation are utterly important to insulin resistance development [90,
103].
Other defects in insulin signaling accounted for obesity include reduced concentrations of
GLUT4 in adipocytes [141]. Nonetheless, GLUT4 levels in skeletal muscle remain within the
normal range, being observed AM abnormal distribution of this glucose transporter [142].
Reduced glucose uptake might also result from the increase in proteins that inhibit insulin
signaling cascade. Protein tyrosine phosphatase (PTPases) acts as negative regulators of
insulin signaling cascade. Recent studies state that the main function of PTPase 1B (PTP 1B)
is to suppress insulin action. Obese individuals have increase in expression of PTP 1B in
adipose tissue and skeletal muscle. Indivíduos obesos apresentam aumento da expressão de
PTP 1B no tecido adiposo e musculatura esquelética. However, weight loss of 10% of total
body mass results in increase of insulin sensitivity proportionally to reduced levels and action
of PTP 1B [143, 144].
As far as pancreas is concerned, in DM2, beta cell function is altered at the postprandial
phase. There is loss of rapid response to postprandial insulin secretion, leading to
compensatory hypersecretion and hypertrophy of pancreatic islets [104, 145]. Moreover,
defect in GLUT translocation to cell membrane avoid the suitable utilization of glucose by the
tissues and excessive circulating glucose causes hyperglycemia [88, 146].
Among all physiological effects of incretins, glucagon suppression appears as the most
significant. Patients with DM2 present hyperglucagonemia concomitant with low levels of
GLP-1, even when glycemia is present [101, 147]. However, before DM2 onset, at insulin
resistance, incretin therapy may be fruitful to avoid pancreas failure and to enhance pancreatic
beta cell mass [148].
Functional interactions have been found between the exocrine and endocrine pancreas.
For example, many diabetic patients experience changes in pancreatic exocrine function.
However, the impaired exocrine function in these patients may not be directly linked to
insulin deficiency since abnormal pancreatic exocrine functions have also been observed in
some patients with DM2 [46, 51]. Insulin deficiency in diabetic patients may be due to the
inadequate actions of insulin on the potentiation of secretin and CCK stimulated secretion,
induction of amylase gene transcription, and down-regulation of its own receptors [51, 64].
However, hyperinsulinemia alone did not inhibit bicarbonate secretion. In contrast,
hyperinsulinemia with normoglycemia reduces the bicarbonate secretion, demonstrating that
the inhibitory effect of hyperglycemia on pancreatic secretion may be independent of insulin
[97]. More recently, it has been reported that elevated plasma levels of PP are associated with
increased intra-abdominal fat accumulation and thus insulin resistance in humans [149].
FETAL PROGRAMMING OF PANCREAS ALTERATIONS

From the moment of conception, an organism’s future is all orchestrated by the quantity
and quality of nutrition obtained through the maternal-fetal interface, that is, the placenta. The
relative distribution of nutrients among the mother, placenta and fetus is partly responsible for
the regulation and the phenotypic expression of fetal growth. Variation in the quality or
quantity of nutrients consumed during pregnancy can exert permanent and powerful effects
upon the developing fetus [150]. Programming alters offspring physiology and metabolism
with both immediate and lasting consequences. Maternal nutrition in gestation and lactation
shapes offspring development and health [151].
Epidemiological studies have investigated the importance of adequate nutrition during
fetal development in humans [152, 153] and in animals [154] as one of the critical factors
contributing to the etiology of disease in adult life, probably imputable to the potential of the
organism to modulate “biological switches” when encountering an altered nutritional
environment during the early stages of life. Once these biological switches are imprinted, the
physiology of the organism is permanently modified, abnormally responding to various
stimuli later in life. Consistent evidence in the literature indicates that fetal programming
leads to major changes in the endocrine pancreas that in exocrine, in the example of the
maternal undernutrition during gestation leads to hyperinsulinemia and insulin resistance,
often associated with obesity in adult offspring [155].
Pancreatic neoplasms, both benign and malignant, are uncommon during pregnancy.
Their occurrence during pregnancy leads to dilemmas in diagnosis, management, and timing
of surgical treatment. In all cases, the goal is to minimize both maternal and fetal risk. In
addition, given the poor overall survival for patients with pancreatic adenocarcinoma,
consideration and discussion of termination of the pregnancy are also important depending on
the stage at diagnosis, gestational age at diagnosis, and maternal wishes/beliefs. There can be
significant maternal consequences if definitive surgery or other therapy is delayed for fetal
maturation, this includes intrauterine growth restriction, compression of surrounding
structures, pancreatitis, and tumor rupture [156].
To investigate the effects of malnutrition on fetal development, researchers have utilized
historical clinical and epidemiological data obtained during times of war or famine. A rare
opportunity to study the relevance of these historical findings was presented in individuals
who were prenatally exposed to famine during the Dutch Hunger Winter (World War II in the
winter of 1944–45) [153]. This period of maternal undernutrition resulted in offspring with
low birth weights and impaired glucose tolerance who were more likely to develop DM2 and
obesity at the age of 50 years [157]. These data provide empirical support for the hypothesis
that early life environmental conditions can cause epigenetic changes in humans that persist
throughout their life [158].
The embryonic and early postnatal periods entail various developmental processes that
permanently affect organ development, structure and metabolism, as well as cellular
differentiation and organogenesis [159]. The “thrifty phenotype hypothesis” proposes that
there is an adaptive response to optimize the growth of vital organs due to peripheral organs;
thus, the weights of the liver, kidneys and pancreas are reduced, but the brain is spared [160].
Experimental induction of intrauterine growth restriction in the rat and mouse usually reduces
fetal growth and leads to low birth weight in rodents [43]. Despite the similar endpoint, the
cellular and physiologic mechanisms that contribute to alterations in beta cell mass differ
depending on the nature of the nutritional insult [161].
Furthermore, such adaptations during critical windows of development may permanently
program the beta cell mass and fetal metabolism to enhance the fetus's chances of survival.
These findings have been expanded on by the “Predictive Adaptive Response” hypothesis,
which proposes that the fetus dynamically interacts with and detects the environment into
which it will be born, thus adapting to gain a competitive advantage after birth [162].
However, this advantage becomes detrimental to the programmed individual/offspring when
it meets with nutritional abundance in later life [163]. Similarly, recovery with a normal diet
after birth restores adult body weight (catch-up growth) but does not improve insulin
insufficiency [164].
Evidence from Animal Models
Animal models of malnutrition have been established during different periods of

development such as caloric restriction [165], excessive fetal glucocorticoid exposure [166],
protein restriction [167], uterine artery ligation [168], gestational diabetes [169] and high-fat
diets [155]. The restricted protein model of growth restriction is the best characterized and the
most widely studied of all of the animal models of nutrition [170]. These studies have shown
that a reduction in the availability of nutrients during fetal development programs the
endocrine pancreas and insulin tissues.
In pregnant rats fed a diet of semistarvation throughout pregnancy, intrauterine growth
retardation develops. The offspring show a decreased beta cell mass at birth, glucose
intolerance associated with insulinopenia becomes manifest [165]. Taken together, there is a
correlation between the duration of caloric restriction and the reduction in beta cell mass.
During embryonic development fewer Ngn3 and Pdx1 positive cells are present in the
pancreas of calorically restricted fetuses in comparison to controls, indicating that low energy
diet decreases the beta cell precursor pool [171]. Represents a significant stress to the
pregnant dams and leads to endogenous increase in glucocorticoid secretion, high
glucocorticoid levels can downregulate the number of beta cells [171].
In humans, glucocorticoids are administered during late gestation to treat neonatal

respiratory morbidity and maternal asthma. Since glucocorticoids are known to regulate the
beta cell mass during development, pharmacological exposure to glucocorticoids or inhibition
of the placental 11-beta-hydroxysteroid dehydrogenase type 2, the enzyme protecting the
fetus from maternal glucocorticoids can lead to intrauterine growth retardation [172]. In the
fetus, the insulin content of the beta cells is already reduced; a proposed mechanism involves
downregulation of the transcription factor Pdx1, Nkx6.1 and Pax6. Additionally,
dexamethasone has a pro-apoptotic effect on beta cells, which could further explain its
negative effect [166, 173].
When the restricted diet model is employed from the time of conception in the rat,
neogenesis seems not to be affected, beta cell proliferation is lower and apoptosis is
increased, which may be associated with lower expression in the islets of the pancreas of IGF-
II [174]. Therefore, the mass and number of beta cells are reduced [171]. The reduction is
more pronounced if a fetal low protein diet is applied during the last week of pregnancy,
especially during this period that is characterized by the highest beta cell proliferating activity
in the fetus [171, 175], during which it begins to regulate its own glucose homeostasis [176].
On the other hand, the alpha cell and the delta cell mass remains unchanged in restricted
animals compared to controls [174]. Under investigated circumstances, protein restriction has
been found to reduce beta cell area and cause islets to be irregularly shaped in weanlings [34],
with improper cell distribution within the islet, which is a finding typically observed in
diabetic animal models [177].
A model of restricted blood flow to the fetus has been developed that consists of the
ligation of uterine arteries in rats at embryonic days 18–19, mimicking utero-placental
deficiency and women who smoke during pregnancy. Intrauterine growth restriction induced
by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory
defects followed by the development of insulin resistance, decline in beta cell mass, reduced
islets vascularity, glucose intolerance, impaired first phase insulin secretion, hyperinsulinism
and diabetes in adulthood [178]. Since beta cell mass and function are normal at birth, it has
been hypothesized that gene expression may be altered at birth and may then remain altered
during postnatal development [179].
Changes in eating habits and/or increasingly sedentary lifestyles more recently adopted
form of developmental programming reflects society in both affluent and developing
countries [180]. High fat programming is induced by maternal high saturated fat intake during
defined periods of gestation and/or lactation and programs the physiology and metabolism of
the offspring in early life. Hyperglycemia and compromised beta cell development were
demonstrated in neonatal rats programmed with a gestational high-fat diet [181]. Gestational
high-fat programming impairs insulin release and reduces Pdx1 and glucokinase
immunoreactivity, with adverse changes in beta cell development and function in neonatal
and weanling offspring. High fat programming is likely to result in beta cell failure and
eventual DM2 [182].
Gestational diabetes can occur due to a pre-existing diabetic state or the development of
glucose intolerance during pregnancy, which is caused by increased placental transport of
glucose, insulin and other nutrients from the mother to the fetus [176]. Gestational diabetes
causes severe maternal hyperglycemia resulting in hyper-stimulation of fetal islets followed
by beta cell degranulation, disorganization, and finally secretory failure [183]. Depending on
the severity of gestational diabetes, babies may either be macrosomic or growth restricted
[184]. The combination of a latent diabetogenic tendency and the metabolic stress of
pregnancy may result in gestational diabetes, by this mechanism can be passed from one
generation to another [161].
The most frequently cited examples in this respect are those of the Pima Indian women of
Arizona, which is a population with a remarkably high incidence of DM2 that is attributed, at
least in part, to strong genetic inheritance [185]. A comparison of children born to diabetic,
pre-diabetic and non-diabetic Pima women showed that there was up to a six-fold higher
prevalence of DM2 in individuals born to diabetic compared to non-diabetic women [186].
The figure 8 summarizes the animal models of programming.
Figure 8. The fetal programming hypothesis: flow diagram illustrating proposed effects of intrauterine
malnutrition on the fetus and long-term effects on metabolism and diabetes mellitus type 2 (DM2),
these effects can be passed to the subsequent offspring via transgenerationality.
Mechanisms of Programming
It is remarkable that different insults in fetal life produce the same detrimental
consequences in adulthood, suggesting that a mechanism promoting this common offspring
phenotype may underlie the early life programming of the adult diseases [187]. The molecular
mechanisms responsible for intrauterine programming of beta cells are still elusive, but two
hypotheses have recently emerged involving the programming of mitochondria and epigenetic
regulation [7].
Epigenetics involves molecular mechanisms that promote mitotically or meiotically

heritable alterations in gene expression potential but that do not alter the genomic DNA
sequence [188]. Although the exact mechanism that underlies these phenomena is poorly
understood, DNA methylation [189], various modifications of histone proteins [190] and the
control of RNA expression by non-coding RNAs [191] remain key potential candidates, and
these three mechanisms also interact with one another.
The genetic and/or epigenetic alterations in putative pancreatic adult stem/progenitor
cells and/or their early progenies may, however, contribute to their acquisition of a
dysfunctional behavior as well as their malignant transformation into pancreatic cancer
stem/progenitor cells. More particularly, the activation of distinct tumorigenic signaling
cascades (Notch, Hedgehog, Wtn pathways and other diverse signaling elements) may play a
major role in the sustained growth, survival, metastasis and/or drug resistance of pancreatic
cancer stem/progenitor cells and their further differentiated progenies [192].
It has been proposed that programming of mitochondrial function may be a key
adaptation that enables a fetus to survive in a limited-energy environment, because the
mitochondria play a vitally role in the modulation of metabolic intensity. The concept of
mitochondrial programming may apply especially to cells that have a high energy
requirement, such as beta cells [161]. The activity of antioxidant enzymes in pancreatic islets
is particularly low in comparison with other tissues and this was associated with a depressed
antioxidant defense system and increased oxidative stress [39]. Beta cell mitochondria are the
regulators of glucose-stimulated insulin secretion, and it has been proposed that an early
malnutritional environment may reprogram mitochondrial function. These alterations can be
transmitted from one generation to another and specifically occur in the endocrine pancreas
through a reduction or increase in litter size and the downregulation of the expression of
insulin mRNA, which leads to a reduction in the glucose responsiveness of pancreatic insulin
secretion [7]. Epidemiological studies have shown that low mitochondrial function is
observed in patients with DM2 [193].
This condition combined with malnutrition during fetal life and age-associated leading to
progressive beta cell loss and dysfunction [194], with increased oxidative stress, impaired
antioxidant defense capacity, increased markers of islet fibrosis, and elevated lipid
peroxidation, all of which are observed in DM2, [195]. More interestingly, the insulin
resistance trait is transmitted to a well-nourished second and third generations (F2 and F3
generations) of rodents [196, 197] (Fig. 8). Transgenerational effects can be defined as the
capacity of an acquired physiological phenotype or disease to be transmitted to subsequent
generations [198].
This fetal programming of impaired glucose tolerance, DM2, gestational diabetes and/or
metabolic syndrome might considerably contribute to the burden of diabetes, as seen in the
last decades, all over the world and major significance for public health in the immediate and
the far future. So much so that nutritionists, clinicians, and researchers agree that optimal
nutrition during early growth is vital to health outcome. While recent animal studies [199]
suggest that maternal dietary supplementation with methyl donors and cofactors in late
pregnancy can ameliorate the metabolic effects of growth restriction, we are still a long way
from any kind of human intervention.
FUTURE RESEARCH
Diseases that affect the pancreas, most notably both type 1 (DM1) and type 2 diabetes are
major and growing world-wide health problems, largely due to complications. The cost of
these complications in personal and financial terms is enormous, despite impressive
improvements in treatment, including self-monitoring of glucose, advances in insulin therapy,
new ways to detect tumors, chemotherapy and radiotherapy, immunotherapy, new
medications and higher standards of care, too many people continue to develop disabling
complications. Progress on each of these fronts, together with small but encouraging
improvements from the past, offers hope for the future of pancreatic disease patients.
Studies of experimental human models are not only prohibited but are also difficult
because they are restricted to autopsies or samples from pancreas donors. The use of animal
models is very useful in the development of novel therapeutic strategies and therefore the
creation of experimental models is of major emphasis on our current research. Various animal
models are commonly used in order to induce pathologic condition and available to represent
the clinically relevant conditions: DM1 (bio-breeding rat, chemically-induced models -
streptozotocin, alloxan), DM2 (knockout mice and transgenic models, Zucker diabetic fatty
rat, diets and fetal programming of pancreas alterations), pancreatitis (surgical - duct
obstruction induced model- and non-surgical methods, drug induction, choline-deficient
ethionine diet-induced, administration of cerulein and arginine) and pancreatic cancer
(subcutaneous injection of a pancreatic cancer cell suspension and, more commonly, the
surgical orthotopic implantation of pancreatic tumor fragments and chemically induce-
specific carcinogen, 7,12-dimethylbenz(a)anthracene - DMBA) [200].
Basic Techniques for Pancreatic Research
Several typical parameters should be examined and recorded in in vivo functional studies
of the pancreas; they include animal survival, body mass, food intake and water consumption.
Blood samples are usually collected to determine glucose or insulin levels. The oral glucose
tolerance test (OGTT) or intraperitoneal glucose tolerance test (IGTT) are also common
methods used to assess the animals’ abilities to reverse hyperglycemia. In these assays,
glucose solution is either gavaged or injected, and blood glucose levels are then monitored
within 120 min. The animals’ insulin sensitivity can be assessed by an insulin tolerance test
wherein insulin is administered intraperitoneally and subsequent changes in blood glucose
levels are monitored, the shape of glucose curve can be utilized to assess future risk for DM2
[201].
The gold standard for investigating and quantifying insulin resistance is the
hyperinsulinemic euglycemic clamp [202]. In this method, insulin is continuously perfused
into the animal and the amount of glucose required to compensate for the increased insulin
levels without causing hypoglycemia is carefully examined and recorded. The test is rarely
performed in clinical care, but is used in medical and animal research as capacity of insulin-
responsive tissues (i.e. muscle, adipose and liver) to extract glucose from circulation at a
given insulin concentration [34].
Other data obtained from blood samples is insulin resistance. This can be evaluated by
the Homeostatic Model Assessment index {HOMA-IR = [insulin (KU/mL) x glucose
(mmol/L)]/22.5} [203]. Also you can get data from pancreatic beta cell function through
HOMA-B, this can be obtained using the following formula: HOMA-B=20×fasting plasma
insulin (in μ-units/mL)/fasting plasma glucose (in mmol/L)−3.5 [203]. The accuracy and
precision of the estimate have been determined by comparison with independent measures of
insulin resistance and beta cell function using hyperglycemic and euglycemic clamps and an
intravenous glucose tolerance test [204].
Measure of whole body insulin sensitivity can be conveniently expressed as an insulin
sensitivity index (Ki) can be evaluated as the slope of the fall in glucose over 15 min: Ki =
([glucose]t=0 - [glucose]t=15)/15 min [205]. Since Ki reflects the rate of glucose removal, larger
values indicate greater tissue insulin sensitivity. Besides the HOMA, a more recent method is
the quantitative insulin sensitivity check index (QUICKI), is the logarithm of the value from
one of the HOMA equations {1 / (log(fasting insulin µU/mL) + log(fasting glucose mg/dL)},
which estimates insulin resistance by fasting insulin and glucose concentrations [206].
The physiological response of an islet to glucose-stimulated insulin secretion is often
studied as a functional correlate of in vivo physiology, beside capacity of beta cells to release
insulin in response to a secretagogues (i.e., like amino acids - arginine, glyceraldehydes, and
K+ ions, drugs) are also commonly used to test islet secretory capacity [207]. The ability to
recognize increasing concentrations of glucose as a graded stimulus for acute insulin release
is a unique and major characteristic of pancreatic beta cells. It has long been known that this
glucose responsiveness is normally established in the few days that follow birth, even though
beta cells are already equipped in the late prenatal period with most of their adult features [6].
Nevertheless, when circulating insulin levels are evaluated, together with prevailing
glucose concentrations, or when insulin secretion is assessed by more sophisticated
techniques, like deconvolution of plasma C-peptide curve by using kinetics parameters [208],
an impairment of beta cell function is detected. Moreover, other parameters of beta cell
function like the proinsulin to insulin ratio, the pulsatility of insulin secretion, and the
competence (or efficiency) of the beta cell are abnormal in DM2 [209]. In human
experiments, measurements of the acute serum insulin response to glucose and arginine
correlate well with estimates of beta cell mass [210].
In investigate laboratories commonly employed experimental techniques for pancreatic
research include, but are not limited to, molecular biology and functional studies. In terms of
molecular techniques, expression studies of a particular gene at the mRNA level are
indispensable. Polymerase chain reaction (PCR) is a typical strategy used to compare gene
expression levels in a semi-quantitative manner, which the DNA polymerase used to amplify
(replicate many times) a piece of DNA by in vitro enzymatic replication [211]. Quantitative
real-time PCR can be applied to measure accumulation of gene products of interest by
analysis of a fluorophore during the exponential stages of the PCR (Sybr Green and the
Taqman probe).
Adds, indispensable for pancreatic research was Western blotting employing antibodies
for particular proteins of interest is the most common method used to assess protein
expression levels [212]. Also the enzyme-linked immunosorbent assay (ELISA) methodology
should be used in which the amount of the target protein or peptide in the sample is
proportionally reflected by a colorimetric method [213], such as (pro)insulin or C-peptide,
bromodeoxyuridine and cell death. In basic research to understand the distribution and
localization of biomarkers and differentially expressed proteins specimens, either paraffin-

embedded or cryo-preserved, are fixed and labeled through incubation with specific
antibodies against the proteins of interest. Immunoreactivity is reflected in staining or
fluorescence intensity, thus allowing an assessment of protein expression levels with co-
localization of target proteins within a cell (immunocytochemistry) or tissue
(immunohistochemistry) can be achieved [214]. Co-application of two or more antibodies can
be used to demonstrate simultaneous expression of proteins with fluorescent labeling
protocols, which requires a fluorescent microscope for detection, mainly confocal imaging
system.
Exocrine Pancreas: Intervention Strategies
Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas.
Pancreatitis exhibits both acute and chronic manifestations. Assessments
of exocrine pancreatic function, such as fecal fat quantification and C-triglyceride breath test,
are the method of choice for diagnosis [21]. Surgical treatment options include drainage
operations on the pancreas, pancreatic resection or a combination of both. With optimal
surgical treatment performed and good patient's compliance, operations for chronic
pancreatitis have low number of post-operative complications and relatively good long-term
results [215].
Enzyme substitution therapy should ideally mimic the physiological pattern
of pancreatic exocrine secretion, and pancreatic enzymes in the form of enteric-coated
minimicrospheres are considered as the most elaborated commercially available enzyme
preparations. An improved knowledge of pancreatic stellate cells biology may be
therapeutically targeted to inhibit, thereby inhibiting the progression of
chronic pancreatitis and its complications [216]. The other parameter of successful treatment
of chronic pancreatitis is relieved from long-lasting pain and improvement of the quality of
life.
Chronic pancreatitis is a major risk factor for the development of pancreatic cancer,
which is the fourth leading cause of cancer death in humans [217]. The majority of pancreatic
malignant tumors are adenocarcinomas of the ductal type, whereas acinar cell carcinoma is
unusual. In addition to this, cigarette smoking, diabetes, obesity and dietary mutagen
exposure are the most consistent risk factors implicated in the development of pancreatic
cancer; however, the genetic and molecular changes underlying the epidemiological
association between these factors and pancreatic cancer remain largely unknown, and only 5-
10% are hereditary in nature. Despite of recent advances in understanding its molecular
biology, treatment options remain limited, the prognosis for pancreatic cancer has not
changed substantially for at least the last 20 years [218].
Currently, a multimodal-screening approach of endoscopic ultrasound, magnetic
resonance imaging and computed tomography are the most effective methods to detect
pancreatic cancer in high-risk patients. Future options for early detection of this malignancy
are focused on new molecular markers, cancer stem cells, tumor microenvironment,
telomerase enzyme, receptor-targeted imaging using multifunctional nanoparticles, detection
of glycan changes and epigenetics [217].
Although tumor surgical resection, radiotherapy and chemotherapy, alone or in

combination, may represent a potential curative treatment for the patients diagnosed with
localized pancreatic ductal adenocarcinoma (PDA) at an early stage, the rapid progression to
metastatic, recurrent and lethal disease states underlines the urgent need to develop new
therapeutic regimen options [219]. The combination of cytotoxic agents that are able to block
distinct tumorigenic cascades activated in pancreatic cancer stem/progenitor cells and their
further differentiated progenies during PDA initiation and progression represents a new
promising strategy for treating patients who have aggressive PDA [192]. More particularly,
these targeted therapies could be used in combination with current clinical chemotherapeutic
drug regimens such as gemcitabine and/or 5-flurouracil for overcoming drug resistance and
improving the efficacy of treatments for the patients with locally advanced and/or metastatic
PDA [220].
Therefore, targeting tumor stromal cells, including activated myofibroblasts, stellate cells
and bone marrow-derived endothelial progenitor cells that may promote PDA progression and
treatment resistance, may also represent a potential adjuvant strategy for treating the
aggressive and metastatic PDAs [221]. In support of this, the use of pharmacological agents,
including antibodies and specific or dual tyrosine kinase inhibitors targeting the vascular
endothelial factor receptor, alone or in combination therapies with other drugs such as
gemcitabine, has been reported to inhibit angiogenesis, tumor growth and/or the metastatic
spread of pancreatic cancer cells in animal models in vivo [192].
In addition, the molecular targeting of the pancreatic cancer stem/progenitor cells and/or
their early progenies endowed with a self-renewal potential and their local microenvironment
may also constitute a promising approach for improving the current clinical treatments against
aggressive and recurrent PDAs [222]. Further research is necessary to more precisely
establish the gene expression patterns of normal and malignant pancreatic stem/progenitor
cell progenies and putative beta cell precursors versus their differentiated progenies in order
to identify the specific biomarker patterns as well as the molecular mechanisms that may
regulate their biological behavior in vivo and/or after their ex vivo expansion [220]. The
identification of the specific intrinsic factors that govern the decision between the self-
renewal versus differentiation of normal and malignant pancreatic stem/progenitor cells as
well as the influence of the extracellular signals from their local microenvironment “niche”
on their behavior is notably of immense interest for the design of new therapeutic strategies
[222].
These future studies should lead to the identification of specific growth factors, cytokines
and/or chemokines and host cells that control the expansion and commitment of these
immature cells into the specific differentiated pancreatic cell lineages in physiological and
pathological conditions [223]. Hence, the establishment of the specific properties of normal
versus malignant pancreatic stem/progenitor cells is essential for the successful formulation
of stem cell based therapeutic approaches that could be translated into treatment and even a
cure for diabetes patients as well as the patients with locally advanced and metastatic PDAs,
which remain incurable with the current conventional therapies in the clinics [192].
Pancreatic Cell Isolation and Transplantation
In the context of pancreatic cancer research, such application becomes a useful technique
in studying the metastatic properties of the cells under different microenvironment. The
whole pancreas can also be isolated and cultured under suitable conditions, with enough
growth factors is required so that the pancreas will be developed to mimic the actual
developmental scenario in the embryos. And in some protocols, the pancreatic duct-derived
epithelial cells, pancreatic stem cell and islets are separated while allowing the studying
pancreas which serves as a good platform to reveal its developmental changes and
pathophysiological processes not yet understood [224].
The development of islet and acinar cell isolation methods, in particular the isolation of
islets, greatly facilitates functional studies. There have been numerous reports comparing the
isolation outcomes achieved using different protocol collagenases with various proteases,
different doses and time [225-227]. But, a typical digestion protocol calls for intra-ductal
administration of collagenase so as to achieve a more thorough infusion and digestion process
was described a long time ago [228] and continues today (Fig. 9). A continuous digestion
process disassembles the organ into fragments of decreasing sizes; the small islet fraction is
separated from the exocrine tissue using density gradient centrifugation. On the other hand,
the protocols for the pancreatic acinar cell isolation have been well described previously, the
process appears to be indifferent to which typical enzyme digestion procedure is used [229].
Transplantation of pancreatic tissue, as either the intact pancreas or isolated islets, is a
treatment option for some individuals with diabetes [230]. Whole pancreas transplantation
is a surgical procedure with considerable risk postoperative and immunossupression-related
complications. The transplantation of islets, in contrast, is minimally invasive and has
low morbidity, but currently it does not achieve the same level of tight glucose control or
durability as intact pancreas transplantation and has its own potential complications [231].
The majority of whole pancreas transplantation are simultaneous pancreas-kidney
transplantation, then was defined three types of pancreas transplants: pancreas and kidney
transplant at the same time (diabetes and kidney failure), pancreas transplant after a kidney
transplant (diabetes who have already had a kidney transplant) and pancreas transplant only
(diabetes who do not have kidney disease) [232]. The surgical technique more commonly is
side-to-side anastomosis of the donor duodenum and the recipient ileum [231]. Pancreas
transplantation has demonstrated to be efficacious in significantly improving the quality of
life of people with diabetes, eliminates the need for exogenous insulin, frequent daily blood
glucose measurements and many of the dietary restrictions [233].
However, pancreas transplants, as well as islet transplants, require lifelong
immunosuppression to prevent rejection of the graft and potential recurrence of the
autoimmune process that might again destroy beta cell [234]. In an analysis [233] of technical
failure rates remain high after pancreas transplants; while rates have decreased over the last
decade. 937 pancreas transplants were performed, of these, 123 (13.1%) grafts were lost due
to technical reasons (thrombosis, leaks, infections, pancreatitis and bleeding). There are many
varied explanations for these outcomes, including preservation times and the condition of the
donated pancreas or recipient obesity.
The recent success of the Edmonton protocol for islet transplantation has brought about a
new era for adequate control of euglycemic status [230, 235]. Then, islets are isolated from
donor pancreata using enzymatic digestion technique, as stated above (Fig. 9). Clinical islet
transplantation is normally performed through infusion of the isolated islets into the hepatic
portal vein via a percutaneous transhepatic ultrasound and angiography guided approach
[230]. Once in the portal vein, the blood flow and pressure carries the islets to the liver where
they encounter small diameter capillaries that cannot be traversed. In such a mechanical way
the islets stay in place, and new capillaries incorporate them in an anatomical form [235]. The
source of the islets for transplantation may be the patient’s own pancreas mainly when total
pancreatectomy is required due to different conditions (pancreatitis, cancer or severe
trauma). With increasing numbers of transplants, a number of advances has been reported
[236].
Figure 9. Schematic diagram illustrating the basic experimental procedures for islet isolation in mice.
(a) Intra-ductal injection of collagenase (Ga, is gallbladder); (b) distension and digestion of exocrine
pancreas; (c) incubated and centrifugation, showing the islets arranged along the ducts; (d) isolated
islets are hand-picked under microscope and destined to specific searches.
Current limitations include the fact that the transplanted islet grafts gradually lose their
secretory function and thus may ultimately succumb to failure due to inadequate
revascularization, hepatic steatosis, allograft host immune rejection and effects of the
immunosuppression [231]. The inner core of the islets, constituted predominantly by insulin-
secreting beta cells, is especially susceptible to insufficiency of oxygen and nutrients,
therefore, various strategies have been developed to maintain beta cell graft function and islet
survival in vivo, leading to improvement in islet transplantation [237]. Minimization of
rejection of grafted tissues is being addressed by studies of immuno-isolation of transplanted
islets by microencapsulation. Encapsulation of islets with biomaterials can provide a physical
barrier while allowing the passage of glucose, insulin, oxygen and nutrient, at the same time,
preventing the entry of large molecules like antibodies [238]. Until recently it is has been
difficult to show efficacy in large-animals models or humans, only in rodents, but work to
find better biomaterials and strategies continues.
The major benefit of islet transplantation has been improvement in glycemic score and
lability index, C-peptide secretion was maintained in the majority of subjects for up to 5
years, although most reverted to using some insulin. The results, though promising, still point
to the need for further progress in the availability of transplantable islets, improving islet
engraftment, preserving islet function, and reducing toxic immunosuppression [239]. Several
surrogate markers for vascular disease, including intima-media thickness and endothelial
function, have been shown to improve, and there are indications of some beneficial effects on
other diabetic complications [240]. But solid-organ transplantation offers a greater chance for
durable insulin independence compared to islet transplant [231].
Yet studies using transplanted mouse models have revealed profound functional
impairment in islet grafts retrieved from the liver. In view of the fact that the loss of islet graft
functions might be partly attributable to the necessity for multiple islet donors to cure each
individual DM1 patient. New optimal anatomical site for islet transplantation, such as the
renal capsule, spleen, or the omental pouch, have been reported in animal studies [200]. There
is increasing new excitement for the use of unlimited alternative sources of transplantable
islets, such as xenogeneic (i.e., obtained from other species such as porcine islets) or derived
from human stem cells [241], manipulated the differentiation of the cells with genetic
engineering, transdifferentiation of acinar cells with injection of adenoviruses expressing
transcription factors – Pdx1 and Neurogenin3 [231].
Pancreatic Plasticity
The progressive decline of beta cell function over the years does not seem an irreversible
process because some data suggest that treatment can temporarily improve beta cell function
[242]. An alternative strategy to exogenous cell replacement therapy might be fostering
endogenous beta cell regeneration. Therefore, knowledge of the mechanisms regulating beta
cell plasticity in both embryonic and adult life, as well as in pathological conditions, is of
particular interest. It is suggests that new beta cell formation might occur throughout life.
However, it remains largely unclear through which molecular and cellular mechanisms it
occurs [243].
Studies also revealed that the rate of replication of beta cells (neogenesis) is not impaired
in type 2 diabetic subjects who, however, have an increased rate of apoptosis. This suggests
that treatment strategies for patients with DM2 should include agents that may delay and/or
prevent beta cell apoptosis [244]. With the development of newer antihyperglycemic agents,
it is clear that combination therapy targeting the fundamental defects that underlie DM2 is
both a viable and rational approach for managing patients early in the course of their disease.
Future therapeutic regimens must involve drugs with different mechanisms of action to target
the multiple contributors of disease progression [244].
The inherent plasticity of the adult pancreatic organ is an area of great interest. Not
surprisingly, one organ that has been explored as a source of reprogrammable cells is the
liver. The liver and pancreas share their endodermal origin, and the existence of a bipotential
progenitor cell with the ability to give rise to hepatic or pancreatic fate is now generally
accepted. Several attempts have been made to generate pancreatic cell types from adult liver
cells by overexpression of pancreas-specific transcription factors [245]. Until recently, the
identity of the hepatic cell that adopted a pancreatic fate had remained elusive.
A common approach to identifying progenitor cells within the adult pancreas is to induce
damage to trigger regeneration. Evidence is accumulating that pancreatic duct cells are the
multipotent progenitor cells responsible for neogenesis [246]. Although pancreatic ducts are
believed to harbor precursors for endocrine and exocrine lineages, either the ducts harbor a
pool of cells that behave as stem cells, or the ducts are capable of dedifferentiating into a
more progenitor-like state in culture or upon injury. To develop this type of approach as a
treatment option, it would be critical to be able to expand the duct progenitor population in
the absence of injury, perhaps using either a gene therapy approach or small chemical
compounds [41, 246].
Plasticity in adult pancreatic cells not only provides a unique opportunity to expand the
number of ‘‘desired’’ cell types, e.g., insulin-producing beta cells, but also carries risks with
regard to initiation of neoplastic transformation. Under these conditions, acinar to ductal
metaplasia occurs, followed by the formation of pancreatic intraepithelial neoplasia, lesions
that lead to developing pancreatic adenocarcinoma over time. Furthermore, other embryonic
signaling pathways implicated in pancreas development, including Notch, Wnt and Hedgehog
signaling, also appear to play crucial roles during acinar regeneration and neoplastic
transformation [27].
Endocrine Pancreas: Intervention Strategies
Many trials showed that DM2 can be prevented but few of them directly addressed the
issue of beta cell protection by the intervention used in the study. It is reasonable to conclude
that in these trials diabetes prevention (table 4), which was based on the use of lifestyle
changes (diet and/or exercise) or different drugs (tolbutamide, acarbose, metformin,
glitazones, bezafibrate, orlistat, angiotensina converting enzyme inhibitors, angiotensin II
receptor blockers or pravastatin), depended also, or mainly, on a protection of the beta cells
but in most studies data on insulin secretion are not available or are insufficient to draw
consistent conclusions [247, 248].
The most commonly prescribed blood-glucose lowering agents, metformin and
sulphonylureas, may temporarily improve glycemic control, however, these drugs do not alter
the continuous decline in beta cell function in DM2 patients [248], table 4. Combination
therapies with agents that reduce the workload on the beta cell, that strengthen beta cell health
and lifestyle changes are necessary. A combined approach should be started very early in the
disease, if progressive beta cell failure is to be prevented [244, 248].
However, PPAR-gamma agonists, incretin-mimetic agents (GLP-1 analogs or inhibitors
of DPP-IV) and inhibitors of the rennin-angiotensin system seem to have favorable effects on
beta cell morphology and volume [248-250]. The mechanisms of beta cell protection in these
trials, if any, remain unknown. They could be various and likely included reduced
glucotoxicity, lipotoxicity, insulin resistance, inflammation, oxidant stress and/or apoptosis,
an amelioration of islet blood flow and/or favorable changes in cation balance within the islets
[247], shown in table 4. One of the most exciting features of GLP-1 receptor signaling is the
potential to expand beta cell mass by both islet neogenesis and inhibiting apoptosis, remains a
promising strategy for the preservation of beta cell mass [148].
Table 4. Interventions able to reduce the incidence of type 2 diabetes and improved beta cell function
Beta cell
Intervention Class Effect DM2 Comments
function
Diet and exercises - - +++ + Long-term
Reducing hepatic glucose Continuous
Biguanide
production, improving +++ decline in beta First-line drug
(Metformin)
insulin sensitivity cell function
Insulin sensitizers
Thiazolidinediones
(Rosiglitazone, PPAR-gamma agonists ++ ++ Hepatotoxicity
Pioglitazone)
Sulfonylurea Decline in beta cell
Inducing beta cell
(Tolbutamide, +++ + function,
membrane
K+ATP Glibenclamide) loss of glycemic control
depolarization and Ca2+
Meglitinide
influx +++ Postprandial glucose
(Repaglinide)
Increases activity of No long-term studies,
GLP-1 Analogs Liraglutide, Exenatide +++ ++
the GLP-1 high cost
Increases activity of No long-term studies,
DPP-4 Inhibitors Sitagliptin +++ ++
the GLP-1 high cost
Alpha-glucosidase
Acarbose carbohydrates blocker + Postprandial glucose
inhibitors
More recently, short-term initial intensive insulin therapy in recently diagnosed DM2
patients had favorable effects on recovery of beta cell function and prolonged glycemic
remission as compared to oral hypoglycemic agents. Since similar reductions in glucose
levels were achieved in the groups following intensive treatment, these data suggest that, in
addition to reducing glucolipotoxicity, insulin treatment may improve beta cell function by
inducing beta cell rest [251].
CONCLUSION
Nowadays, the priorities in the treatment of pancreatic disease remain lifestyle changes
and pharmacological and surgical interventions to minimize the adverse environment
(metabolism and inflammation) and consequent progressive impairment of pancreatic
function. As a result, an important increase of the type 2 diabetes mellitus associated with
metabolic syndrome has affected a growing number of people around the world, with
increasing morbidity and cardiovascular risk. However, the deep knowledge about the
pancreas functions and the physiopathological mechanisms of pancreas disease allow
expecting to a better treatment of the pancreas dysfunction in the near future. Associated to
that, newer perspectives with the use of the stem cells and gene therapy are each time more a
reality in the medical practice. There are reasons to believe that these and other new
initiatives may soon significantly improve the medical management of pancreas disease.
However, one must to reinforce that good habits in the food intake and regular physical
activity are important coadjutants to the health in all aspects.
REFERENCES
[1] Busnardo AC, DiDio LJ, Tidrick RT, Thomford NR. History of the pancreas. Am. J.
Surg. 1983;146:539-50.
[2] Pictet RL, Clark WR, Williams RH, Rutter WJ. An ultrastructural analysis of the
developing embryonic pancreas. Dev. Biol. 1972;29:436-67.
[3] Jensen J. Gene regulatory factors in pancreatic development. Dev. Dyn. 2004;229:176-
200.
[4] Robb P. The development of the islets of Langerhans in the human foetus. Q. J. Exp.
Physiol. Cogn. Med. Sci. 1961;46:335-43.
[5] Jorgensen MC, Ahnfelt-Ronne J, Hald J, Madsen OD, Serup P, Hecksher-Sorensen J.
An illustrated review of early pancreas development in the mouse. Endocr. Rev.
2007;28:685-705.
[6] Dhawan S, Georgia S, Bhushan A. Formation and regeneration of the endocrine
pancreas. Curr. Opin. Cell Biol. 2007;19:634-45.
[7] Remacle C, Dumortier O, Bol V, Goosse K, Romanus P, Theys N, et al. Intrauterine
programming of the endocrine pancreas. Diabetes Obes. Metab. 2007;9 Suppl 2:196-
209.
[8] Hill D, Lebenthal E. Congenital abnormalities of the exocrine pancreas. In: Go V,

Dimagno E, Gardner J, Lebenthal E, Reber H, Scheele G, editors. The Pancreas:
Biology, Pathobiology, and Disease. New York: Raven Press Ltd.; 1993. p. 1029-40.
[9] Hebrok M, German MS. Development oh the endocrine pancreas. In: Groot LJD,
Jameson JL, editors. Endocrinology. 6th ed. Philadelphia; 2010. p. 592-602.
[10] Bonner-Weir S, Smith FE. Islet cell growth and the growth factors involved. Trends
Endocrinol. Metab. 1994;5:60-4.
[11] Rutter WJ, Kemp JD, Bradshaw WS, Clark WR, Ronzio RA, Sanders TG. Regulation
of specific protein synthesis in cytodifferentiation. J. Cell Physiol. 1968;72:Suppl 1:-18.
[12] Sarkar SA, Kobberup S, Wong R, Lopez AD, Quayum N, Still T, et al. Global gene
expression profiling and histochemical analysis of the developing human fetal pancreas.
Diabetologia. 2008;51:285-97.
[13] Nekrep N, Wang J, Miyatsuka T, German MS. Signals from the neural crest regulate
beta-cell mass in the pancreas. Development. 2008;135:2151-60.
[14] Edlund H. Pancreatic organogenesis--developmental mechanisms and implications for
therapy. Nat. Rev. Genet. 2002;3:524-32.
[15] Puri S, Hebrok M. Cellular plasticity within the pancreas--lessons learned from
development. Dev. Cell. 2010;18:342-56.
[16] Rose SD, Swift GH, Peyton MJ, Hammer RE, MacDonald RJ. The role of PTF1-P48 in
pancreatic acinar gene expression. J. Biol. Chem. 2001;276:44018-26.
[17] Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of
the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors.
Nat. Genet. 2002;32:128-34.
[18] Jensen J, Heller RS, Funder-Nielsen T, Pedersen EE, Lindsell C, Weinmaster G, et al.
Independent development of pancreatic alpha- and beta-cells from neurogenin3-
expressing precursors: a role for the notch pathway in repression of premature
differentiation. Diabetes. 2000;49:163-76.
[19] Gradwohl G, Dierich A, LeMeur M, Guillemot F. neurogenin3 is required for the
development of the four endocrine cell lineages of the pancreas. Proc. Natl. Acad. Sci.
US. 2000;97:1607-11.
[20] Leung PS. Overview of the pancreas. Adv Exp Med Biol 2010;690:3-12.
[21] Scharfmann R. Pancreatic development as a basis for the definition of new therapies for
diabetes. Endocr. Dev. 2007;12:1-11.
[22] Masui T, Swift GH, Hale MA, Meredith DM, Johnson JE, Macdonald RJ.
Transcriptional autoregulation controls pancreatic Ptf1a expression during development
and adulthood. Mol. Cell Biol. 2008;28:5458-68.
[23] Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for
pancreas development in mice. Nature. 1994;371:606-9.
[24] Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, et al. Agenesis
of human pancreas due to decreased half-life of insulin promoter factor 1. J. Clin.
[25] Kordowich S, Mansouri A, Collombat P. Reprogramming into pancreatic endocrine
cells based on developmental cues. Mol. Cell Endocrinol. 2009.
[26] Gannon M, Ables ET, Crawford L, Lowe D, Offield MF, Magnuson MA, et al. pdx-1
function is specifically required in embryonic beta cells to generate appropriate
numbers of endocrine cell types and maintain glucose homeostasis. Dev. Biol.
2008;314:406-17.
[27] Heiser PW, Hebrok M. Development and cancer: lessons learned in the pancreas. Cell
Cycle. 2004;3:270-2.
[28] Piper K, Brickwood S, Turnpenny LW, Cameron IT, Ball SG, Wilson DI, et al. Beta
cell differentiation during early human pancreas development. J. Endocrinol.
2004;181:11-23.
[29] Hara A, Kadoya Y, Kojima I, Yamashina S. Rat pancreatic islet is formed by
unification of multiple endocrine cell clusters. Dev. Dyn. 2007;236:3451-8.
[30] Frantz ED, Peixoto-Silva N, Pinheiro-Mulder A. Endocrine pancreas development:
effects of metabolic and intergenerational programming caused by a protein-restricted
diet. Pancreas. 2012;41:1-9.
[31] Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, et
al. The vascular basement membrane: a niche for insulin gene expression and Beta cell
proliferation. Dev. Cell. 2006;10:397-405.
[32] [32] Leung PS. Physiology of the pancreas. Adv. Exp. Med. Biol. 2010;690:13-27.
[33] [33] Kim SK, Hebrok M. Intercellular signals regulating pancreas development and
function. Genes Dev. 2001;15:111-27.
[34] Green AS, Rozance PJ, Limesand SW. Consequences of a compromised intrauterine
environment on islet function. J. Endocrinol. 2010;205:211-24.
[35] Adam PA, Teramo K, Raiha N, Gitlin D, Schwartz R. Human fetal insulin
metabolismearly in gestation. Response to acutelevation of the fetal glucose
concentration and placental tranfer of human insulin-I-131. Diabetes. 1969;18:409-16.
[36] Kervran A, Randon J, Girard JR. Dynamics of glucose-induced plasma insulin increase
in the rat fetus at different stages of gestation. Effects of maternal hypothermia and fetal
decapitation. Biol. Neonate. 1979;35:242-8.
[37] Kaung HL. Growth dynamics of pancreatic islet cell populations during fetal and
neonatal development of the rat. Dev. Dyn. 1994;200:163-75.
[38] Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the
remodeling of the endocrine pancreas in the neonatal rat. Endocrinology.
1997;138:1736-41.
[39] Reusens B, Remacle C. Programming of the endocrine pancreas by the early nutritional
environment. Int. J. Biochem. Cell Biol. 2006;38:913-22.
[40] Inuwa IM, El Mardi AS. Correlation between volume fraction and volume-weighted
mean volume, and between total number and total mass of islets in post-weaning and
young Wistar rats. J. Anat. 2005;206:185-92.
[41] Bonner-Weir S. Perspective: Postnatal pancreatic beta cell growth. Endocrinology.
2000;141:1926-9.
[42] Bonal C, Avril I, Herrera PL. Experimental models of beta-cell regeneration. Biochem.
Soc. Trans. 2008;36:286-9.
[43] Schwitzgebel VM, Somm E, Klee P. Modeling intrauterine growth retardation in
rodents: Impact on pancreas development and glucose homeostasis. Mol. Cell
Endocrinol. 2009;304:78-83.
[44] Petersen O. Human Physiology. Oxford: Blackwell; 2007.
[45] Williams JA, Goldfine ID. The insulin-pancreatic acinar axis. Diabetes. 1985;34:980-6.
[46] Chey WY, Chang T. Neural hormonal regulation of exocrine pancreatic secretion.
Pancreatology. 2001;1:320-35.
[47] Petersen KF, Shulman GI. New insights into the pathogenesis of insulin resistance in
humans using magnetic resonance spectroscopy. Obesity. (Silver Spring) 2006;14 Suppl
1:34S-40S.
[48] DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion
responsible for NIDDM. Diabetes. 1988;37:667-87.
[49] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit
and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes.
2003;52:102-10.
[50] Hardt PD, Bretz L, Krauss A, Schnell-Kretschmer H, Wusten O, Nalop J, et al.
Pathological pancreatic exocrine function and duct morphology in patients with
cholelithiasis. Dig. Dis. Sci. 2001;46:536-9.
[51] Hardt PD, Krauss A, Bretz L, Porsch-Ozcurumez M, Schnell-Kretschmer H, Maser E,
et al. Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus.
Acta Diabetol. 2000;37:105-10.
[52] Murayama KM, Drew JB, Nahrwold DL, Joehl RJ. Cholecystokinin antagonist prevents
hyperamylasemia and improves pancreatic exocrine function in cerulein-induced acute
pancreatitis. Pancreas. 1990;5:439-44.
[53] Otsuki M. Pathophysiological role of cholecystokinin in humans. J. Gastroenterol.
Hepatol. 2000;15 Suppl:D71-83.
[54] Iwatsuki N, Petersen OH. Pancreatic acinar cells: acetylcholine-evoked electrical
uncoupling and its ionic dependency. J. Physiol. 1978;274:81-06.
[55] Iwatsuki N, Petersen OH. Electrical coupling and uncoupling of exocrine acinar cells. J.
Cell Biol. 1978;79:533-45.
[56] Githens S. The pancreatic duct cell: proliferative capabilities, specific characteristics,
metaplasia, isolation, and culture. J. Pediatr. Gastroenterol. Nutr. 1988;7:486-506.
[57] Domschke W, Greenberg GR, Domschke S, Bloom SR, Mitznegg P, Sprugel W, et al.
Endogenous acid releases secretin in man. Acta Hepatogastroenterol. (Stuttg)
1977;24:262-3.
[58] Pandol SJ. Neurohumoral control of exocrine pancreatic secretion. Curr. Opin.
Gastroenterol. 2004;20:435-8.
[59] Hanssen LE. The effect of atropine on secretin release and aspirated bicarbonate
secretion after duodenal acidification in man. Scand. J. Gastroenterol. 1980;15:465-9.
[60] Bonner-Weir S, Sharma A. Pancreatic stem cells. J. Pathol. 2002;197:519-26.
[61] Schuit FC, Huypens P, Heimberg H, Pipeleers DG. Glucose sensing in pancreatic beta-
cells: a model for the study of other glucose-regulated cells in gut, pancreas, and
hypothalamus. Diabetes. 2001;50:1-11.
[62] German MS. Glucose sensing in pancreatic islet beta cells: the key role of glucokinase
and the glycolytic intermediates. Proc. Natl. Acad. Sci. US. 1993;90:1781-5.
[63] Unger RH, Dobbs RE, Orci L. Insulin, glucagon, and somatostatin secretion in the
regulation of metabolism. Annu. Rev. Physiol. 1978;40:307-43.
[64] Sorensen H, Winzell MS, Brand CL, Fosgerau K, Gelling RW, Nishimura E, et al.
Glucagon receptor knockout mice display increased insulin sensitivity and impaired
beta-cell function. Diabetes. 2006;55:3463-9.
[65] Ma X, Zhang Y, Gromada J, Sewing S, Berggren PO, Buschard K, et al. Glucagon

stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon
receptors. Mol. Endocrinol. 2005;19:198-212.
[66] Ueno N, Asakawa A, Satoh Y, Inui A. Increased circulating cholecystokinin contributes
to anorexia and anxiety behavior in mice overexpressing pancreatic polypeptide. Regul.
Pept. 2007;141:8-11.
[67] Liu YL, Semjonous NM, Murphy KG, Ghatei MA, Bloom SR. The effects of
pancreatic polypeptide on locomotor activity and food intake in mice. Int. J. Obes.
(Lond) 2008;32:1712-5.
[68] Lai KC, Cheng CH, Leung PS. The ghrelin system in acinar cells: localization,
expression, and regulation in the exocrine pancreas. Pancreas. 2007;35:e1-8.
[69] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a
growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-60.
[70] Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for
ghrelin in the central regulation of feeding. Nature. 2001;409:194-8.
[71] Mathur A, Marine M, Lu D, Swartz-Basile DA, Saxena R, Zyromski NJ, et al.
Nonalcoholic fatty pancreas disease. HPB. (Oxford) 2007;9:312-8.
[72] Fernandes-Santos C, Carneiro RE, Mendonca LS, Aguila MB, Mandarim-de-Lacerda
CA. Rosiglitazone aggravates nonalcoholic Fatty pancreatic disease in C57BL/6 mice
fed high-fat and high-sucrose diet. Pancreas. 2009;38:e80-6.
[73] Pitt HA. Hepato-pancreato-biliary fat: the good, the bad and the ugly. HPB (Oxford)
2007;9:92-7.
[74] Schaefer JH. The normal weight of the pancreas in the adult human being: a biometric
study. Anat. Rec. 1926;32:119-32.
[75] Ogilvie RF. The islands of Langerhans in 19 cases of obesity. J. Pathol. Bacteriol.
1933;37:473-81.
[76] Walters MN. Adipose atrophy of the exocrine pancreas. J. Pathol. Bacteriol.
1966;92:547-57.
[77] Olsen TS. Lipomatosis of the pancreas in autopsy material and its relation to age and
overweight. Acta Pathol. Microbiol. Scand. A. 1978;86A:367-73.
[78] Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB, Mandarim de
Lacerda CA. A mouse model of metabolic syndrome: insulin resistance, fatty liver and
non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J.
Clin. Biochem. Nutr. 2010;46:1-12.
[79] Papachristou GI, Papachristou DJ, Avula H, Slivka A, Whitcomb DC. Obesity
increases the severity of acute pancreatitis: performance of APACHE-O score and
correlation with the inflammatory response. Pancreatology. 2006;6:279-85.
[80] Segersvard R, Sylvan M, Herrington M, Larsson J, Permert J. Obesity increases the
severity of acute experimental pancreatitis in the rat. Scand. J. Gastroenterol.
2001;36:658-63.
[81] Vasseur S, Folch-Puy E, Hlouschek V, Garcia S, Fiedler F, Lerch MM, et al. p8
improves pancreatic response to acute pancreatitis by enhancing the expression of the
anti-inflammatory protein pancreatitis-associated protein I. J. Biol. Chem.
2004;279:7199-207.
[82] Robertson RP. Beta-cell deterioration during diabetes: what's in the gun? Trends
[83] Lee Y, Lingvay I, Szczepaniak LS, Ravazzola M, Orci L, Unger RH. Pancreatic
steatosis: harbinger of type 2 diabetes in obese rodents. Int. J. Obes. (Lond)
2010;34:396-400.
[84] Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and
clinical implications. Diabetes. 1995;44:863-70.
[85] Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic
pancreatitis. J. Gastroenterol. Hepatol. 2008;23:34-41.
[86] Souza-Mello V, Gregorio BM, Relvas-Lucas B, da Silva Faria T, Aguila MB,
Mandarim-de-Lacerda CA. Pancreatic ultrastructural enhancement due to telmisartan
plus sitagliptin treatment in diet-induced obese C57BL/6 mice. Pancreas. 2011;40:715-
22.
[87] DeFronzo RA. Insulin resistance: a multifaceted syndrome responsible for NIDDM,
obesity, hypertension, dyslipidaemia and atherosclerosis. Neth. J. Med. 1997;50:191-7.
[88] DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med. Clin. North. Am.
2004;88:787-835, ix.
[89] Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus
and its complications. Part 1: diagnosis and classification of diabetes mellitus
provisional report of a WHO consultation. Diabet. Med. 1998;15:539-53.
[90] Sesti G. Pathophysiology of insulin resistance. Best Pract. Res. Clin. Endocrinol.
Metab. 2006;20:665-79.
[91] Butler PC, Rizza RA. Contribution to postprandial hyperglycemia and effect on initial
splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or
NIDDM patients. Diabetes. 1991;40:73-81.
[92] Meier J, Butler PC. Insulin secretion. In: Endocrinology adult and pediatric: Elsevier;
2010. p. 624-35.
[93] Dahlgren GM, Nolkrantz K, Kennedy RT. Effect of intracellular delivery of energy
metabolites on intracellular Ca2+ in mouse islets of Langerhans. Life Sci.
2005;77:2986-97.
[94] Tsuura Y, Ishida H, Okamoto Y, Kato S, Sakamoto K, Horie M, et al. Glucose
sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new
genetic model of NIDDM. Diabetes. 1993;42:1446-53.
[95] Ranganath LR. The entero-insular axis: implications for human metabolism. Clin.
Chem. Lab. Med. 2008;46:43-56.
[96] Berry SM, Fink AS. Exogenous insulin does not influence CCK- and meal-stimulated
pancreatic secretion. Pancreas. 1996;12:345-50.
[97] Howard-McNatt M, Simon T, Wang Y, Fink AS. Insulin inhibits secretin-induced
pancreatic bicarbonate output via cholinergic mechanisms. Pancreas. 2002;24:380-5.
[98] [98] Zick Y, Whittaker J, Roth J. Insulin stimulated phosphorylation of its own
receptor. Activation of a tyrosine-specific protein kinase that is tightly associated with
the receptor. J. Biol. Chem. 1983;258:3431-4.
[99] Rojas FA, Hirata AE, Saad MJ. Regulation of insulin receptor substrate-2 tyrosine
phosphorylation in animal models of insulin resistance. Endocrine. 2003;21:115-22.
[100] DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans.
Diabetes/metabolism reviews. 1987;3:415-59.
[101] Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in

maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes.
1987;36:274-83.
[102] Pilar Lopez M, Gomez-Lechon MJ, Castell JV. Role of glucose, insulin, and glucagon
in glycogen mobilization in human hepatocytes. Diabetes. 1991;40:263-8.
[103] Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin
receptor substrate (IRS) system in human metabolic disorders. FASEB J. 2001;15:2099-
111.
[104] Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid
metabolism. Nature. 2001;414:799-806.
[105] Thorens B, Charron MJ, Lodish HF. Molecular physiology of glucose transporters.
Diabetes Care. 1990;13:209-18.
[106] Sharma MD, Garber AJ, Farmer JA. Role of insulin signaling in maintaining energy
homeostasis. Endocr. Pract. 2008;14:373-80.
[107] Chiasson JL, el Achkar GG, Ducros F, Bourque J, Maheux P. Glucose turnover and
gluconeogenesis during pregnancy in women with and without insulin-dependent
diabetes mellitus. Clin. Invest. Med. 1997;20:140-51.
[108] Bock G, Dalla Man C, Campioni M, Chittilapilly E, Basu R, Toffolo G, et al.
Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in
people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes.
2006;55:3536-49.
[109] Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology.
2007;132:2131-57.
[110] Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-65.
[111] Irwin N, McClean PL, Hunter K, Flatt PR. Metabolic effects of sustained activation of
the GLP-1 receptor alone and in combination with background GIP receptor
antagonism in high fat-fed mice. Diabetes Obes. Metab. 2009;11:603-10.
[112] Lamont BJ, Drucker DJ. Differential antidiabetic efficacy of incretin agonists versus
DPP-4 inhibition in high fat fed mice. Diabetes. 2008;57:190-8.
[113] Komatsu R, Matsuyama T, Namba M, Watanabe N, Itoh H, Kono N, et al.
Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide.
Diabetes. 1989;38:902-5.
[114] Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in a
subset of endocrine cells in the small intestine. Regul. Pept. 2003;114:189-96.
[115] Naslund E, Bogefors J, Skogar S, Gryback P, Jacobsson H, Holst JJ, et al. GLP-1 slows
solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am.
J. Physiol. 1999;277:R910-6.
[116] Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 induces cell
proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine
cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology. 2000;141:4600-
5.
[117] Delmeire D, Flamez D, Hinke SA, Cali JJ, Pipeleers D, Schuit F. Type VIII adenylyl
cyclase in rat beta cells: coincidence signal detector/generator for glucose and GLP-1.
Diabetologia. 2003;46:1383-93.
[118] Horiuchi A, Iwatsuki K, Ren LM, Kuroda T, Chiba S. Dual actions of glucagon: direct
stimulation and indirect inhibition of dog pancreatic secretion. Eur. J. Pharmacol.
1993;237:23-30.
[119] Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.
Diabetes. 1988;37:1595-607.
[120] Chen YD, Golay A, Swislocki AL, Reaven GM. Resistance to insulin suppression of
plasma free fatty acid concentrations and insulin stimulation of glucose uptake in
noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 1987;64:17-21.
[121] Shulman GI. Cellular mechanisms of insulin resistance. J. Clin. Invest. 2000;106:171-6.
[122] Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic
mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat. Rev. Mol.
Cell Biol. 2008;9:193-205.
[123] Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75-85.
[124] Harris MI, Eastman RC. Early detection of undiagnosed diabetes mellitus: a US
perspective. Diabetes Metab. Res. Rev. 2000;16:230-6.
[125] Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, et al. Selective beta-cell loss
and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J. Clin.
[126] Taylor SI. Deconstructing type 2 diabetes. Cell. 1999;97:9-12.
[127] Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of
nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by
moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603-8.
[128] Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular
disease in Type II diabetes: the epidemiological evidence. Diabetologia. 2001;44:2107-
14.
[129] Paulsson JF, Andersson A, Westermark P, Westermark GT. Intracellular amyloid-like
deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of
transgenic mice overexpressing the gene for human IAPP and transplanted human
islets. Diabetologia. 2006;49:1237-46.
[130] Jaikaran ET, Clark A. Islet amyloid and type 2 diabetes: from molecular misfolding to
islet pathophysiology. Biochim. Biophys. Acta. 2001;1537:179-203.
[131] Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int. J. Obes.
Relat. Metab. Disord. 2000;24 Suppl 4:S28-32.
[132] Savage DB, Petersen KF, Shulman GI. Mechanisms of insulin resistance in humans and
possible links with inflammation. Hypertension. 2005;45:828-33.
[133] Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its
role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet.
1963;1:785-9.
[134] DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the
missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270-87.
[135] Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin.
Liver Dis. 2009;13:545-63.
[136] Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of
free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase
activity. J. Clin. Invest. 1999;103:253-9.
[137] Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, et al.
Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest.
1996;97:2859-65.
[138] Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL. Insulin receptor
phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol
3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J.
Clin. Invest. 1995;95:2195-204.
[139] Sinha MK, Pories WJ, Flickinger EG, Meelheim D, Caro JF. Insulin-receptor kinase
activity of adipose tissue from morbidly obese humans with and without NIDDM.
Diabetes. 1987;36:620-5.
[140] Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, et al. Studies on
the mechanism of insulin resistance in the liver from humans with noninsulin-
dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor
structure, and kinase activity. J. Clin. Invest. 1986;78:249-58.
[141] Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for
insulin resistance and diabetes mellitus. N. Engl. J. Med. 1999;341:248-57.
[142] Zierath JR, He L, Guma A, Odegoard Wahlstrom E, Klip A, Wallberg-Henriksson H.
Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal
muscle from patients with NIDDM. Diabetologia. 1996;39:1180-9.
[143] Ahmad F, Azevedo JL, Cortright R, Dohm GL, Goldstein BJ. Alterations in skeletal
muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human
obesity and diabetes. J. Clin. Invest. 1997;100:449-58.
[144] Ahmad F, Considine RV, Bauer TL, Ohannesian JP, Marco CC, Goldstein BJ.
Improved sensitivity to insulin in obese subjects following weight loss is accompanied
by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism. 1997;46:1140-
5.
[145] Kahn SE. Clinical review 135: The importance of beta-cell failure in the development
and progression of type 2 diabetes. J. Clin. Endocrinol. Metab. 2001;86:4047-58.
[146] Kahn SE, Prigeon RL, Schwartz RS, Fujimoto WY, Knopp RH, Brunzell JD, et al.
Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as
explanations for metabolic diversity. J. Nutr. 2001;131:354S-60S.
[147] Ranganath LR. Incretins: pathophysiological and therapeutic implications of glucose-
dependent insulinotropic polypeptide and glucagon-like peptide-1. J. Clin. Pathol.
2008;61:401-9.
[148] Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of
dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and
function in a rodent model of type 2 diabetes. Diabetes. 2006;55:1695-704.
[149] Tong J, Utzschneider KM, Carr DB, Zraika S, Udayasankar J, Gerchman F, et al.
Plasma pancreatic polypeptide levels are associated with differences in body fat
distribution in human subjects. Diabetologia. 2007;50:439-42.
[150] Langley-Evans SC, McMullen S. Developmental origins of adult disease. Med. Princ.
Pract. 2010;19:87-98.
[151] Cerf ME. High fat programming of beta-cell failure. Adv. Exp. Med. Biol. 2010;654:77-
89.
[152] Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal
nutrition and cardiovascular disease in adult life. Lancet. 1993;341:938-41.
[153] Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, et al.
Glucose tolerance in adults after prenatal exposure to famine. Lancet. 1998;351:173-7.
[154] Blondeau B, Garofano A, Czernichow P, Breant B. Age-dependent inability of the
endocrine pancreas to adapt to pregnancy: a long-term consequence of perinatal
malnutrition in the rat. Endocrinology. 1999;140:4208-13.
[155] Armitage JA, Taylor PD, Poston L. Experimental models of developmental
programming: consequences of exposure to an energy rich diet during development. J.
Physiol. 2005;565:3-8.
[156] Boyd CA, Benarroch-Gampel J, Kilic G, Kruse EJ, Weber SM, Riall TS. Pancreatic
Neoplasms in Pregnancy: Diagnosis, Complications, and Management. J. Gastrointest.
Surg. 2011.
[157] Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP. Obesity at the age
of 50 y in men and women exposed to famine prenatally. Am. J. Clin. Nutr.
1999;70:811-6.
[158] Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent
epigenetic differences associated with prenatal exposure to famine in humans. Proc.
Natl. Acad. Sci. US. 2008;105:17046-9.
[159] Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions
of endocrine disruptors and male fertility. Science. 2005;308:1466-9.
[160] Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty
phenotype hypothesis. Diabetologia. 1992;35:595-601.
[161] Reusens B, Theys N, Dumortier O, Goosse K, Remacle C. Maternal malnutrition
programs the endocrine pancreas in progeny. Am. J. Clin. Nutr. 2011;94:1824S-9S.
[162] Gluckman PD, Hanson MA. The consequences of being born small - an adaptive
perspective. Horm. Res. 2006;65 Suppl 3:5-14.
[163] Bol VV, Delattre AI, Reusens B, Raes M, Remacle C. Forced catch-up growth after
fetal protein restriction alters the adipose tissue gene expression program leading to
obesity in adult mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009;297:R291-9.
[164] Dahri S, Reusens B, Remacle C, Hoet JJ. Nutritional influences on pancreatic
development and potential links with non-insulin-dependent diabetes. Proc. Nutr. Soc.
1995;54:345-56.
[165] Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat beta-cell
development. Diabetologia. 1997;40:1231-4.
[166] Drake AJ, Walker BR, Seckl JR. Intergenerational consequences of fetal programming
by in utero exposure to glucocorticoids in rats. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 2005;288:R34-8.
[167] Snoeck A, Remacle C, Reusens B, Hoet JJ. Effect of a low protein diet during
pregnancy on the fetal rat endocrine pancreas. Biol. Neonate. 1990;57:107-18.
[168] Simmons RA, Templeton LJ, Gertz SJ. Intrauterine growth retardation leads to the
development of type 2 diabetes in the rat. Diabetes. 2001;50:2279-86.
[169] Van Assche FA, Holemans K, Aerts L. Long-term consequences for offspring of
diabetes during pregnancy. Br. Med. Bull. 2001;60:173-82.
[170] Langley-Evans SC. Nutritional programming of disease: unravelling the mechanism. J.
Anat. 2009;215:36-51.
[171] Dumortier O, Blondeau B, Duvillie B, Reusens B, Breant B, Remacle C. Different
mechanisms operating during different critical time-windows reduce rat fetal beta cell
mass due to a maternal low-protein or low-energy diet. Diabetologia. 2007;50:2495-

503.
[172] Lindsay RS, Lindsay RM, Waddell BJ, Seckl JR. Prenatal glucocorticoid exposure
leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid
dehydrogenase inhibitor carbenoxolone. Diabetologia. 1996;39:1299-305.
[173] Shen CN, Seckl JR, Slack JM, Tosh D. Glucocorticoids suppress beta-cell development
and induce hepatic metaplasia in embryonic pancreas. Biochem. J. 2003;375:41-50.
[174] Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet JJ, et al. A low protein diet
alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and
is associated with a reduced pancreatic expression of insulin-like growth factor-II.
Endocrinology. 1999;140:4861-73.
[175] Chamson-Reig A, Thyssen SM, Arany E, Hill DJ. Altered pancreatic morphology in the
offspring of pregnant rats given reduced dietary protein is time and gender specific. J.
Endocrinol. 2006;191:83-92.
[176] Aerts L, Van Assche FA. Animal evidence for the transgenerational development of
diabetes mellitus. Int. J. Biochem. Cell Biol. 2006;38:894-903.
[177] Janssen SW, Hermus AR, Lange WP, Knijnenburg Q, van der Laak JA, Sweep CG, et
al. Progressive histopathological changes in pancreatic islets of Zucker Diabetic Fatty
rats. Exp. Clin. Endocrinol. Diabetes. 2001;109:273-82.
[178] Ham JN, Crutchlow MF, Desai BM, Simmons RA, Stoffers DA. Exendin-4 normalizes
islet vascularity in intrauterine growth restricted rats: potential role of VEGF. Pediatr.
Res. 2009;66:42-6.
[179] Stoffers DA, Desai BM, DeLeon DD, Simmons RA. Neonatal exendin-4 prevents the
development of diabetes in the intrauterine growth retarded rat. Diabetes. 2003;52:734-
40.
[180] Erhuma A, Bellinger L, Langley-Evans SC, Bennett AJ. Prenatal exposure to
undernutrition and programming of responses to high-fat feeding in the rat. Br. J. Nutr.
2007;98:517-24.
[181] Gniuli D, Calcagno A, Caristo ME, Mancuso A, Macchi V, Mingrone G, et al. Effects
of high-fat diet exposure during fetal life on type 2 diabetes development in the
progeny. J. Lipid Res. 2008;49:1936-45.
[182] Cerf ME, Chapman CS, Muller CJ, Louw J. Gestational high-fat programming impairs
insulin release and reduces Pdx-1 and glucokinase immunoreactivity in neonatal Wistar
rats. Metabolism. 2009;58:1787-92.
[183] Fall C. Maternal nutrition: effects on health in the next generation. Indian J. Med. Res.
2009;130:593-9.
[184] Fernandez-Twinn DS, Ozanne SE. Early life nutrition and metabolic programming.
Ann. N. Y. Acad. Sci. 2010;1212:78-96.
[185] Hanson RL, Elston RC, Pettitt DJ, Bennett PH, Knowler WC. Segregation analysis of
non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene
effect. Am. J. Hum. Genet. 1995;57:160-70.
[186] Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers.
Diabetes Care. 2007;30 Suppl 2:S169-74.
[187] Guan H, Arany E, van Beek JP, Chamson-Reig A, Thyssen S, Hill DJ, et al. Adipose
tissue gene expression profiling reveals distinct molecular pathways that define visceral
adiposity in offspring of maternal protein-restricted rats. Am. J. Physiol. Endocrinol.

Metab. 2005;288:E663-73.
[188] Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat.
Rev. Genet. 2007;8:253-62.
[189] Waterland RA, Travisano M, Tahiliani KG. Diet-induced hypermethylation at agouti
viable yellow is not inherited transgenerationally through the female. FASEB J.
2007;21:3380-5.
[190] Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on
epigenetic gene regulation. Mol. Cell Biol. 2003;23:5293-300.
[191] Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6-21.
[192] Mimeault M, Batra SK. Recent insights into the molecular mechanisms involved in
aging and the malignant transformation of adult stem/progenitor cells and their
therapeutic implications. Ageing Res. Rev. 2009;8:94-112.
[193] Bruce KD, Hanson MA. The developmental origins, mechanisms, and implications of
metabolic syndrome. J. Nutr. 2010;140:648-52.
[194] Rashidi A, Kirkwood TB, Shanley DP. Metabolic evolution suggests an explanation for
the weakness of antioxidant defences in beta-cells. Mech. Ageing Dev. 2009;130:216-
21.
[195] Tarry-Adkins JL, Chen JH, Jones RH, Smith NH, Ozanne SE. Poor maternal nutrition
leads to alterations in oxidative stress, antioxidant defense capacity, and markers of
fibrosis in rat islets: potential underlying mechanisms for development of the diabetic
phenotype in later life. FASEB J. 2010;24:2762-71.
[196] Peixoto-Silva N, Frantz ED, Mandarim-de-Lacerda CA, Pinheiro-Mulder A. Maternal
protein restriction in mice causes adverse metabolic and hypothalamic effects in the F1
and F2 generations. Br. J. Nutr. 2011;106:1364-73.
[197] Frantz ED, Aguila MB, Pinheiro-Mulder AR, Mandarim-de-Lacerda CA.
Transgenerational endocrine pancreatic adaptation in mice from maternal protein
restriction in utero. Mech. Ageing Dev. 2011;132:110-6.
[198] Zambrano E. [The transgenerational mechanisms in developmental programming of
metabolic diseases]. Rev. Invest. Clin. 2009;61:41-52.
[199] Gatford KL, Simmons RA, De Blasio MJ, Robinson JS, Owens JA. Review: Placental
programming of postnatal diabetes and impaired insulin action after IUGR. Placenta.
2010;31 Suppl:S60-5.
[200] Leung PS. Basic techniques for pancreatic research. Adv. Exp. Med. Biol.
2010;690:109-30.
[201] Abdul-Ghani MA, Lyssenko V, Tuomi T, Defronzo RA, Groop L. The shape of plasma
glucose concentration curve during OGTT predicts future risk of type 2 diabetes.
Diabetes Metab. Res. Rev. 2010;26:280-6.
[202] DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying
insulin secretion and resistance. Am. J. Physiol. 1979;237:E214-23.
[203] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting
plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-9.
[204] Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes
Care. 2004;27:1487-95.
[205] Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, et al.

Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with
euglycemic and hyperglycemic glucose clamp studies. J. Clin. Endocrinol. Metab.
1989;68:374-8.
[206] Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative
insulin sensitivity check index: a simple, accurate method for assessing insulin
sensitivity in humans. J. Clin. Endocrinol. Metab. 2000;85:2402-10.
[207] Carvalho CP, Martins JC, da Cunha DA, Boschero AC, Collares-Buzato CB.
Histomorphology and ultrastructure of pancreatic islet tissue during in vivo maturation
of rat pancreas. Ann. Anat. 2006;188:221-34.
[208] Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, et al. Abnormal
patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N. Engl. J.
Med. 1988;318:1231-9.
[209] Cretti A, Lehtovirta M, Bonora E, Brunato B, Zenti MG, Tosi F, et al. Assessment of
beta-cell function during the oral glucose tolerance test by a minimal model of insulin
secretion. Eur. J. Clin. Invest. 2001;31:405-16.
[210] Robertson RP. Estimation of beta-cell mass by metabolic tests: necessary, but how
sufficient? Diabetes. 2007;56:2420-4.
[211] Mullis K, Faloona F, Scharf S, Saiki R, Horn G, Erlich H. Specific enzymatic
amplification of DNA in vitro: the polymerase chain reaction. Cold Spring Harb. Symp.
Quant. Biol. 1986;51 Pt 1:263-73.
[212] Burnette WN. "Western blotting": electrophoretic transfer of proteins from sodium
dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic
detection with antibody and radioiodinated protein A. Anal. Biochem. 1981;112:195-
203.
[213] Lequin RM. Enzyme immunoassay (EIA)/enzyme-linked immunosorbent assay
(ELISA). Clin. Chem. 2005;51:2415-8.
[214] Burnett R, Guichard Y, Barale E. Immunohistochemistry for light microscopy in safety
evaluation of therapeutic agents: an overview. Toxicology. 1997;119:83-93.
[215] Dominguez-Munoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J.
Gastroenterol. Hepatol. 2011;26 Suppl 2:12-6.
[216] Apte M, Pirola R, Wilson J. New insights into alcoholic pancreatitis and pancreatic
cancer. J. Gastroenterol. Hepatol. 2009;24 Suppl 3:S51-6.
[217] Almhanna K, Philip PA. Defining new paradigms for the treatment of pancreatic
cancer. Curr. Treat Options Oncol. 2011;12:111-25.
[218] Krautz C, Ruckert F, Saeger HD, Pilarsky C, Grutzmann R. An update on molecular
research of pancreatic adenocarcinoma. Anticancer Agents Med. Chem. 2011;11:411-7.
[219] Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A
randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic
cancer. N. Engl. J. Med. 2004;350:1200-10.
[220] Hu WG, Liu T, Xiong JX, Wang CY. Blockade of sonic hedgehog signal pathway
enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells. Acta
Pharmacol. Sin. 2007;28:1224-30.
[221] Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al.
Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer
Res. 2008;68:918-26.
[222] Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Lohr JM, et al. Pancreatic cancer
microenvironment. Int. J. Cancer. 2007;121:699-705.
[223] Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, et al. Blockade of
hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm
for combination therapy in solid cancers. Cancer Res. 2007;67:2187-96.
[224] Chen H, Sun B, Pan S, Jiang H, Sun X. Dihydroartemisinin inhibits growth of
pancreatic cancer cells in vitro and in vivo. Anticancer Drugs. 2009;20:131-40.
[225] O'Dowd JF. The isolation and purification of rodent pancreatic islets of Langerhans.
Methods Mol. Biol. 2009;560:37-42.
[226] Li DS, Yuan YH, Tu HJ, Liang QL, Dai LJ. A protocol for islet isolation from mouse
pancreas. Nat. Protoc. 2009;4:1649-52.
[227] Andrades P, Asiedu C, Ray P, Rodriguez C, Goodwin J, McCarn J, et al. Islet yield
after different methods of pancreatic Liberase delivery. Transplant. Proc. 2007;39:183-
4.
[228] Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from
the rat pancreas. Diabetes. 1967;16:35-9.
[229] Schulz HU, Letko G, Spormann H, Sokolowski A, Kemnitz P. An optimized procedure
for isolation of rat pancreatic acinar cells. Anat. Anz. 1988;167:141-50.
[230] Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet
transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-
free immunosuppressive regimen. N. Engl. J. Med. 2000;343:230-8.
[231] Weir GC, Gaglia JL. Pancreatic and Islet Transplantation. In: Groot LJD, Jameson JL,
editors. Endocrinology. 6th ed. Philadelphia; 2010. p. 943-58.
[232] Squifflet JP, Gruessner RW, Sutherland DE. The history of pancreas transplantation:
past, present and future. Acta Chir. Belg. 2008;108:367-78.
[233] Humar A, Ramcharan T, Kandaswamy R, Gruessner RW, Gruessner AC, Sutherland
DE. Technical failures after pancreas transplants: why grafts fail and the risk factors--a
multivariate analysis. Transplantation. 2004;78:1188-92.
[234] Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet
transplantation in type 1 diabetes. Diabetes Care. 2006;29:935.
[235] Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al.
International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med.
2006;355:1318-30.
[236] Alejandro R, Barton FB, Hering BJ, Wease S. 2008 Update from the Collaborative Islet
Transplant Registry. Transplantation. 2008;86:1783-8.
[237] Rickels MR, Kamoun M, Kearns J, Markmann JF, Naji A. Evidence for allograft
rejection in an islet transplant recipient and effect on beta-cell secretory capacity. J.
Clin. Endocrinol. Metab. 2007;92:2410-4.
[238] Duvivier-Kali VF, Omer A, Parent RJ, O'Neil JJ, Weir GC. Complete protection of
islets against allorejection and autoimmunity by a simple barium-alginate membrane.
Diabetes. 2001;50:1698-705.
[239] Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, et al. Five-year
follow-up after clinical islet transplantation. Diabetes. 2005;54:2060-9.
[240] Tharavanij T, Betancourt A, Messinger S, Cure P, Leitao CB, Baidal DA, et al.
Improved long-term health-related quality of life after islet transplantation.
Transplantation. 2008;86:1161-7.
[241] Baiu D, Merriam F, Odorico J. Potential pathways to restore beta-cell mass: pluripotent
stem cells, reprogramming, and endogenous regeneration. Curr. Diab. Rep.
2011;11:392-401.
[242] Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial
intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J.
Med. 2003;348:383-93.
[243] Criscimanna A, Bertera S, Esni F, Trucco M, Bottino R. The Enigma of Beta Cell
Regeneration in the Adult Pancreas: Self-Renewal Versus Neogenesis. In: Wagner D,
editor. Type 1 Diabetes Complications: InTech; 2011. p. 367 - 90.
[244] DeFronzo RA, Abdul-Ghani MA. Preservation of beta-cell function: the key to diabetes
prevention. J. Clin. Endocrinol. Metab. 2011;96:2354-66.
[245] Wandzioch E, Zaret KS. Dynamic signaling network for the specification of embryonic
pancreas and liver progenitors. Science. 2009;324:1707-10.
[246] Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, et al. Carbonic
anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine
pancreas after birth. Proc. Natl. Acad. Sci. US. 2008;105:19915-9.
[247] Bonora E. Protection of pancreatic beta-cells: is it feasible? Nutr. Metab. Cardiovasc.
Dis. 2008;18:74-83.
[248] van Raalte DH, Diamant M. Glucolipotoxicity and beta cells in type 2 diabetes mellitus:
target for durable therapy? Diabetes Res. Clin. Pract. 2011;93 Suppl 1:S37-46.
[249] Souza-Mello V, Gregorio BM, Cardoso-de-Lemos FS, de Carvalho L, Aguila MB,
Mandarim-de-Lacerda CA. Comparative effects of telmisartan, sitagliptin and
metformin alone or in combination on obesity, insulin resistance, and liver and pancreas
remodelling in C57BL/6 mice fed on a very high-fat diet. Clin. Sci. (Lond)
2010;119:239-50.
[250] Yuan L, Li X, Xu GL, Qi CJ. Effects of renin-angiotensin system blockade on islet
function in diabetic rats. J. Endocrinol. Invest. 2010;33:13-9.
[251] Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy
on beta-cell function and glycaemic control in patients with newly diagnosed type 2
diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-60.
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Pancreas: Anatomy, diseases and health implications

Article · September 2012

Eliete Frantz Vanessa Souza-Mello

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PANCREAS: ANATOMY, DISEASES

Eliete Dalla Corte Frantz, Vanessa de Souza-Mello

cultured under suitable conditions, a technique which is commonly used in researches

Nkx - Homeobox protein

The mature pancreas is a bifunctional organ primarily consisting of exocrine tissue

pancreatic hormone-expressing cells developed. Figure 1 summarizes a raft of proposed

ectopic expression specifically in adult pancreatic Pdx1-positive cells resulted in

Later Stage of Pancreatic Development

This aggregation process, termed “isletogenesis”, occurs with a “ribbon-like”

FUNCTIONAL STRUCTURE OF THE PANCREAS

Exocrine Pancreas and Insulin-Acinar Axis

Table 1. Exocrine pancreas: cells and function

Type of cell Secretion Function

On the contrary of exocrine pancreas, endocrine pancreas represents only 2% of total

Table 2. Endocrine pancreas: cells and secretion

Type of cell Secretion Function

Pancreas remodeling includes all features derived from abnormal functioning of

Through analysis of light microscopy can be estimated volume density of steatosis in

Transmission Electron Microscopy

Also by electron microscopy analysis can be evaluated organization of mitochondria,

THE GLUCOSE HOMEOSTASIS AND THE PANCREAS

Insulin plays its role in target organs by phosphorylation of a transmembrane insulin

Glucose Homeostasis and Incretins

Glucose homeostasis is determined by a balance between hepatic glucose production,

Table 3. Metabolic events during fast and postprandial phases

Period Glucagon Insulin Stimulation Inhibition

Insulin Resistance and Metabolic Outcomes

Insulin resistant state is characterized by a combination of factors that include resistance

FETAL PROGRAMMING OF PANCREAS ALTERATIONS

Evidence from Animal Models

Animal models of malnutrition have been established during different periods of

In humans, glucocorticoids are administered during late gestation to treat neonatal

Epigenetics involves molecular mechanisms that promote mitotically or meiotically

Basic Techniques for Pancreatic Research

localization of biomarkers and differentially expressed proteins specimens, either parafﬁn-

Exocrine Pancreas: Intervention Strategies

Although tumor surgical resection, radiotherapy and chemotherapy, alone or in

Pancreatic Cell Isolation and Transplantation

Endocrine Pancreas: Intervention Strategies

[8] Hill D, Lebenthal E. Congenital abnormalities of the exocrine pancreas. In: Go V,

[65] Ma X, Zhang Y, Gromada J, Sewing S, Berggren PO, Buschard K, et al. Glucagon

[101] Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in

mass due to a maternal low-protein or low-energy diet. Diabetologia. 2007;50:2495-

adiposity in offspring of maternal protein-restricted rats. Am. J. Physiol. Endocrinol.

[205] Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, et al.

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