CELLULAR MECHANISMS

OF DIABETES MELLITUS
t
TYPES OF DIABETES MELLITUS
Mainly there are 2 types of diabetes mellitus

• Type 1 diabetes mellitus

• Type 2 diabetes mellitus

TYPE 1 DIABETES MELLITUS
 It is also called insulin dependent diabetes
mellitus.
 It is characterized by pancreatic beta cell

destruction and insulin deficiency.

 Mostly occur in children and young adults.
 More specifically, type 1 DM patients with a

disease onset at age 0 to 14 years and within 1

year of diagnosis show more inflamed islets
(68%) and fewer islets with residual beta cells
(39%) than in patients with onset at 15 to 39
years of age.
TYPE 2 DIABETES MELLITUS
 It is also called adult onset or non insulin
dependent diabetes mellitus.

 Mostly that is characterized by high blood

sugar, insulin resistance, and impaired
insulin secretion
DIFFERENCE BETWEEN
TYPE 1 AND TYPE 2
DIABETES
MELLITUS
TYPE 1 DM
 Autoimmune destruction of
B cells
 Insulin is always necessary
in treatment.
 Age: <30 years.
 Association with obesity:
NO.
 GENETIC
PREDISPOSITION:relatively
weak(50% concordance in
identical twins),polygenic.
 Associated with HLA-DR3
and HLA-DR4.
TYPE 2 DM
 Increase resistance to
insulin,progressive
pancreatic B cell failure.
 Insulin is sometimes
necessary in treatment.
 Age: >40 years.
 Association with obesity:
YES.
 GENETIC
PREDISPOSITION:relatively
strong(90% concordance in
twins),polygenic.
 No any association with
genetic presdisposition.
T
 Glucose intolerence is
severe
 Insulin sensitivity is high.
 Ketoacidosis is common.
 B-cell numbers in the islets
decrease.
 Serum insulin level
decrease’.
 Clinical symptoms of
polyuria,polydipsia,polypha
gia and weight loss is
common.
 HISTOLOGY: islets
leukocytic infiltrate.
 Glucose intolerence is mild
to moderate.
 Insulin sensitivity is low.
 Ketoacidosis is rare.
 B-cells numbers in the
islets variable(with
lymphoid deposition).
 Serum insulin level is
variable.
 Clinical symptoms of
polyuria,polydipsia,polypha
gia and weight loss is
sometimes.
 HISTOLOGY: islet amyloid
polypeptide(IAPP) deposits.
 CELLULAR
MECHANISM
OF
TYPE 1
DIABETES MELLITUS
It is catabolic disorder in which
circulating insulin is virtually absent,
plasma glucagon is increased, and
pancreatic b cells fails to respond to all
insulogenic stimuli. so exogenous insulin
is required to reverse catabolic
state,prevent ketosis,reduce
hyperglycemia, and decrease blood
glucose.
 Beta cell mass then begins to decrease, and insulin
secretion progressively declines, although normal glucose
tolerance is maintained. The rate of decline in beta cell
mass varies widely among individuals, with some
patients progressing rapidly to clinical diabetes and
others evolving more slowly. Features of diabetes do not
become evident until a majority of beta cells are
destroyed (70–80%). At this point, residual functional beta
cells exist but are insufficient in number to maintain
glucose tolerance. The events that trigger the transition
from glucose intolerance to frank diabetes are often
associated with increased insulin requirements, as might
occur during infections or puberty.
Type 1 diabetes mellitus is a result of
interaction of

. Genetic factors
. Immunologic factors
. Environmental factors
GENETIC FACTORS
The major susceptibility gene for type 1DM is
located in HLA gene on chromosome 6.
polymorphism in HLA complex account for
40-50% of the genetic risk of developing type
1 DM. this region contain genes that encode
the class 11 major histocompitability
complex (MHC) molecules, which present
antigen to helper T cells and thus are involves
in initiating the immune response
 Most individuals with type 1 DM have the
HLA DR3 and/or DR4 haplotype.
Refinements in genotyping of HLA loci have
shown that the haplotypes DQA1*0301,
DQB1*0302, and DQB1*0201 are most
strongly associated with type 1 Dm
 The risk of TID among offspring ranges

from 2% to 4% if the mother was affected.

Compared to 6% to9% if father was affected
and risk tolls to 30% when both parents are
affected.
 The pancreatic islets have a modest infiltration
of lymphocytes (a process termed insulitis). After
beta cells are destroyed, it is thought that the
inflammatory process abates and the islets
become atrophic. Studies of the autoimmune
process of type 1 DM have identified the
following abnormalities in the humoral and
cellular arms of the immune system:
 (1) islet cell autoantibodies.
 (2) activated lymphocytes in the islets,

peripancreatic lymph nodes, and systemic

circulation;
 (3) T lymphocytes that proliferate when

stimulated with islet proteins

 (4) release of cytokines within the insulitis.
INDUCTION
AND
PROGRESSION
OF INSULITIS.
THE COLLABORATION
BETWEEN
MACROPHAGES AND T
CELLS IN THE
DESTRUCTION OF
PANCREATIC Β CELLS.
molecules expressed by
pancreatic β-cells involved
in their destruction
or protection.
REGULATORY T CELLS
THAT HAVE LOST
FOXP3 EXPRESSION
MAY CONTRIBUTE TO
AUTOIMMUNE DISEASE.
 CELLULAR
MECHANISM
OF

TYPE 1 DIABETES
MELLITUS
TYPE 2 DIABETES MELLITUS
 insulin resistance develops as a consequence of the effects of
inflammatory and hormonal factors, endoplasmic retiulum (ER)
stress, and accumulation of by-products of nutritional
‘overload’ in insulin-sensing tissues.
 the triggering factor for the transition from an obese, insulin-
resistant state to full-blown type2 diabetes is β-cell failure,
which involves both a partial loss of β-cell mass and a
deterioration of β-cell function.
 ]
Insulin resistance, which is the inability of cells to respond
adequately to normal levels of insulin, occurs primarily within
the muscles, liver, and fat tissue.[43] In the liver, insulin normally
suppresses glucose release. However, in the setting of insulin
resistance, the liver inappropriately releases glucose into the
blood.
MECHANISM OF INSULIN RESISTANCE
 insulin resistance is a direct consequence of obesity-
associated exposure of tissues to elevated dietary nutrients,
resulting in the accumulation of toxic metabolic by-products.
 These effects can be explained in part by their common
ability to activate 5′-AMP-activated protein kinase (AMPK)6,
an enzyme that responds to a fall in ATP and a rise in AMP
levels by activating both glucose and fatty acid oxidation.
Interestingly, leptin levels are increased and adiponectin
levels are decreased in insulin-resistant obese humans and
animals, which suggests that obesity leads to a state of leptin
resistance and adiponectin deficiency.Mice with an adipose-
specific knockout of the GluT4glucose transporter have
impaired insulin sensitivity in muscle and liver13
 . High-fat diets or obesity result in activation of the transcription
factor nF-κB.
.overexpression of a consti-tutively active version of the nF-κB-
activating kinase, IκB kinase catalytic subunit-β(IKKβ), in the liver of
normal rodents results in liver and muscle insulin resistance and
diabetes
 . In rodents, macrophage infiltration of adipose tissue is stimulated

within 1week of high-fat feeding and appears to involve increased

adipocyte expression of monocyte chemotactic protein-1 (McP1),
which recruits monocytes to sites of injury and infection23,24. This
may be a mechanism by which inflammatory signalling is enhanced
during the development of diabetes. overall, evidence is accumulating
that insulin resistance is at least partly caused by changes in hormone
and cytokine production by the liver, adipose tissue and infiltrating
immune cells in response to chronic exposure to lipids and other
metabolic fuels.
lipid-derived metabolites begin to accumulate
outside of the adipose depots(including skeletal
muscle, heart and liver) in response to high-fat
diets and the onset of obesity.
METABOLIC
OVERLOAD IN THE
LIVER AND
SKELETAL MUSCLE
Mechanisms of β‑cell
failure in type 2
diabetes
CELLULAR
MECHANISM
OF

TYPE 1 DIABETES
MELLITUS
 Insulin secretion isinadequate to compensate for the insulin resistance,
leading to hyperglycemia that is detected by routine glucose screening in
pregnancy. Thus, chronic insulin resistance is a central component of the
pathophysiology of GDM.Human pregnancy is characterized by a series of
metabolic changes that promote adipose tissue accretion in early
gestation,followed by insulin resistance and facilitated lipolysis in late
pregnancy. In early pregnancy, insulin secretion increases,while insulin
sensitivity is unchanged, decreased or may even increase. (1) However,in late
gestation, maternal adipose tissue depots decline, while postprandial free
fatty acid (FFA) levels increase and insulin-mediated glucose disposal
worsens by 40–60% compared with prepregnancy (2).The ability of insulin to
suppress wholebody lipolysis is also reduced during late pregnancy (3), and
this is further reduced in GDM subjects (4), contributing to greater
postprandial increases in FFAs, increased hepatic glucose production, and
severe insulin resistance (2,5–7). Although various placental hormones have
been suggested to reprogram maternal physiology to meet fetal needs, the
cellular mechanisms for this complex transition remain obscure (8). Further,
the critical molecular mechanisms involved in increasing maternal lipid flux
in obese women throughout pregnancy that may underlie skeletal muscle
insulin resistance and increased fetal fuels are just beginning to be
investigated.
 PLACENTAL HORMONES AND ADIPOKINES IN THE INSULIN
RESISTANCE OF PREGNANCY
 Placentalderived hormones are believed to be a major factor in
reprogramming maternal physiology to achieve an insulin-
resistant state. Human placental lactogen (hPL) increases up to
30-fold throughout pregnancyand induces insulin release from
the pancreas in pregnancy (11). Studies outside of pregnancy
indicate that hPL can cause peripheral insulin resistance(12),
although the results have been variable (13). Another hormone
recently implicated in the insulin resistance of pregnancy is
human placental growth hormone (hPGH), which differs from
pituitary growth hormone by 13 amino acids.hPGH increases six-
to eightfold during gestation and replaces normal pituitary growth
hormone in the maternal circulation by 20 weeks’ gestation
(8).Much like the well-documented effects of excess pituitary
growth hormone on insulin sensitivity, overexpression of hPGH in
transgenic mice comparable to levels seen in the third trimester
of pregnancy causes severe peripheral insulin resistance
evidence has shown that an important effect of hPGH is to
specifically increase the expression of the p85 subunit of
phosphatidylinositol(PI) 3-kinase in skeletal
muscle. Studies in pregnant and nonpregnant humans indicate that
increases in the p85 subunit of PI 3-kinase acts as a dominant-
negative competitor to
forming a PI 3-kinase heterodimer with the p110 subunit, thereby
inhibiting PI 3-kinase activity and preventing furtherinsulin signaling
downstream
 Recent prospective studies have implicated
 adiponectin from adipocytes and secreted factors, such as
TNF-, as active candidates in mediating insulin resistance of
pregnancy. Collectively, these factors,known as “adipokines,”
include leptin,adiponectin, TNF-, interleukin-6, resistin,and
others. TNF- is a cytokine, produced not only from
monocytes and macrophages, but also from T-cells,
neutrophils,fibroblasts, and adipocytes.
 TNF- impairs insulin signaling by increasing serine
phosphorylation of insulin receptor substrate (IRS)-1 (18,19)
and diminishing insulin receptor (IR) tyrosine kinase activity
 Studies in pregnancy have reported that changes in insulin
sensitivity from early (22–24 weeks) to late (34 –36 weeks)
gestation correlate with plasma TNF and that circulating TNF-
may be produced by the placenta and skeletal muscle to induce
or exacerbate insulin resistance through mechanisms that remain
to be determined.
 Increasing adiposity is correlated with the secretion of
proinflammatory cytokines from adipose tissue.
 Recent findings also show that adiponectin secretion and
adiponectin mRNA levels in white adipose tissue decline with
advancing gestation, even in lean women , suggesting that
there are pregnancy associated factors that reduce adiponectin
levels. Circulating levels of adiponectin have been shown to
correlate with whole body insulin sensitivity, presumably
working though adiponectin receptors in skeletal muscle and
liver (34). Adiponectin stimulates glucose uptake in skeletal
muscle and reduces hepatic glucose production through its
effect on AMP activated protein kinase. Thus, adiponectin can
be viewed as an endogenous insulin-sensitizing hormone.
Several studies have demonstrated that, similar to obese
patients and type 2 diabetic patients, adiponectin levels are
reduced in former GDM patients and are lower in GDM women
during late pregnancy compared with pregnant control subjects
matched for BMI (37–40). TNF- and other proinflammatory
mediators suppress the transcription of adiponectin in
adipocytes , which might explain the lower levels of serum
adiponectin in individuals with GDM
potential mechanisms for
insulin resistance in skeletal
muscle during late
pregnancy in human
gestational diabetes
COMPLICATIONS OF DIABETES MELLITUS

Vascular Non-vascular

Micrvascular Macrovascular
a. Microvascular.
  1. Eye disease
    Retinopathy (nonproliferative/proliferative)
    Macular edema
 2.  Neuropathy
    Sensory and motor (mono- and polyneuropathy) 1. Vascular
    Autonomic
  3. Nephropathy
b. Macrovascular.
  1. Coronary artery disease
  2. Peripheral arterial disease
  3. Cerebrovascular disease
2. Other Non vascular.
  1. Gastrointestinal (Gastroparesis, Diarrhea)
  2. Genitourinary (Uropathy/Sexual Dysfunction)
  3. Dermatologic
  4. Infectious
  5. Cataracts
  6. Glaucoma
  7. Periodontal disease
POLYOL
PATHWAY
HEXOSAMINE
PATHWAY
PROTEIN KINASE C
PKC PATHWAY
ADVANCED
GLYCOSYLATED END
PRODUCTS (AGE)
PATHWAY
The enediol pathway
Oxidative stress
 BCQ’s
1) Major susceptibility gene for type 1 DM is
located in the HLA region on

1) chromosome 6
2) Chromosome 9
3) Chromosome 10
4) Chromosome 8
5) Chromosome 2
 2) During induction progression insulitis
which protein will decrease insulin secretion?

 A) PDx1
 B) PDX2
 C) PDX3
 D) PDX4
 E) PDX5
 In which pathway glucose is converted to
sorbitol?

 1.hexosamine pathway
 2.Enediol pathway
 3.pKc pathway
 4.polyol pathway
 5.oxidative stress
 P85-p11o complex is formed in?

 1. type 1 DM
 2. type 2 DM
 3. Gestational DM
 4.diabetic ketoacidosis
 Which cofactor will cause glucotoxicity in
polyol pathway?

 1. NADPH
 2.NADP
 3.NAD
 4.NADH
 5.FADH