Beta cells de-differentiation and trans-differentiation

Introduction

Type I Diabetes Mellitus(T1D) is characterized by autoimmune mediated β ell death while Type 2
diabetes(T2D) involves peripheral insulin resistance, Beta cell dysfunction and Apoptosis. Pancreatic
β cells are unable to secrete insulin due to a complete loss of functional β cells in T1D and due to
peripheral insulin resistance in T2D. It was believed until 1999 that the cause of deficit in β cell mass
is beta cell death (~ 90% in long-standing T1D ~ 65% in long-standing T2D). But this theory was
confronted by performing many studies in animal models and stated that rather than β cell death,
the deficit in β cell mass is due to β cell dedifferentiation or trans differentiation.

Dedifferentiation

In this process there is no programmed cell death of β cells & they revert to a less developed or even
progenitor -like state. This results in shortage in number and loss of function/identity which leads to
reduction of “functional β cell mass” & hence there will be no insulin secretion.

Transdifferentiation

In this process the mature β cells converts into another mature cells without returning backwards
towards primitive precursor-like state and β cells transforms into other pancreatic endocrine cell
types such as α cells and δ cells.

Transcription

The synthesis of RNA from DNA is called transcription and it is catalyzed by the enzyme RNA
Polymerase. It requires transcription factors (additional protenis required to initiate transcription).

Mechanism of diabetic β-cell failure due to Pancreatic β-cell dedifferentiation

Following two Mechanisms are involved in the process of dedifferentiation.

1.there is Down-regulation of β-cell-augmented genes e.g. those genes having βcell-specific

transcription factors, the surface glucose transporters, and proteins involved in glucose and insulin
synthesis metabolism.

2.There is Up-regulation of those genes which are low in the expression of normal βcells or
“forbidden” genes.

These two mechanisms result in loss of essential β-cell function i.e. synthesis and secretion of
insulin which is the key reason of both T1D and T2D.
Dedifferentiation of β-cell in human and mouse pancreatic islet due to pathophysiological
conditions

β-cells are soft and pliable and may dedifferentiate in poorly controlled diabetic human patients
who suffer from long duration of hyperglycemia.

Animal studies which have been done on T2D mouse models such as db/db mice and in those mouse
models in which 90 % partial pancreatectomy (PPx) was done, β-cells did suffer from
dedifferentiation which was also characterized by downregulation of many genes such as PDX1 and
MAF BZIP Transcription Factor A (MafA).

KATP Channel Mutation & FoxO1 knockout mice

One study was performed on, mice who had a gain-off function mutation in inward rectifier
potassium channel 6.2 (Kir6.2) which is a gene encoding a component of the KATP channel exhibited
upregulation of of Ngn3 and downregulation of insulin gene expression in β-cells

One another study was performed on FoxO1 knockout mice who was underage and had multiple
pregnancies and it showed β-cell dedifferentiation and it exhibited upregulation of islet progenitor
cell markers such as Ngn3, Oct4, Nanog, and L-Myc.

forkhead box O1 (FOXO1) transcription factor

FOXO1, by controlling critical transcription factors, such as NGN3 and NKX6-1, impairs beta cell
differentiation in the human fetal pancreas by negative feedback mechanism. The development of
T2D in humans involves β-cell dedifferentiation to Ngn3-like precursor cells and trans differentiation
to other endocrine gland cells.

Obesity and β-cell dedifferentiation

A study was performed in human T2D patients which showed endocrine precursor cell marker,
aldehyde dehydrogenase 1A3 (ALDH1A3 so Immunostaining of the pancreas in mice was done with
antibodies to ALDH1A3 and FoxO1 and also mice was fed 13 weeks high-fat diet (HFD) showed signs
of β-cell dedifferentiation but not in low-fatdiet (LFD) mice , which strongly proposes a relationship
between obesity and β-cell dedifferentiation.

β-cell dedifferentiation in human T2D patients

A study was conducted for β-cell dedifferentiation on islets from 15 diabetic human T2D patients and
15 nondiabetic organ donors by using markers of endocrine ancestry, β-cellspecific TFs, and the
endocrine precursor cell marker, ALDH1A3 and it showed that pancreatic β-cells were
dedifferentiated and transformed into α- and δ- “like” cells in human T2D.

Mechanisms that trigger β-cell dedifferentiation

In another study on db/db mice chronic hyperglycaemia was induced independent of plasma fatty
acid levels, resulted in β-cell dedifferentiation. Without affecting blood lipid levels, hyperglycaemia
was reverted to normoglycaemia by using phlorizin with reinstated islet gene expression and normal
β-cell mass, signifying that hyperglycaemia activates β-cell dedifferentiation

β-cell dedifferentiation by Glucotoxicity

β-cell dedifferentiation is caused by Glucotoxicity through oxidative stress. The accumulation

of Reactive oxygen species in β-cells due to oxidative stress has resulted in downregulation
of β-cell TFs for instance PDX1 and MafA which ultimately led to decreased insulin synthesis

β-cell dedifferentiation due to Endoplasmic reticulum stress

endoplasmic reticulum stress induced by islet inflammation resulted in β-cell

dedifferentiation which showed degranulated β-cells in non-obese diabetic (NOD) mice.

Hedgehog (Hh) signaling

β-cell function and insulin secretion are impaired by Increased Hh signaling.

 Activation of Renin-angiotensin system

β-cell dedifferentiation is caused by The Renin-angiotensin system (RAS) activation which

resulted in decreased insulin secretion via NF-κB signaling leads to β-cell failure.

Is it possible to avoid or reverse β-cell dedifferentiation?

Weight reduction and lifestyle modification can result in lessening in pancreatic fat in those
patients in whom β-cell dedifferentiation was induced by Chronic overnutrition.

Pairfeeding has reversed β-cell dedifferentiation in db/db mice, with upregulation of

FoxO1and downregulation of ALDH1A3. Pair-feeding reduced serum lipid levels, which may
be the main cause behind reversal of β-cell dedifferentiation.

The longterm caloric restriction (CR) intervention in db/db mice meaningfully decreased β-
cell dedifferentiation and it was linked with upregulation of PDX1, Glut2& MafA .

A study done on Goto-Kakizaki (GK) rats, a non-obese spontaneous T2DM model, showed
decreased dedifferentiation of pancreatic β-cells after Roux-en-Y gastric bypass surgery
(RYGB) surgery, indicating a weight loss-independent factor of βcell dedifferentiation.

In some Lineage-tracing experiments dedifferentiated β-cells redifferentiated to mature

insulin-positive β-cells after treatment with chronic insulin.

Notch signaling is reactivated during dedifferentiation. So, suppressing Notch will reduce β-
cell dedifferentiation.

β- cell number can be improved by inhibiting the dopamine signal. And MicroRNAs has role
in the conservation of adult β-cell identity

Transdifferentiation of pancreatic β-cell

It’s a process in which a mature endocrine cell converts into another mature cell type
without returning backwards towards a primitive precursor-like state.

Following three factors promote reprogramming. Extreme physical injury, chemical stresses
and genetic mutations.

How transdifferentiation can be done between α- and β-cells int pancreatic islets

α-cells transformed into β cells after Pancreatic duct ligation (PDL) and partial
pancreatectomy (PPx) in mice.

Transdifferentiation of - α-cells into cells was also seen in human pancreas and it showed
upregulation of PDX1, PAX4 and MafA.

Glucagon-like peptide-1 (GLP-1) has transformed α-to-βcells in mice

In one study Arx in α cells was deleted due to which α cells transformed into β cells

Can duct cells transform into β-cells?

Duct cells transformed into β cells after Pancreatic duct ligation (PDL) and partial
pancreatectomy (PPx) in mice.

Adult mouse pancreatic duct cells can be transdifferentiated into β-cells by the induction of
transgenic over-expression of interferon-γ (IFN-γ), co-expression of two growth factors
gastrin and transforming growth factor α (TGFα) in the duct cells, or hepatic upregulation of
the cytokine TNF-like weak inducer of apoptosis (TWEAK).

Conversion of duct cells into β-like cells in mice have been seen after upregulation of Ngn3,
MafA and PDX1.

Transdifferentiation of acinar cells into β-cell

Acinar cells are transformed into β cells after Pancreatic duct ligation (PDL) and partial
pancreatectomy (PPx) in mice.

Acinar cells can be converted into functional β-cells by upregulation of PDX1, Ngn3 and MafA
.

β cells can be cultured by transdifferentiation of pancreatic acinar cells by induction of

epidermal growth factor (EGF) along with ciliary neurotrophic factor (CNTF), nicotinamide
and leukemia inhibitory factor (LIF).

Transdifferentiation from acinar cells into β-cells in humans

It is possible to convert Acinar cells into β-cells in human pancreas if we treat acinar cells
with EGF or activate the signal transducer and activator of transcription 3 (STAT3) and
mitogen-activated protein kinase (MAPK).

Transdifferentiation of hepatocytes to β-cells

The upregulation of PDX1 and Ngn3 through the induction of platelet-derived growth factor
(PDGF) has been seen in the transdifferentiation of hepatocytes into β-cells .

PDX1 and soluble factors EGF can be used to convert human hepatocytes to functional β
cells.