This document discusses the role of epigenetics in type 2 diabetes (T2D). It describes how environmental factors like undernutrition can induce chronic metabolic and hormonal changes through epigenetic mechanisms like DNA methylation and histone modification, enhancing the risk of T2D later in life. Specific genes involved in insulin production and secretion like INS and PPARGC1A show changes in DNA methylation and histone markers in pancreatic cells and tissues of T2D patients. Factors like obesity, diet, exercise and aging can also influence epigenetic changes linked to T2D risk and complications through various mechanisms. While research is still ongoing, epigenetics appears to play an important part in the development and pathology of

1. Epigenetics and Type 2 Diabetes
Fatemeh Shirani
PhD student in Nutrition
shirani_ir@yahoo.com

2. The prevalence of type 2 diabetes.

5. Gelfand EV et al, 2006; Vasudevan AR et al, 2005* working definition

6. (a) In nondiabetic subjects,
insulin suppresses glucose
production from the liver and
stimulates glucose uptake into
skeletal muscle and adipose
tissue.
(b) T2D patients display defects
in insulin secretion in pancreas
and insulin action in target
tissues.
As a result, glucose uptake
decreases and hepatic glucose
production increases
resulting in hyperglycemia.
Pathophysiology of hyperglycemia in T2D

7. Genetics and risk
of developing T2D

9. The Role of Epigenetics
In 1992, Hales and Barker :
Environmental factors experienced in early life may enhance the
risk of T2D in later life.
In particular: under-nutrition and low birth weight
• impaired insulin secretion
• insulin resistance
• relation to adult T2D
Inadequate nutrition: by inducing
Chronic alterations in metabolism
Hormone levels
Cell numbers
contributes to the risk of T2D

10. Molecular Basis of Epigenetics
Two primary mechanisms identified
Methylation of cytosine
nucleotides in DNA
Posttranslational modification
to histone proteins includes
acetylation
methylation
phosphorylation

11. Cytosine Methylation
Methylation of cytosine occurs at
CpG dinucleotides.
Often located just upstream of
genes (promoter regions).
Associated with attenuation of
expression of nearby genes.

12. Histone Modification
• Histones are the proteins that organize the
genetic material.
• Have a high percentage of basic amino acids,
which gives histones an overall positive
charge.
• Positively charged amino acids associate
with the overall negative charge of the DNA.

13. Histone Modification
• Most histone modification occurs on the
extended tails of histone proteins.
• Modifications influence the association of
histones with the DNA and patterns of gene
expression.
• Best studied modification is histone acetylation.

14. The regulation of insulin (INS) gene expression
INS gene in human pancreatic islets:
Active genes including:
These patterns of histone modifications are not present in other
cell types.
CpG sites INS promoter are demethylated in insulin-producing
beta cells.
hyperacetylation of histone 4 (H4)
dimethylation of H3K4 (H3K4me2)
Methylation of CpG sites INS promoter
suppresses insulin gene expression

15. Data-mining analysis suggests an epigenetic
pathogenesis for type 2 diabetes.
J Biomed Biotechnol. 2005;2005(2):104-112.
Methylation and chromatin are top hits, implicitly related to T2D.
Common phenotypes involved in the onset and pathology of T2D:
changes in DNA methylation
S-adenosylmethionine, the main physiological donor of methyl groups,
was decreased in the erythrocytes of patients with T2D.
Treatment with S-adenosylmethionine improves insulin sensitivity in rats
an increase in skeletal muscle mitochondrial DNA density

16. Peroxisome proliferator-activated receptor gamma
coactivator 1 alpha (PGC-1a)
encoded by PPARGC1A)
• A transcriptional coactivator of mitochondrial genes involved in
normal ATP-production and insulin secretion from the pancreatic
beta cells.
• DNA methylation is increased in a promoter region of
PPARGC1A in pancreatic islets from patients with T2D
• Increase in DNA methylation correlates with a decrease in
PPARGC1A mRNA expression

17. PPARGC1A expression
positively correlated with
glucose-stimulated insulin
secretion.
In skeletal muscle from patients with T2D, an
increase in DNA methylation parallels
a decrease in PPARGC1A mRNA expression
and mitochondrial content with a high
proportion of non-CpG methylation in the
region of the promoter of PPARGCIA.

18. Aging, Type 2 Diabetes,
and Epigenetic Changes

19. The Role of Nutrition and Obesity
in Epigenetics of Type 2 Diabetes
• Obesity and diet are important factors in the susceptibility to T2D
• Boys whose mothers were exposed to famine in early and mid gestation
during the Dutch Hunger Winter had twice the rate of obesity over controls.
• Prenatal famine exposure is related to increases in fasting pro-insulin and
insulin concentrations at 120 min in the OGTT, an association with
insulin resistance.
• Offspring of mothers with diet-treated gestational diabetes or type 1 diabetes
(T1D) have an increased risk of the metabolic syndrome, central obesity,
high plasma triglycerides, and high blood pressure, symptoms associated
with increased risk of cardiovascular disease and T2D

20. Offspring were heavier, fatter,
insulin-resistant, and had an
altered immune response to
allergenic challenges

21. Encoded by the LEP gene, is a hormone that regulates
energy uptake and expenditure
Primarily expressed in differentiated adipocytes of
white adipose tissue.
DNA methylation in the Lep promoter is modulated by
high-fat diet–induced obesity in rats.
LEPTIN:

23. Exercise and Epigenetics
Skeletal muscle cells take up glucose through an insulin-
dependent translocation of the glucose transporter GLUT4.
In acute exercise: transcription of GLUT4 increases
as does GLUT4 protein expression.
The promoter of GLUT4 contains a transcription factor–
binding site for the myocyte enhancer factor 2 (MEF2)
MEF2 is critical for regulation of GLUT4 expression

24. In the resting state
HDAC5 is associated with
MEF2, which inhibits
GLUT4mRNA expression(a).
With exercise
AMPK is activated and
relocates into the nucleus.
This leads to phosphorylation
and removal of HDAC5 from
the nucleus and enables PGC-
1ato bind to MEF2 and attract
HATs to MEF2.
This in turn stimulates MEF2
activity and results in
increased GLUT4mRNA
expression(b).
The effect of exercise on mRNA expression of
GLUT4

25. Diabetic Complications
and Epigenetic Changes
Vascular inflammation and increased expression of
inflammatory genes are major events in the progression
of diabetic complications.
The transcription factor nuclear factor k-B (NF-kB) regulates
expression of genes involved in inflammatory diseases including
diabetic complications and atherosclerosis.
Hyperg lycemia induces NF-kB activity and expression of
proinflammatory cytokines in monocytes.

26. Based on current knowledge, it is evident that epigenetic
mechanisms play an important role in the pathogenesis of
T2D and its complications. However, we are still only
beginning to comprehend which and how epigenetic factors
affect T2D