Epigenetics and type 2 diabetes

Epigenetics and Type 2 Diabetes

Fatemeh ShiraniPhD student in Nutrition

[email protected]

The prevalence of type 2 diabetes.

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

(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 increasesresulting in hyperglycemia.

Pathophysiology of hyperglycemia in T2D

Genetics and risk of developing T2D

The Role of EpigeneticsIn 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 T2DInadequate nutrition: by inducing

Chronic alterations in metabolismHormone levelsCell numbers

contributes to the risk of T2D

Molecular Basis of Epigenetics

Two primary mechanisms identified

Methylation of cytosine

nucleotides in DNA

Posttranslational modification

to histone proteins includes

acetylation

methylation

phosphorylation

Cytosine MethylationMethylation of cytosine occurs at

CpG dinucleotides.Often located just upstream of genes (promoter regions).Associated with attenuation of expression of nearby genes.

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.

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.

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 promotersuppresses insulin gene expression

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

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

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.

Aging, Type 2 Diabetes, and Epigenetic Changes

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

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

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:

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

In the resting stateHDAC5 is associated with

MEF2, which inhibits GLUT4mRNA expression(a).

With exerciseAMPK is activated and

relocates into the nucleus. This leads to phosphorylationand 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

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.

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