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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