Feature: Epigenetics and diabetes

Even many years after successful therapy, lifestyle and dietary changes to reduce high blood-glucose levels, some Type 2 (non-insulin-dependent) diabetics continue to suffer diabetes-like health problems and poor quality of life. It is as if diabetics’ cardiovascular responses become habituated to the individual’s formerly excessive blood-glucose levels.

The phenomenon of ‘glycaemic memory’ has long puzzled diabetes clinicians and researchers. Now, researchers at the Baker Heart and International Diabetes Institute (Baker IDI) have made a crucial advance that explains how exposure to high blood-glucose levels drives epigenetic changes that underlie the syndrome. The new understanding of the mechanisms involved suggests the syndrome could be treated with novel therapies to reverse the epigenetic changes.

Glycaemic memory syndrome involves a variety of cardiovascular problems normally associated with chronically high blood glucose levels and insulin resistance. They include heart attack, stroke, atherosclerosis, kidney failure, vision loss due to diabetic retinopathy, memory loss, cognitive problems and mood disorders. But the underlying cause of the syndrome has only recently begun to come to light.

In 2008, Baker IDI’s scientific executive officer, physician Dr Mark Cooper, and Professor Assam El-Osta, head of human epigenetics, published a paper in the Journal of Experimental Medicine showing that transient high blood glucose levels induced persistent methylation-mediated epigenetic changes in the cells lining the aorta. It was the first indication that epigenetic mechanisms caused glycaemic memory.

As a complement to their human aortic tissue study, Cooper and Dr Ana Calkin took plaque samples from 30 atherosclerotic mice. Half had been exposed to high blood glucose levels to induce Type 2 diabetes, while the rest had been fed a high-fat diet but were maintained at normal blood-glucose levels. Gene expression patterns in atherosclerotic plaques and plasma lipid from the aortas of the diabetic mice were strongly concordant with the in vitro glucose-response patterns in epithelial cells from human aortas and diabetic patient lipid patterns, respectfully. Haviv believes the lipids capture some of the signalling cascades that lead to the epigenetic changes we observe in the human patients.

Methylation types

Two types of methylation occur, says Haviv. One involves methylation of CpG islands – sites with extended C-G base-pair repeats – that are relatively unresponsive to environmental cues. “CpG island methylation is more tightly regulated during replication and causes relatively irreversible changes – the cell commits to some function and doesn’t lose this silencing mark again. The other mechanism is gene silencing by post-translational modification of histone proteins, particularly H3 and H4.”

The basic structural unit of chromatin is the nucleosome, a segment of DNA wound around a core of histone protein. According to Haviv, up to 70 amino acids in the amino terminals of histones H3 and H4 are actually redundant to the nucleosome’s structure, but essential for regulating the genes in that region of the genome.

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