Don't Blame your Gene: The origin of diabetes

Sep 3rd 2009
From The Economist print edition

GENES are acquired at conception and carried to the grave. But the same gene can be expressed differently in different people—or at different times during an individual’s life. The differences are the result of what are known as epigenetic marks, chemicals such as methyl groups that are sometimes attached to a gene to tell it to turn out more of a vital protein, or to stop making that protein altogether.

Many researchers believe epigenetic marks hold the key to understanding, and eventually preventing, a number of diseases—and one whose epigenetic origins they are particularly interested in is type 2, or late-onset, diabetes. Juleen Zierath and her colleagues at the Karolinska Institute in Stockholm, Sweden, are trying to find out how people develop insulin resistance, the underlying cause of type 2 diabetes.

Insulin is a hormone produced by the pancreas. When all is going well, it lets cells know when they need to mop up glucose from the blood, usually just after a person has eaten. If the hormone is absent or is produced in insufficient quantities because of damage to the pancreatic cells that secrete it, the result is classical (or type 1) diabetes. But people with insulin resistance—and thus the late-onset version of the disease—do produce insulin. Their problem is that their glucose-absorbing cells cannot heed its advice. The sugar stays in their bloodstreams, where it damages the vessels, leading to ailments such as heart disease, kidney failure and blindness.

As they report in Cell Metabolism, Dr Zierath and her team decided to look at one of the main consumers of glucose: muscle tissue. They took muscle biopsies from 17 healthy people, 17 people with type 2 diabetes and eight people with early signs of insulin resistance, so-called “pre-diabetics” . They then compared the patterns of the methyl groups attached to the genes of the healthy volunteers with those of the diabetic and pre-diabetic ones.

As it turned out, they found hundreds of genes in which the patterns differed systematically, so to whittle the problem down they concentrated on those involved in the function of the mitochondria. These are the components of a cell that extract energy from glucose and use it to manufacture a chemical called ATP, which is the universal fuel of biological processes. Having fewer or less effective mitochondria causes a drop in demand for glucose, and might thus cause a cell to become insulin resistant.

Even narrowing the question down like this, though, left 44 genes to look at. Of these, Dr Zierath and her team picked one called PGC-1 alpha for further study. This gene is involved in the development of mitochondria, and the extra epigenetic marks the researchers found on it in diabetics and pre-diabetics had the effect of instructing the cells the marked genes were located in to produce fewer and smaller mitochondria than is normal.

The next question was how those marks got there. It is well known that poor diet and lack of exercise make insulin resistance more likely, so one hypothesis is that these things change the epigenetic marks on genes such as PGC-1 alpha. To test that idea, the researchers bathed cells in glucose and fats (chosen as surrogates for bad diet and lack of exercise for obvious reasons) and also in inflammation- producing proteins called cytokines. These proteins, they knew, are produced abundantly in the obese. And obesity, the consequence of bad diet and lack of exercise, is another risk factor for type 2 diabetes. Lo and behold, doses of both fats and cytokines caused PGC-1 alpha to be methylated.

Next, Dr Zierath wanted to know if she could prevent that. So, this time, before bathing the healthy cells in fats or cytokines, the team added a chemical that blocks the activity of DNMT3B, an enzyme which they found methylates PGC-1 alpha. When that was done, no extra methyl groups appeared.

These findings have two interesting implications. First, the fact the team was able to stop PGC-1 alpha being methylated suggests that a drug might be developed to do the same. Second, they show that bodily abuse can stretch all the way down to the genetic level. As Dr Zierath puts it, “we are not victims of our genes. If anything, our genes are victims of us.”

Don't blame your genes. They may be simply getting bad instructions -- from you.

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