Joslin Diabetes Center Research | Diabetes and Genetics
by C. Ronald Kahn, M.D., President and Director, Joslin Diabetes Center; Mary K. Iacocca Professor of Medicine at Harvard Medical School
With the growing worldwide epidemic of diabetes, a key question is to what extent is diabetes in our genes and to what extent is it due to changes in our environment? For the parent of a child with diabetes, the questions are more personal: Why does my child have diabetes? No one in my family has it. Did I do something wrong? Does diabetes skip a generation?
Diabetes is often described as a geneticists nightmare because the disease occurs in multiple forms, involves interactions between genes and the environment, and is so complex. Type 1 (insulin-dependent) diabetes is an autoimmune disease in which the immune system destroys the insulin-producing beta cells of the pancreas. This process is controlled by a number of genes, the most important of which are the genes regulating the immune system. These genes, called MHC genes, create the risk for diabetes, but not diabetes itself. About 40% of people in the U.S. carry one or more of these risk genes, but only about one out of 100 in this category (about 0.4% of the U.S. population) will actually develop the disease. This reflects the fact that there are likely one or more environmental factors that trigger diabetes in these genetically susceptible individuals.
What exactly these environmental factors are remains unknown. Recent evidence from the BabyDiab study in Germany and the DAISY study in the U.S. suggests that there may be some early dietary factor, since there is a correlation between diabetes and early introduction of cereals and other foods into the diet of infants at genetic risk of the disease. Other possible environmental triggers under study are viruses or environmental toxins. Since the incidence of developing type 1 diabetes is increasing in westernized societies, identifying these triggers is important. The autoimmune process in type 1 diabetes often starts years prior to the clinical presentation of the disease, however, making these environmental triggers difficult to detect. As a result of this complex interaction, even though most children will inherit genes that create the risk of diabetes, only about 7% of children with diabetes have a parent or sibling with the disease, giving the appearance that diabetes skips a generation.
One interesting aspect of the genetics of type 1 diabetes demonstrated by researchers at Joslin Diabetes Center is that offspring of mothers with type 1 diabetes have a much lower risk of developing type 1 diabetes than offspring of fathers with the disease (2% for mothers vs. 7% for fathers) or the siblings of people with type 1 diabetes. This appears to be due to something protective about the uterine environment in the mother with diabetes. More than 90% of people with diabetes have the type 2 form of the disease. It is this form that also accounts for the current epidemic of the disease, which, in the U.S., now affects more than 18 million people, a number that is increasing by almost one million per year. Type 2 diabetes is also linked to other common metabolic problems, including obesity; hypertension; blood lipid abnormalities; and accelerated atherosclerosis, in what is often referred to as the metabolic syndrome, or Syndrome X.
Type 2 diabetes has the greatest genetic influence and the most complicated genetics. While in a low percentage of families there may be a single genetic defect leading to type 2 diabetes, in most individuals type 2 diabetes is both polygenic and heterogeneous. This means that type 2 diabetes requires the interaction of two or more genes (polygenic), and in different individuals the genes involved can be different (heterogeneous). Furthermore, in contrast to type 1 diabetes, the most important or most common genes in type 2 diabetes have not yet been identified. What is clear is that offspring of parents with type 2 diabetes have a greater than 20% risk of developing the disease, and if both parents have type 2 diabetes, the risk is more than 50%.
Several approaches are used by scientists to try to identify the genes for this disease. One approach is to use techniques to scan each of the chromosomes for hot spots (loci) that may be linked to the disease. Using this approach, researchers in several centers have identified loci that appear to be linked to the disease. A second approach has been to focus on certain candidate genes that are found in important pathways for control of glucose metabolism. These have also yielded some positive findings.
The most exciting new approach, however, is the use of DNA chips. These allow investigators to measure the activity of thousands of genes at a time in any given tissue. Two recent studies one from a group at Massachusetts Institute of Technology collaborating with investigators from Finland, and the second from investigators at the Joslin Diabetes Center collaborating with researchers in San Antonio, Texas have identified genes involved in the function of mitochondria of cells as being most altered in the muscle of patients with type 2 diabetes. Similar alterations are also found in offspring who have normal glucose levels, suggesting that the condition may be inherited. Recent studies from Yale University have shown that mitochondria are also altered in aging, creating a link between age and type 2 diabetes. Mitochondria are the parts of the cell most involved in glucose and energy metabolism.
Although the genetics of type 2 diabetes have been hard to sort out, the role of the environment in the epidemic of the disease is easy to understand. In type 2 diabetes, a major factor leading to disease is insulin resistancethat is, a decrease in the ability of tissues to respond to insulin, the major hormone involved in the control of blood glucose. Two major environmental factors leading to the epidemic of type 2 diabetes are the increasing level of obesity and decreasing level of activity in modern life; both of these factors result in the creation of more insulin resistance.
What is most important to remember, however, is that it is not so much what one eats, but how much one eats, that leads to obesity. Low-carbohydrate diets, like the Atkins or South Beach diets, or low-fat diets, like the Pritikin diet, are not as important as what the scale reads at the end of the day. So the best diet to prevent diabetes is whatever diet keeps a person as close as possible to their ideal weight. Increasing physical activity not only helps keep the weight down, but also increases the amount of glucose going into muscle despite the insulin resistance.
The importance of this healthy lifestyle cannot be overestimated. In the multicenter Diabetes Prevention Program sponsored by NIHs National Institute of Diabetes and Digestive and Kidney Diseases, lifestyle modification reduced the probability of diabetes by more than 60% in individuals with the highest risk for developing the disease. The pharmaceutical industry continues to look for medications that would be as effective, but for now, the best advice for people with a family history of type 2 diabetes is keep your weight normal and stay active. This may be what it takes to avoid this complex disease.
This article first appeared in the Nov. 1, 2004 issue of Time Magazine.
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