Glucose Metabolism Defect In Rare Form Of Type 2 Diabetes Revealed

November 25, 1997

A defect in a gene recently linked to a rare inherited form of Type 2 diabetes impairs the pathway that breaks down blood sugar and provides the main signal for insulin secretion in the pancreas, report researchers at The Rockefeller University in the Nov. 25 Proceedings of the National Academy of Sciences. This work provides the first insight into the molecular mechanism of this disease and opens new avenues for developing better therapies to treat more common forms of late-onset diabetes.

"We have found that a gene called HNF4alpha, which we showed earlier to be implicated in a subset of Type 2 diabetes called MODY1, is critical in the regulation of a number of genes involved in glucose homeostasis and glycolysis," says study co-author Markus Stoffel, M.D., Ph.D., assistant professor and head of the Laboratory of Metabolic Diseases.

Diabetes affects the way food is metabolized and broken down into a simple sugar called glucose. In the pancreas, beta cells secrete insulin, the hormone that promotes absorption of glucose and other nutrients by cells. When glucose increases in the bloodstream--for example, after eating--a molecule on the beta cell called the glucose transporter-2 takes up the sugar. The pancreatic beta cells then sense the glucose concentration, and certain enzymes break glucose down, which provides a signal for insulin production and secretion. As glucose increases in the blood, more glucose is taken up by cells and metabolized and insulin secretion increases. The defect in HNF4alpha impairs this pathway.

There are two major forms of diabetes. Type 1 diabetes occurs when the body's immune system destroys beta cells. Type 2 diabetes, the more common type accounting for more than 90 percent of cases, is caused by ineffective insulin secretion or improper insulin action on target tissues such as muscle, leading to impaired glucose uptake from the blood and increased levels of blood glucose.

Genes are some of the most important risk factors for Type 2 diabetes, although environment also plays a role in the disease. Most common forms of diabetes are polygenic, meaning that more that one gene is involved in the disease, making it difficult to identify the genes responsible. But in about 1 to 3 percent of cases, inheritance follows a classic autosomal dominant pattern: anyone in a family who has one copy of the defective gene is likely to develop hyperglycemia, or increased levels of blood glucose. Known as maturity onset-diabetes of the young (MODY), this form of diabetes usually develops before age 25.

Scientist have found four diabetes genes, each linked to a different form of MODY. In December 1996, Stoffel, in collaboration with researchers at the Howard Hughes Medical Institute at the University of Chicago and the University of Michigan Medical Center, mapped MODY1, a particularly rare but severe form of Type 2 diabetes, to a gene called HNF4alpha.

The protein produced by HNF4alpha belongs to a class of proteins called transcription factors, molecules that switch other genes on or off, and is known to regulate gene expression in the liver, kidney and intestine.

In the new study, Stoffel and co-author Stephen A. Duncan, Ph.D., assistant professor in the Laboratory of Molecular Cell Biology, show that the defect in HNF4alpha that causes MODY1 is a loss of function mutation, meaning that the disease develops due to the inactivation of this gene.

"We have also shown that there is gene-dosage effect-if the gene's activity is decreased, there is a corresponding reduction in a related transcription factor called HNF1alpha, which is important for insulin production," explains Stoffel.

Stoffel and Duncan developed a novel technique to study the effect of HNF4alpha on glucose transport and metabolism. Using embryonic stem (ES) cells-cells found in early stages of the embryo that can theoretically turn into any tissue in the body-the researchers produced clumps of about 2000 cells that contain the visceral endoderm and later develop into the yolk sac. Genes that are expressed in the liver, like HNF4alpha, are also expressed in the visceral endoderm. The yolk sac, which is the main tissue that produces insulin during development, acts like a gut, providing nutrients to the embryo. This feature makes the visceral endoderm a good model to study pancreatic beta cells, explains Duncan.

"The visceral endoderm provides a physiological system for the genetic dissection of metabolic pathways," says Stoffel.

When HNF4 was removed from the visceral endoderm, the scientists found a decrease in activity of several genes that act at different stages of the insulin-secretion signaling and insulin-production pathway.

These new findings suggest that drugs designed to target HNF4alpha activity could lead to improved treatments for Type II diabetes.

"Activating HNF4alpha would lead to an increased expression of the glucose transporter-2 and the enzymes of glucose metabolism, increasing the rate of glucose metabolism and increasing insulin production and secretion," says Stoffel.

Diabetes is one of the world's most common inherited diseases, occurring in three out of every 100 people. In the United States alone, an estimated 16 million people have the disease, and about half of these people are not diagnosed. Associated with long-term complications that affect almost every major part of the body, diabetes contributes to blindness, heart disease, kidney failure, and nerve damage.

Stoffel is an Irma Hirschl Scholar, a Pew Scholar and Robert and Harriet Heilbrunn Professor. Duncan is a Naomi Judd American Liver Scholar and an Alexandrine and Alexander Sinsheimer Scholar. This work was supported by the American Diabetes Association.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created five centers to foster collaborations among scientists to pursue investigations of Alzheimer's Disease, of biochemistry and structural biology, of human genetics, of sensory neurosciences and of the links between physics and biology.

Rockefeller University

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