New Theories of Type 2 Diabetes Emerging

[Boston, August 2000] ó New research published in the July 26 issue of Molecular Cell suggests that insulin action in the liver is both important in the development of type 2 diabetes and normal liver growth and function. This research, coupled with other studies that have come out in the past several years, is resulting in an evolving, more complex picture of what may cause type 2 diabetes in humans and the importance of insulin for normal tissue function.

Type 2 affects an estimated 15 million Americans and 150 million people worldwide and is a major cause of heart disease, blindness, kidney disease, nerve damage and more.

Traditionally, scientists looking for the causes of type 2 diabetes and better ways to treat the disease have focused much of their energy on the roles that the pancreas plays (because it produces insulin that helps convert food into energy), and the role of insulin receptors in muscle and fat tissue, which traditionally have been considered the prime targets of insulinís action as it enables the body to convert food into energy.

But according to researchers at Joslin Diabetes Center in Boston, Vanderbilt University in Nashville, and Yale University in New Haven, mice that are genetically altered so that insulin action in the liver is lost not only become dramatically insulin resistant, ultimately developing diabetes, but also show major changes in liver growth and function.

"The liver is a major location in the body where glucose is taken up and stored, and also the major site where insulin, the hormone controlling glucose metabolism, is degraded or broken down," says C. Ronald Kahn, M.D., President of Joslin Diabetes Center and one of the studyís authors. "In the last couple of years research has suggested that insulin resistance in the liver might be a later factor in the development of diabetes, causing the liver to over-produce glucose and resulting in high blood sugars in people with type 2 diabetes."

Believing that insulin action on the liver might play a more central role in metabolism, the research team developed a genetically altered mouse model in which insulin signaling in the liver was disrupted by inactivating the insulin receptor in that organ only. Normally, the insulin receptor serves as a lock on cells, and through a complex series of signals between insulin, other hormones and the insulin receptor, the receptor is "unlocked," enabling glucose metabolism and normal cell function.

What the researchers discovered is that this insulin receptor defect in the liver alone was sufficient to cause major abnormalities in glucose metabolism ó despite the presence of insulin levels that were as much as 40 times higher than normal, and perfectly normal insulin receptor function in all other body tissues.

As the mice aged, they also began to exhibit altered liver function, with an 80% decrease in liver size and low levels of albumin production (another major protein produced by the liver).

What this research suggests, in combination with research by other scientists over the past couple of years, is that type 2 diabetes is a much more complex disease than previously thought, says Dr. Kahn. This research suggests that a defect in the insulin receptor or in insulin signaling in the liver might not only play a central role in the development of diabetes, but also that insulin is important for normal liver function. Other recent research by Dr. Kahnís lab has shown that insulin resistance in the insulin-producing beta cells themselves can also trigger a decreased insulin production that may contribute to type 2 diabetes. From research such as this, new theories about a cause for type 2 diabetes are beginning to emerge.

What does this all mean for the future of type 2 diabetes treatment?

"First, we need to see whether the kinds of results we are obtaining in mice also are true in humans," says Dr. Kahn. "Then we need to pinpoint where precisely in the insulin signaling process the defect occurs in humans."

Research in humans hasnít identified any "smoking gun" as yet. There is no significant genetic difference that has been identified in humans with type 2 diabetes that is tied to the production of a certain substance in the insulin signaling process, for example. Scientists therefore think that there may be several subtle mutations that each cause a small abnormality, and that only when multiple problems occur does diabetes develop.

There ultimately may be several different types of type 2 diabetes identified, based on which points in the insulin signaling pathway are defective. The end result may be the development of a whole new series of different drugs aimed specifically at these different defects ó ultimately, making a more specific approach to treatment that are more individualized to the particular defects a patient has that is causing their diabetes.

Authors of the Molecular Cell article are M. Dodson Michael, Rohit N. Kulkarni and C. Ronald Kahn of Joslin Diabetes Center; Catherine Postic and Mark A. Magnuson of Vanderbilt University School of Medicine; and Steven F. Previs and Gerald I. Shulman of Yale University School of Medicine.