[Previous Months][Date Index][Thread Index][Join - Register][Login]
[Message Prev][Message Next][Thread Prev][Thread Next]

[IP] From the Joslin site

New Theories of Type 2 Diabetes Emerging

[Boston, August 2000] 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 

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 
insulin’s 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 study’s 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 
— 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 

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. 
Kahn’s 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 hasn’t 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 — 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.
for HELP or to subscribe/unsubscribe, contact: HELP@insulin-pumpers.org
send a DONATION http://www.Insulin-Pumpers.org/donate.shtml