GLP-1 Analogs

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Manmade, structurally altered chemical versions of glucagon-like peptide-1 (or GLP-1), which may someday play a role in treating both Type 1 and Type 2 diabetes.

GLP-1 is made in the intestine and is released in response to meals. It stimulates insulin secretion by the pancreatic beta cells in a glucose-dependent manner. That is, it stimulates insulin secretion only when there is a lot of glucose in the bloodstream. In that way, it can control blood glucose levels while minimizing the risk of hypoglycemia, or low blood sugar.

GLP-1 has other potentially beneficial effects in diabetes as well: It delays gastric emptying, which blunts high blood glucose after meals. It curbs appetite. Most remarkably, it appears to promote beta-cell regeneration, which could make it useful in treating Type 1 diabetes. And it inhibits apoptosis (programmed cell death) in beta cells, improving their survival.

Amylin Pharmaceuticals, of San Diego, California, in collaboration with Eli Lilly and Company of Indianapolis, Indiana, is testing a long-acting analog of GLP-1 called exenatide (brand name Byetta) in both people with Type 1 and people with Type 2 diabetes. In fact, Byetta received marketing approval from the U.S. Food and Drug Administration in April 2005 as an adjunctive treatment for Type 2 diabetes that is not already adequately controlled by metformin, a sulfonylurea drug, or both. Novo Nordisk is testing another long-acting GLP-1 analog in people with Type 2 diabetes called liraglutide. A number of other companies also have GLP-1 analogs under development.

The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring a clinical trial to study the effects of exenatide in people who have had Type 1 diabetes for at least five years but whose pancreases still make some insulin. The trial is designed to determine whether exenatide can improve the ability of the pancreas to make insulin and help control blood glucose levels. Because there is concern that the drug could activate the autoimmune process that causes Type 1 diabetes, the drug will be tried with and without adjunctive immunosuppression.

Researchers are also interested in GLP-1 in the context of islet transplantation, an experimental treatment in which insulin-producing pancreatic islets are transplanted into people with Type 1 diabetes. Transplantation is very traumatic to beta cells, and many of them die off or stop functioning during transplantation and engraftment. It often takes tissue from multiple donor pancreases to make one transplant recipient insulin independent. Researchers are about to embark on a clinical trial of giving GLP-1 or a GLP-1 analog to islet transplant recipients at the time of transplantation and for eight weeks thereafter. They hope that this treatment can decrease the death of beta cells during transplantation and engraftment — and perhaps even get beta cells to regenerate.

In other studies, GLP-1 analogs will be given to people who have already undergone islet transplantation but still require some injected insulin, to see whether this treatment will restore insulin independence.

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