Removal of Glucagon Receptors Eliminates Need for Insulin in Mouse Diabetes Model

A study conducted in a group of genetically engineered mice found that lack of glucagon receptors eliminated the need for insulin after destruction of their pancreatic beta cells caused the animals to become diabetic.

Glucagon is a hormone secreted by the pancreas that raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood glucose levels fall too low, which causes the liver to convert stored glycogen into glucose and release it into the bloodstream. Glucagon also stimulates the release of insulin, so that glucose can be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that maintains blood glucose levels at the optimal level.

To better study the relationship between glucagon and insulin, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) genetically engineered a line of mice to lacked cell surface receptors for glucagon. These animals and a normal control group were then made diabetic by the destruction of their pancreatic beta cells.

Results published in the January 26, 2011, online edition of the journal Diabetes revealed that within six weeks after beta-cell destruction the control mice became hyperglycemic hyperketonemic, polyuric, and displayed the weight loss, wasting of muscle, loss of appetite, and general debility characteristic of a chronic disease. On the other hand, the glucagon receptor negative mice, which had experienced comparable beta-cell destruction, had none of these clinical or laboratory manifestations of diabetes.

"These findings suggest that if there is no glucagon, it does not matter if you do not have insulin,” said senior author Dr. Roger Unger, professor of internal medicine at the University of Texas Southwestern Medical Center. "This does not mean insulin is unimportant. It is essential for normal growth and development from neonatal to adulthood. But in adulthood, at least with respect to glucose metabolism, the role of insulin is to control glucagon, and if you do not have glucagon, then you do not need insulin.”

"Matching the high insulin levels needed to reach glucagon cells with insulin injections is possible only with amounts that are excessive for other tissues,” said Dr. Unger. "Peripherally injected insulin cannot accurately duplicate the normal process by which the body produces and distributes insulin. If these latest findings were to work in humans, injected insulin would no longer be necessary for people with type I diabetes.”

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University of Texas Southwestern Medical Center