Murine model of human hyperinsulinism

June 30, 2001

Scientists have developed a mouse model of human familial hyperinsulinism.

Familial hyperinsulinism (HI) is a rare inherited disorder that results from the unregulated release of insulin by pancreatic b cells. As published in G&D, researchers from UPENN Medical Center have generated a strain of mice in which the gene Foxa2 is specifically deleted in pancreatic b cells. By doing so, these researchers have created a high fidelity murine model of familial hyperinsulinism.

Previous attempts to investigate the role of Foxa2 in b cell physiology were thwarted by the fact that mice which are completely deficient for Foxa2 lack a pancreas. In a stunning example of the utility of transgenic technology, Dr. Klaus Kaestner and colleagues used tissue-specific gene ablation to generate mice that are deficient for Foxa2 only in pancreatic b cells. Dr. Kaestner and colleagues demonstrated that mice deficient for Foxa2 in b cells succumb to severe hyperinsulinemic hypoglycemia within the first weeks of life.

Dr. Kaestner and colleagues found that the deletion of Foxa2 in b cells disrupts the normal function of the b cells' KATP ion channels to couple glucose metabolism and insulin secretion. The body normally responds to increased glucose metabolism by closing b cell KATP channels, a physiological response that ultimately leads to the release of insulin into the bloodstream. However, due to the disruption of the KATP channels , these mutant mice release insulin into the bloodstream even during periods of severely low blood glucose levels. Dr. Kaestner and colleagues have thus identified the KATP ion channel as a novel target of Foxa2 in pancreatic b cells.

Another interesting observation made by this research team is that mice deficient for Foxa2 in b cells also display a decreased level of glucagon secretion from a cells. Taken together, this work provides the first genetic evidence that Foxa2 is required in pancreatic b cells to maintain normal glucose homeostasis, and thereby establishes Foxa2 as a novel candidate gene for human HI. In addition to lending insight into the molecular basis of this devastating disease, the mouse model that Dr. Kaestner and colleagues have developed will serve as an invaluable tool in the design and testing of therapeutic strategies to combat familial hyperinsulinism.

Cold Spring Harbor Laboratory

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