Type 2 diabetes is a common endocrinological disorder that affects between six and ten percent of the Western world, and is the sixth leading cause of death by disease in the United States. Type 2 diabetes is characterized by the progressive resistance of muscle and fat tissue to insulin, followed by the deterioration of insulin secretion by the pancreas.
As published in the August 1 issue of Genes & Development, Dr. Derek Le Roith and colleagues at the NIH have discovered that by selectively mutating an insulin-like receptor in muscle cells, they can generate a high fidelity mouse model of human type 2 diabetes.
Under normal conditions, pancreatic beta cells secrete insulin in response to elevated blood glucose levels. Muscle cells respond to insulin by increasing glucose uptake from the bloodstream. In type 2 diabetes patients, muscle and fat tissue becomes resistant to insulin, causing the beta cells to initially increase insulin secretion. Eventually, though, the beta cells become unable to compensate for this increasing insulin resistance, and they fail to respond to elevated blood glucose levels. The first identifiable symptom of type 2 diabetes is usually the inability of muscle to respond to normal blood glucose levels.
Several attempts have been made to develop a mouse model of type 2 diabetes, but all have been unable to recapitulate the full range of clinical features. Dr. Le Roith and colleagues, however, pioneered a new strategy towards this effort. Dr. Le Roith and colleagues generated transgenic mice that had a mutated version of the insulin-like growth factor -I (IGF-I) receptor in their muscle cells. IGF-I and insulin are structurally and functionally similar; both stimulate glucose uptake by muscle cells. The IGF-IR mutant mice displayed progressive insulin resistance in their peripheral tissues, and by five weeks of age developed type 2 diabetes.
The strain of mice that Dr. Le Roith and colleagues developed fully recapitulates the clinical features of type 2 diabetes, and therefore represents a marked advance in diabetes research. Dr. Le Roith and colleagues have developed an extremely useful model with which to study the pathogenesis of type 2 diabetes, and test potential therapeutic strategies.
Genes & Development