A Mouse Model for Type 2 Diabetes

Diabetes affects over 120 million people worldwide (16 million in the US) and is a major health problem with associated health costs estimated at almost $100 billion dollars. Type 2 diabetes affects as many as 10% of the population of the Western World (with 15 million patients in the US alone) and arises from a heterogeneous etiology, with secondary effects from environmental influences. Risk factors for type 2 diabetes include obesity, high blood pressure, high triglycerides and age. Type 2 diabetes is an active area for drug development and there continues to be a need for novel animal models and research tools to aid in the discovery and development of new, more efficient and cost-effective therapeutics.

Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. In an effort to study the progression of diabetes, researchers at NIDDK have developed a transgenic mouse strain (MKR) with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to skeletal muscle (Genes & Development (2001) 15, 1926-1934). Expression of KR-IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic ß-cell dysfunction developed at a relative early age, resulting in diabetes.

One of the great advantages of the MKR mouse over other mouse models is the early onset of the disease phenotype as seen by insulin resistance (as early as 4 weeks), fasting hyperglycemia (from 5 weeks) and abnormal glucose tolerance (at 7-12 weeks). The MKR mice provide an extremely useful model for the study of type 2 diabetes, its pathogenesis and potential new therapies.