Abstract
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. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. 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 beta-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aging
-
Animals
-
Blood Glucose / metabolism*
-
Diabetes Mellitus, Type 2 / blood
-
Diabetes Mellitus, Type 2 / genetics*
-
Diabetes Mellitus, Type 2 / physiopathology
-
Fatty Acids, Nonesterified / blood
-
Glucose / metabolism*
-
Glucose Clamp Technique
-
Humans
-
Hyperinsulinism
-
Insulin / metabolism
-
Insulin / pharmacology
-
Insulin Resistance / genetics*
-
Insulin Secretion
-
Islets of Langerhans / metabolism
-
Liver / metabolism
-
Mice
-
Mice, Transgenic
-
Muscle, Skeletal / drug effects
-
Muscle, Skeletal / metabolism*
-
Mutagenesis, Site-Directed
-
Prediabetic State / blood
-
Prediabetic State / genetics
-
Prediabetic State / physiopathology
-
Receptor, IGF Type 1 / genetics
-
Receptor, IGF Type 1 / physiology*
-
Receptor, Insulin / genetics
-
Receptor, Insulin / physiology*
-
Triglycerides / blood
-
Triglycerides / metabolism
Substances
-
Blood Glucose
-
Fatty Acids, Nonesterified
-
Insulin
-
Triglycerides
-
Receptor, IGF Type 1
-
Receptor, Insulin
-
Glucose