A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance.
Skeletal muscle insulin resistance is among the earliest detectable defects in humans with type 2 diabetes mellitus. To determine the contribution of muscle insulin resistance to the metabolic phenotype of diabetes, we used the Cre-loxP system to disrupt the insulin receptor gene in mouse skeletal muscle. The muscle-specific insulin receptor knockout mice exhibit a muscle-specific > 95% reduction in receptor content and early signaling events. These mice display elevated fat mass, serum triglycerides, and free fatty acids, but blood glucose, serum insulin, and glucose tolerance are normal. Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type 2 diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized.
Brüning
J C
JC
Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Michael
M D
MD
Winnay
J N
JN
Hayashi
T
T
Hörsch
D
D
Accili
D
D
Goodyear
L J
LJ
Kahn
C R
CR
D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003402:Creatine Kinase / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D007527:Isoenzymes; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019000:Phosphotyrosine / Q000032:analysis; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014764:Viral Proteins
D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D008055:Lipids; D014764:Viral Proteins; D019000:Phosphotyrosine; D002784:Cholesterol; D011972:Receptor, Insulin; D003402:Creatine Kinase; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose