Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles.
NIDDM is a polygenic disease characterized by insulin resistance in muscle, fat, and liver, followed by a failure of pancreatic beta cells to adequately compensate for this resistance despite increased insulin secretion. Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia. At 4-6 months of age, 40% of these double heterozygotes become overtly diabetic. This NIDDM mouse model in which diabetes arises in an age-dependent manner from the interaction between two genetically determined, subclinical defects in the insulin signaling cascade demonstrates the role of epistatic interactions in the pathogenesis of common diseases with non-Mendelian genetics.
Brüning
J C
JC
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Winnay
J
J
Bonner-Weir
S
S
Taylor
S I
SI
Accili
D
D
Kahn
C R
CR
D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000401:mortality; D016883:Diabetic Ketoacidosis / Q000235:genetics / Q000401:mortality; D004195:Disease Models, Animal; D005838:Genotype; D006579:Heterozygote; D006946:Hyperinsulinism / Q000503:physiopathology; D006965:Hyperplasia; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D008099:Liver / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011972:Receptor, Insulin