Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes.
Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.
Shirakami
A
A
Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Toyonaga
T
T
Tsuruzoe
K
K
Shirotani
T
T
Matsumoto
K
K
Yoshizato
K
K
Kawashima
J
J
Hirashima
Y
Y
Miyamura
N
N
Kahn
C R
CR
Araki
E
E
D000818:Animals; D006051:Aurothioglucose; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000737:chemistry; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000032:analysis
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D006051:Aurothioglucose; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin