2000
DOI: 10.2337/diabetes.49.11.1880
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Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.

Abstract: To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2 -/-mice) had a body weight similar to wildtype mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2 -/-mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of ␤-cells was reduced to 83% of that in wild-type mice, wh… Show more

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Cited by 478 publications
(428 citation statements)
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References 29 publications
(48 reference statements)
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“…Insr-, Igf1r-and Irs1-null islets display defective glucose-stimulated insulin release in vitro [6,21,22]. In contrast, in both global Irs2-null mice and RIPCreIrs2KO mice, insulin secretion from isolated islets has been reported to be enhanced [4,9]. While the basis for the discordance in these observations is unclear, they potentially suggest that IRS2 signalling has a negative effect upon insulin synthesis and secretion or that development of islets under conditions of insulin resistance caused by Irs2 deficiency in other tissues programmes the islets to hypersecrete insulin.…”
Section: Discussionmentioning
confidence: 97%
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“…Insr-, Igf1r-and Irs1-null islets display defective glucose-stimulated insulin release in vitro [6,21,22]. In contrast, in both global Irs2-null mice and RIPCreIrs2KO mice, insulin secretion from isolated islets has been reported to be enhanced [4,9]. While the basis for the discordance in these observations is unclear, they potentially suggest that IRS2 signalling has a negative effect upon insulin synthesis and secretion or that development of islets under conditions of insulin resistance caused by Irs2 deficiency in other tissues programmes the islets to hypersecrete insulin.…”
Section: Discussionmentioning
confidence: 97%
“…Through the use of both global and conditional mouse gene targeting strategies we and others have demonstrated that IRS2 plays a key role in the maintenance of pancreatic beta cell mass [3,4,[8][9][10]. Furthermore both INSR and IGF1R have also been demonstrated to act as key regulators of beta cell function using Cre/loxP techniques [5][6][7].…”
Section: Discussionmentioning
confidence: 99%
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“…Among them, IRS-2 plays an essential role in mediating the metabolic actions of insulin in the liver. [7][8][9][10] Thus, the generation of immortalized hepatocyte cell lines derived from individual livers of wildtype and IRS-2 knockout mice has provided an excellent tool for the in vitro study of insulin signaling pathways, which led to the expression of genes involved in the regulation of glucose metabolism in the liver. 11 In the current study, we used these cell lines to evaluate the role of IRS-2 and its signaling in mediating the survival effects of insulin in neonatal hepatocytes.…”
Section: Discussionmentioning
confidence: 99%
“…6 Among the members of the IRS family, IRS-2 triggers insulin actions in the liver. In fact, mice deficient in IRS-2 develop hepatic insulin resistance and fatty liver along with ␤-cell failure, [7][8][9][10] producing a severe type-2 diabetic phenotype. At the mo-lecular level, a defect in PI 3-kinase/Akt signaling occurs in immortalized hepatocytes derived from IRS-2-deficient mice.…”
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confidence: 99%