1998
DOI: 10.1038/36116
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Disruption of IRS-2 causes type 2 diabetes in mice

Abstract: Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin.… Show more

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Cited by 1,627 publications
(1,304 citation statements)
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References 18 publications
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“…In agreement, our results showed that the absence of IRS2 prevents activation of Akt during induction of CAF LTP in hippocampal slices, revealing a possible mechanism for the observed impairment of CAF LTP induction in Irs2 null animals. This observation is consistent with published studies demonstrating that insulin‐mediated activation of Akt signaling is impaired in Irs2 −/− mice (Withers et al 1998; Burks et al 2000). Also in line with our findings that IRS2 is required for CAF LTP, IRS2 deficient mice have impaired hippocampal synaptic plasticity in other paradigms (Costello et al 2012; Martín et al 2012).…”
Section: Discussionsupporting
confidence: 93%
See 1 more Smart Citation
“…In agreement, our results showed that the absence of IRS2 prevents activation of Akt during induction of CAF LTP in hippocampal slices, revealing a possible mechanism for the observed impairment of CAF LTP induction in Irs2 null animals. This observation is consistent with published studies demonstrating that insulin‐mediated activation of Akt signaling is impaired in Irs2 −/− mice (Withers et al 1998; Burks et al 2000). Also in line with our findings that IRS2 is required for CAF LTP, IRS2 deficient mice have impaired hippocampal synaptic plasticity in other paradigms (Costello et al 2012; Martín et al 2012).…”
Section: Discussionsupporting
confidence: 93%
“…Male BDNF +/− mice and their wild‐type littermates (3 months of age; B6CBA background) were obtained and genotyped as previously reported (Ernfors et al 1994; Giralt et al 2009). The generation and routine genotyping of Irs2 +/+ and Irs2‐deficient mice (3 months of age; C57Bl/6 background) have been described previously (Withers et al 1998; Burks et al 2000). Animals were assigned randomly to the different experimental groups.…”
Section: Methodsmentioning
confidence: 99%
“…For example, in Irs2−/ − mice there is diminished β cell mass with impaired glucose tolerance [89,91]; in this model, superposition of haploinsufficiency of the Forkhead transcription factor Foxo1 causes activation of Pdx1 expression in duct cells, and the subsequent recovery of β cell mass [92]. In support of this observation, overexpression of Pdx1 alone in Irs2−/− animals promotes recovery of β cell mass and correction of glucose tolerance throughout life [93].…”
Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning
confidence: 84%
“…Blood glucose, plasma insulin levels, glucose and insulin tolerance tests were performed as previously described [3,8]. Glucose-stimulated insulin secretion in vivo was performed using an i.p.…”
Section: Methodsmentioning
confidence: 99%
“…It has also been demonstrated that insulin receptor and post-receptor signalling mechanisms are required for pancreatic beta cell function [2]. For example, mice with global deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes due to a combination of insulin resistance and beta cell failure [3,4]. Furthermore, cell-specific gene targeting in mice using Cre/loxP-mediated recombination strategies has shown that beta cell deletion of the insulin receptor reduces first-phase insulin release and beta cell insulin content and causes a progressive deterioration in glucose tolerance [5].…”
Section: Introductionmentioning
confidence: 99%