Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes

Ueki, Kohjiro; Okada, Tsuneo; Hu, Jiang; Liew, Chong Wee; Assmann, Anke; Dahlgren, Gabriella M.; Peters, Jennifer L.; Shackman, Jonathan G.; Zhang, Min; Artner, Isabella; Satin, Leslie S.; Stein, Roland; Holzenberger, Martin; Kennedy, Robert T.; Kahn, C. Ronald; Kulkarni, Rohit

doi:10.1038/ng1787

Cited by 239 publications

(222 citation statements)

References 30 publications

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“…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]. However, many of these studies have been compromised by two key features of the RIPCre (B6.Cg-tg(Ins2-cre)25Mgn/J) transgenic mice used to delete the floxed alleles.…”

Section: Discussionmentioning

confidence: 99%

“…Defects in glucose-stimulated calcium mobilisation are thought to be a component of this abnormality. For example, Insr-, Igf1r-and Irs1-deficient islets display reduced increases in intracellular calcium flux, which, in the case of Irs1-null islets, are thought to be in part due to decreased expression of sarco(endo)plasmic reticulum Ca 2+ -ATPase expression [7,26,27]. PIrs2KO beta cells also showed impaired calcium mobilisation in response to glucose, suggesting that IRS2 signalling is also a component of this mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…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]. Deletion of the insulin-like growth factor 1 receptor gene (Igf1r) likewise impairs insulin synthesis and secretion and combined deletion of the insulin receptor gene (Insr) and Igf1r causes marked beta cell failure [6,7]. Using similar techniques, we and others have recently generated 'beta cell-specific' Irs2-null mice that have utilised a rat insulin promoter 2 Cre recombinase transgenic mouse (RIPCre or B6.Cg-tg(Ins2-cre)25Mgn/J) to delete the floxed alleles of Irs2 [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

et al. 2007

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Aims/hypothesis Insulin signalling pathways regulate pancreatic beta cell function. Conditional gene targeting using the Cre/loxP system has demonstrated that mice lacking insulin receptor substrate 2 (IRS2) in the beta cell have reduced beta cell mass. However, these studies have been complicated by hypothalamic deletion when the RIPCre (B6.Cg-tg(Ins2-cre) 25Mgn/J) transgenic mouse (expressing Cre recombinase under the control of the rat insulin II promoter) is used to delete floxed alleles in insulin-expressing cells. These features have led to marked insulin resistance making the beta cellautonomous role of IRS2 difficult to determine. To establish the effect of deleting Irs2 only in the pancreas, we generated PIrs2KO mice in which Cre recombinase expression was driven by the promoter of the pancreatic and duodenal homeobox factor 1 (Pdx1, also known as Ipf1) gene. Materials and methodsIn vivo glucose homeostasis was examined in PIrs2KO mice using glucose tolerance and glucose-stimulated insulin secretion tests. Endocrine cell mass was determined by morphometric analysis. Islet function was examined in static cultures and by performing calcium imaging in Fluo3am-loaded beta cells. Islet gene expression was determined by RT-PCR. Results The PIrs2KO mice displayed glucose intolerance and impaired glucose-stimulated insulin secretion in vivo. Pancreatic insulin and glucagon content and beta and alpha cell mass were reduced. Glucose-stimulated insulin secretion and calcium mobilisation were attenuated in PIrs2KO islets. Expression of the Glut2 gene (also known as Slc2a2) was also reduced in PIrs2KO mice. Conclusions/interpretation These studies suggest that IRS2-dependent signalling in pancreatic islets is required not only for the maintenance of normal beta and alpha cell mass but is also involved in the regulation of insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

et al. 2007

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“…Beta-cell-specific knockout of Igf1r in mice did not affect beta cell mass, but resulted in agedependent impairment of glucose tolerance and defective glucose-stimulated insulin secretion [30,31]. To investigate whether insulin receptor (INSR) plays a compensatory role in beta cell proliferation in the absence of the IGF1R, Ueki et al created a mouse model in which both Insr and Igf1r are disrupted in beta cells [32]. Two weeks after birth, these normoglycaemic mice manifest reduced beta cell mass, increased apoptosis in islets and compromised beta cell function.…”

Section: Discussionmentioning

confidence: 99%

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

et al. 2007

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Aims/hypothesis The Goto-Kakizaki (GK) rat is a spontaneous model of type 2 diabetes. Defective beta cell mass detectable in late fetal age precedes the onset of hyperglycaemia. Our hypothesis was that an embryonic IGF production deficiency might be involved in beta cell mass anomaly in the diabetic GK rat. To test this, we evaluated during pancreatic organogenesis: (1) the beta cell development in GK rats on embryonic day (E) 13.5 and E18.5; (2) IGF2 and IGF1 receptor (IGF1R) pancreatic protein production on E13.5 and E18.5; (3) the in vitro development of GK pancreatic rudiment on E13.5; and (4) the in vitro effect of IGF2 addition on beta cell mass. Materials and methods Beta cell quantitative analyses were determined by immunohistochemistry and morphometry. IGF2 and IGF1R pancreatic protein production was evaluated using western blot analyses. Dorsal pancreatic rudiments were dissected on E13.5, separated from surrounding mesenchyme and cultured for 7 days without or with recombinant IGF2. Results While beta cell mass was already decreased on E18.5, the differentiation of the first beta cells was in fact normal in E13.5 GK pancreas. Moreover, defective IGF2 and IGF1R protein production was detected in GK pancreatic rudiment as early as E13.5. The isolated GK pancreatic rudiment as maintained in vitro mimics the GK beta cell deficiency observed in vivo. This last approach enabled us to show that GK beta cells were fully responsive to IGF2 as far as their net growth is concerned. Conclusions/interpretation In diabetic GK rat, defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly. IGF2 supplementation expands the pool of beta cells.

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“…Amongst the most wellstudied pathways that regulate β cell mass include the insulin receptor substrate 1 and 2 (IRS1 and IRS2) branch of insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF1R) signaling [83,83,84]. Several studies suggest that Pdx1 may act downstream of the IR/IGF1R signaling to promote β cell proliferation [83,[85][86][87][88][89].…”

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes

Cited by 239 publications

References 30 publications

Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

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