Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice

Liu, Y.; Tanabe, Katsuya; Baronnier, Delphine; Patel, Satish; Woodgett, James R.; Cras-Méneur, Corentin; Permutt, M. A.

doi:10.1007/s00125-010-1882-x

Cited by 93 publications

(80 citation statements)

References 41 publications

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“…To measure individual band intensity, background was subtracted for each protein band followed by normalization against the control protein (tubulin). (E) a-e, isolated adult human islets from four independent batches (two [HI-1 and HI-2] from low BMI [26][27] and two [HI-3 and HI-4] from high BMI [40][41][42][43][44][45][46][47][48][49][50] cadaveric donors) with high purity (80-90% for low BMI islets) and low purity (35-40% for high BMI islets) were cultured and equal amounts (50 μg) of human islet lysates or INS-1 CE were fractionated in SDS-PAGE and the transferred peptides were incubated with specific primary antibodies as shown. *p < 0.05; NS, not significant.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study shows that conditional ablation of GSK-3β in islet b-cells in mice results in increased b-cell mass accompanied by increased proliferation and decreased apoptosis. 41 The regenerative potential of human b-cells via proliferation following exposure to growth factor/s has been demonstrated. 42 An unanswered question is if Wnt pathway activation plays any major role in promoting human b-cell proliferation since the importance of Wnt signaling in stimulating primary rodent b-cell proliferation has been reported.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

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GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Stein¹,

Milewski²,

Hara³

et al. 2011

Islets

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Section: Resultsmentioning

confidence: 99%

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Stein¹,

Milewski²,

Hara³

et al. 2011

Islets

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“…Increased expression of miR-132 displays beneficial effects on both beta cell mass and function. Computational prediction algorithms (http://mirsystem.cgm.ntu.edu.tw/) indicate that granuphilin (also known as synaptotagmin-like 4 [SLP-4]), a granule-associated protein that negatively affects insulin release [16], and GSK-3β, which negatively regulates beta cell function and mass [24,25], are potential miR-132 targets. Translational repression of these two genes could explain, at least in part, the phenotypic traits of beta cells overexpressing miR-132.…”

mentioning

confidence: 99%

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

et al. 2013

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Aims/hypothesis MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesityassociated type 2 diabetes and to assess their potential contribution to the development of the disease. Methods MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells. Results MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation. Conclusions/interpretation We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs.

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“…GSK3β is involved in β-catenin turnover and WNT/β-catenin signalling has been shown to regulate neonatal beta cell expansion [29]. Accordingly, GSK3β deficiency results in expanded beta cell mass [30]. These findings prompted us to examine whether the absence of RKIP1 affected GSK3β protein accumulation.…”

Section: Rkip1 Levels In the Mouse Pancreasmentioning

confidence: 99%

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice

Abstract: Aims/hypothesis Glycogen synthase kinase 3β (GSK-3β) is an enzyme that is suppressed by insulin and when elevated results in insulin resistance in skeletal muscle and diabetes.

Cited by 93 publications

References 41 publications

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

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