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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-09-07

AUTHORS

Y. Liu, K. Tanabe, D. Baronnier, S. Patel, J. Woodgett, C. Cras-Méneur, M. A. Permutt

ABSTRACT

Aims/hypothesisGlycogen 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. Its role in beta cell development and function is little known. Because of the enzyme’s anti-proliferative and pro-apoptotic properties, the hypothesis to be tested here was that beta cell specific deficiency of GSK-3β in mice would result in enhanced beta cell mass and function.MethodsMice with beta cell deficiency of GSK-3β (β-Gsk-3β [also known as Gsk3b]−/−) were generated by breeding Gsk-3βflox/flox mice with mice overexpressing the Cre recombinase gene under the control of the rat insulin 2 gene promoter (RIP-Cre mice), and glucose tolerance, insulin secretion, islet mass, proliferation and apoptosis were measured. Changes in islet proteins were investigated by western blotting.ResultsOn a normal diet β-Gsk-3β–/– mice were found to have mild improvement of glucose tolerance and glucose-induced insulin secretion, and increased beta cell mass accompanied by increased proliferation and decreased apoptosis. On a high-fat diet β-Gsk-3β–/– mice exhibited improved glucose tolerance and expanded beta cell mass with increased proliferation relative to that in control mice, resisting fat-fed diabetes. Molecular mechanisms accounting for these phenotypic changes included increased levels of islet IRS1 and IRS2 proteins and phospho-Akt, suggesting enhanced signalling through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and increased islet levels of pancreas/duodenum homeobox protein 1 (PDX1). Inhibition of GSK3 in MIN6 cells in vitro led to increased IRS1 and IRS2 protein levels through inhibition of proteosomal degradation.Conclusions/interpretationThese results are consistent with a mechanism whereby endogenous GSK-3β activity controls islet beta cell growth by feedback inhibition of the insulin receptor/PI3K/Akt signalling pathway. More... »

PAGES

2600-2610

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00125-010-1882-x

DOI

http://dx.doi.org/10.1007/s00125-010-1882-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003540011

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20821187


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88 insulin
89 insulin receptor
90 insulin resistance
91 insulin secretion
92 interpretationThese results
93 islet level
94 islet mass
95 islet proteins
96 kinase-3β
97 levels
98 mass
99 mechanism
100 mice
101 mild improvement
102 molecular mechanisms
103 muscle
104 pancreas/duodenum homeobox protein 1
105 pathway
106 phenotypic changes
107 phosphatidylinositol
108 phospho-Akt
109 pro-apoptotic properties
110 proliferation
111 promoter
112 properties
113 protein
114 protein 1
115 protein levels
116 proteosomal degradation
117 receptors
118 recombinase gene
119 resistance
120 results
121 role
122 secretion
123 skeletal muscle
124 specific deficiencies
125 synthase kinase-3β
126 tolerance
127 vitro
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