Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα

Tuttle, Robyn L.; Gill, Navdeep; Pugh, William; Lee, Jean-Pyo; Koeberlein, Brigitte; Furth, Emma E.; Polonsky, Kenneth S.; Naji, Ali; Birnbaum, Morris J.

doi:10.1038/nm1001-1133

Cited by 493 publications

(470 citation statements)

References 30 publications

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“…Transgenic mice that overexpress Igf2 specifically in beta cells had beta cell hyperplasia by day 3 of life [24,25]. Similar results of beta cell hyperplasia were obtained in transgenic mice overexpressing Igf1 or thymoma viral proto-oncogene 1 (Akt1) specifically in beta cells [25][26][27]. Beta-cell-specific knockout of Irs2 led to adult beta cell mass reduction [28].…”

Section: Discussionsupporting

confidence: 55%

“…Exogenous IGF1 and IGF2 are able to suppress apoptosis in isolated islets from pre-diabetic non-obese diabetic mouse following exposure to proinflammatory cytokines [41]. Igf1 overexpression in transgenic mice protects islets from further apoptotic cell death in response to streptozotocin [25,27]. Similar results of protection against apoptosis were found in transgenic mice with overexpression of effectors of the IGF signalling pathway [27,42].…”

Section: Discussionsupporting

confidence: 53%

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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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Section: Discussionsupporting

confidence: 55%

Section: Discussionsupporting

confidence: 53%

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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“…Consistently with this result, PKB has been shown to play an important role in the regulation of beta cell mass. Indeed, two recent studies have demonstrated that transgenic mice expressing a constitutively active form of PKB had significantly greater beta cell mass than control animals [59,60]. Moreover, these transgenic mice were protected from streptozotocininduced diabetes.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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“…In mammals, three closely related isoforms of PKB are encoded by distinct genetic loci: PKBα/Akt1, PKBβ/Akt2 and PKBγ/Akt3 [23]. The pancreatic beta cell contains high levels of PKBα [24], and the targeted overexpression of PKBα in vivo enhances beta cell mass and function through effects on cell number and cell size [25,26]. Indeed, PKB is increasingly implicated as a key player in the regulation of beta cell growth and survival [27].…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

et al. 2005

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Aims/hypothesis: The gut hormone glucagonlike peptide-1 (GLP-1) decreases beta cell apoptosis in a protein kinase B (PKB)-dependent fashion, and increases islet cell mass and function in vivo. In contrast, cytokines induce beta cell apoptosis, leading to decreased islet mass and type 1 diabetes. In the present study we used rat INS-1E beta cells and primary rat islet cells to examine the potential role of PKB as a mediator of the effect of GLP-1 on cytokine-induced apoptosis. Methods: Cell viability was determined by MTTassay, and apoptosis and necrosis by Hoechst 33342-propidium iodide staining. Immunoblot analysis was used to detect changes in protein expression, including active (phosphorylated) and total PKB, phosphorylated and total glycogen synthase kinase-3β, activated caspase-3 and inducible nitric oxide synthase. Reactive oxygen species were determined by 1,7-dichlorofluorescein (DCF) analysis, and mutant forms of PKB were introduced into cells using adenoviral vectors. Results: Incubation of INS-1E cells with cytokines (IL-1β, TNF-α and interferon-γ; 10-50 ng/ml) for 18 h significantly decreased cell viability (by 44%, p<0.001), cell proliferation (by 80%, p<0.001), and activation of PKB (by 67%, p<0.001). Pre-treatment with exendin-4 (10 −7 mol/l), a long-acting GLP-1 receptor agonist, partially protected the cells against cytokine-induced toxicity (p<0.01) in association with a reduction in cytokine-induced inhibition of PKB phosphorylation (p<0.05). Exendin-4 pre-treatment did not change cell proliferation. Cytokine treatment increased apoptosis (by 156%, p<0.05) and necrosis (from undetectable to 2.6% of cells). These increases were both reduced by pre-treatment with exendin-4 (p<0.05-0.01). Furthermore, cytokine-induced apoptosis and necrosis were significantly increased in cells infected with kinase-dead PKB (p<0.05), and the protective effect of exendin-4 on both parameters was fully abolished in these cells. Similar changes were observed in primary islet cells. In parallel with these changes, exendin-4 decreased the cytokine-induced activation of caspase-3 (by 46%, p<0.05), and decreased levels of inducible nitric oxide synthase (by 71%, p<0.05) and reactive oxygen species (by 27%, p< 0.05). Conclusions/interpretation: The results of our study indicate that GLP-1 plays a protective role against cytokineinduced apoptosis and necrosis in beta cells through a PKB-dependent signalling pathway.

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Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα

Cited by 493 publications

References 30 publications

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

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

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

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