β cell-specific deficiency of the stimulatory G protein α-subunit G
            <sub>s</sub>
            α leads to reduced β cell mass and insulin-deficient diabetes

Xie, Tao; Chen, Min; Zhang, Qinghong; Ma, Zheng; Weinstein, Lee S.

doi:10.1073/pnas.0704796104

Cited by 63 publications

(62 citation statements)

References 42 publications

(45 reference statements)

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“…We therefore speculate that PDX-1 knockdown indirectly reduces GLP-1R and Gs␣. Furthermore, the findings herein are consistent with reduced ␤-cell proliferation in ␤-cell-specific Gs␣ knockout mice (22).…”

Section: Exendin-4 Stimulation Of Cyclin A2supporting

confidence: 86%

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Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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OBJECTIVE-␤-Cell proliferation is an important mechanism underlying ␤-cell mass adaptation to metabolic demands. We have examined effects, in particular those mediated through intracellular cAMP signaling, of the incretin hormone analog exendin-4 on cell cycle regulation in ␤-cells.RESEARCH DESIGN AND METHODS-Changes in islet protein levels of cyclins and of two critical cell cycle regulators cyclin kinase inhibitor p27 and S-phase kinase-associated protein 2 (Skp2) were assessed in mice treated with exendin-4 and in a mouse model with specific upregulation of nuclear cAMP signaling exhibiting increased ␤-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cAMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet ␤-cells.RESULTS-Mice treated with exendin-4 showed increased ␤-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, elevated PDX-1 and Skp2 levels, and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cAMP-cAMP response element binding protein pathway. CBP-S436A islets exhibited elevated cyclin A2, reduced p27, and no changes in D-type cyclins, PDX-1, or Skp2. In cultured islets, exendin-4 increased cyclin A2 and Skp2 and reduced p27. Cyclin A2 overexpression in primary islets increased proliferation and reduced p27. In Min6 cells, cyclin A2 knockdown prevented exendin-4 -stimulated proliferation. PDX-1 knockdown reduced exendin-4 -stimulated cAMP synthesis and cyclin A2 transcription.CONCLUSIONS-Cyclin A2 is required for ␤-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1. Diabetes 57:2371-2381, 2008 P ancreatic ␤-cell mass is dynamic and responds to variations in metabolic demand on insulin production. The inability of the endocrine pancreas to adapt to changing insulin demand (inadequate ␤-cell mass) is found both in type 1 and type 2 diabetes. Increasing ␤-cell mass by regeneration may ameliorate or correct both type 1 and 2 diabetes (1). Within the pancreas, ␤-cells regenerate predominantly by ␤-cell replication (2,3). In this context, insight into the mechanisms underlying ␤-cell proliferation and cell cycle regulation, may provide potential targets for therapy in situations of inadequate ␤-cell mass.The incretin hormone glucagon-like peptide-1 (GLP-1) and its long-acting peptide analog exendin-4 stimulate ␤-cell proliferation in vitro and in vivo (4), leading to increased ␤-cell mass in rodents and amelioration of glucose metabolism in diabetic animal models and human diabetic subjects (4). Downstream effectors of the GLP-1 signaling to the cell nucleus include 1) the epidermal growth factor receptor-phosphoinositol 3-kinase (PI 3-kinase)-protein kinase B (PKB/Akt)-forkhead box transcription factor O1 (FoxO1) pathway (5) and 2) the cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) pathway (4). Activation of the PI 3-kinase pathway results in phosphorylation and nuclear...

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Section: Exendin-4 Stimulation Of Cyclin A2supporting

confidence: 86%

“…On exendin-4 binding to the GLP-1 receptor (GLP-1R), a trimer of G-coupled proteins associates to the GLP-1R, of which Gs␣ is instrumental in generating cAMP via adenylcyclase activation (22). We therefore examined the effects of siRNA-mediated PDX-1 knockdown on GLP-1R and Gs␣ expression.…”

Section: Exendin-4 Stimulation Of Cyclin A2mentioning

confidence: 99%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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“…In contrast to its inhibitory effects on β cell proliferation and insulin production (Xie et al 2007), Gsα deficiency promotes the proliferation of α cells without effect on the transcription and serum level of glucagon in mice with pancreas-selective deletion of Gsα (Xie et al 2010). Normal glucagon expression in the presence of increased α cell numbers suggests that the expression of glucagon per cell is decreased due to Gsα deficiency, indicating that cAMP signaling may have opposite effects on α cell proliferation and glucagon expression.…”

Section: α Cellmentioning

confidence: 95%

“…By contrast, β cell-selective deletion of Gsα in mice leads to severely impaired β cell proliferation and reduced insulin expression, accompanied by hyperglycemia and glucose intolerance (Xie et al 2007), suggesting that cAMP signaling is indispensable for β cell physiology. A recent study has shown that cAMP/PKA/CREB signaling promotes insulin transcription by stimulating the expression of transcription factor MAFA (Fig.…”

Section: Camp/pka In Pancreatic Isletsmentioning

confidence: 97%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

141

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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“…Ϫ/Ϫ fed 6-month-old male mice (at least four mice of each genotype were analyzed, except for Akt1 on May 10, 2018 by guest http://mcb.asm.org/ amount of food in the feeding container was measured at day 0 and day 10 of treatment as previously described (45). Food intake was expressed as grams adjusted by body weight per day per mouse.…”

Section: Mice the Generation Of Akt1mentioning

confidence: 99%

Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice

Chen¹,

Peng²,

Wang

et al. 2009

Molecular and Cellular Biology

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Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2 ؊/؊ mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function. Haplodeficiency of Akt1 in Akt2 ؊/؊ mice, however, converts prediabetes to overt type 2 diabetes, which is also reversed by haplodeficiency of Pten. Akt3 does not appear to contribute significantly to diabetes. Overt type 2 diabetes in Akt1 ؉/؊ Akt2 ؊/؊ mice is manifested by hyperglycemia due to beta-cell dysfunction combined with impaired glucose homeostasis due to markedly decreased leptin levels. Restoring leptin levels was sufficient to restore normal blood glucose and insulin levels in Akt1 ؉/؊ Akt2 ؊/؊ and Akt2 ؊/؊ mice, suggesting that leptindeficiency is the predominant cause of diabetes in these mice. These results uncover a new mechanism linking Akt to diabetes, provide a therapeutic strategy, and show that diabetes induced as a consequence of cancer therapy, via Akt inhibition, could be reversed by leptin therapy.

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β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Cited by 63 publications

References 42 publications

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice

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β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

Cited by 63 publications

References 42 publications

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice

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Product

Resources

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β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes