Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Härndahl, Linda; Jing, Xuefang; Ivarsson, Rosita; Degerman, Eva; Åhrén, Bo; Manganiello, Vincent C.; Renström, Erik; Holst, Lena Stenson

doi:10.1074/jbc.m205401200

Cited by 77 publications

(78 citation statements)

References 51 publications

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“…Regarding how Akt modulates the GLP-1 response, Akt may activate phosphodiesterase 3B (PDE3B), which then hydrolyzes cAMP to AMP. Increased activity of PDE3B may cause rapid breakdown of cAMPs that are produced by GLP-1 activation (Härndahl et al, 2002). PDE3B is highly expressed in β-cells and can be activated by interaction with Akt (Ahmad et al, 2007;Kitamura et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of β-cells. Pretreatment of β-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When β-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when β-cells were exposed to high glucose for 18 h. Treatment of β-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

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Section: Discussionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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“…We used a mouse model that exhibits modest, 2-fold overexpression of the cAMP-degenerating enzyme PDE3B in -cells. Previous control experiments, conducted by us (Härndahl et al 2002), demonstrate the direct effect of overexpression of PDE3B on the reduction of cAMP levels. This has been confirmed through measurements of cAMP and the use of specific PDE3 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…An important role of the PDE3B isoform in regulating insulin secretion has been inferred from studies demonstrating that inhibitors selective for PDE3 increase insulin secretion in mice (Parker et al 1997) as well as in human and rat islets (ElMetwally et al 1997, Ahmad et al 2000. Furthermore, overexpression of PDE3B in clonal -cells and rat islets has been shown to reduce cAMP and the insulinotropic response to glucose and GLP-1 (Härndahl et al 2002). We recently described that a 7-10-fold increase in PDE3 activity in transgenic mice (RIP-PDE3B/7 mice) results in severely disrupted islet structure, impaired first-phase insulin secretion and glucose intolerance (Härndahl et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

Walz

Härndahl²,

Wierup³

et al. 2006

Journal of Endocrinology

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Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether -cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a -cell-specific, 2-fold overexpression of the cAMPdegrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyperglycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacylglycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located -cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of -cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.

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“…Although several PDE proteins regulate insulin secretion [7][8][9][10]45], only PDE3B can be activated by CUGBP1. Actually, PDE3B OE results in reduced insulin secretion by islets and beta cells [9,46,47]; conversely, GSIS is enhanced in islets from Pde3b-null mice [8]. In addition, various hormones including IGF-1 [48] and leptin [49] regulate insulin secretion through phosphorylation of PDE3B.…”

Section: Discussionmentioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Cited by 77 publications

References 51 publications

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

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