β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

Härndahl, Linda; Wierup, Nils; Enerbäck, Sven; Mulder, Hindrik; Manganiello, Vincent C.; Sundler, F.; Degerman, Eva; Åhrén, Bo; Holst, Lena Stenson

doi:10.1074/jbc.m308952200

Cited by 56 publications

(65 citation statements)

References 44 publications

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“…The role and regulation of PDE3B (phosphodiesterase 3B, cGMP-inhibited) has been extensively studied in the regulation of glucose and lipid metabolism, in insulin secretion and in adipocyte functions [24,25,26]. Although malignant beast epithelium was not micro-dissected free of stroma and thus the combined effect of metformin on both malignant and stromal cells (including adipocytes) was examined, in 3/8 cancers a fall in PDE3B protein expression was confirmed by semi-quantitative immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Hadad

Inomata

Jordan

et al. 2011

Breast Cancer Res Treat

264

199

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, Colin Purdie, Susan Bray, et al.. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Research and Treatment, Springer Verlag, 2011, 128 (3) AbstractMetformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer.Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of 8 patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500mg o.d. for one week increased to 1g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis, were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin fixed paraffin embedded cores and serum insulin determination were performed blinded to treatment.7 patients (7/32, 21.9%) receiving metformin withdrew due to gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (p=0.041, paired t-test) and in the metformin arm (p=0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly down-regulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels which affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By Ingenuity Pathway Analysis, the Tumour Necrosis Factor Receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB, MEKK were up-regulated and cdc42 down-regulated; mTOR and AMPK pathways were also affected. Gene Set Analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expressed following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients.This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.

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Section: Discussionmentioning

confidence: 99%

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Hadad

Inomata

Jordan

et al. 2011

Breast Cancer Res Treat

264

199

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“…Indeed, accumulating evidence indicates that intracellular cAMP is an important regulator of insulin secretion either dependent or independent of Ca 2+ [4,5,41]. 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].…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…PDEs have been classified into 11 families according to their amino acid sequence, catalytic characteristics, substrate preference and regulatory properties [6]. Several PDE subtypes and isoforms, including PDE1 [7], PDE3B [8,9], PDE4 [7] and PDE8B [7,10], are known to mediate insulin secretion by pancreatic islets and/or beta cells. Through a feedback mechanism, insulin can reduce intracellular cAMP levels via activation of PDEs either by phosphorylation [11,12] or in the longer term by regulating their protein levels [13,14].…”

Section: Introductionmentioning

confidence: 99%

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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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“…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). Another mouse line with lower, 2-3-fold overexpression (RIP-PDE3B/2) exhibits less severe features.…”

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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β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

Cited by 56 publications

References 44 publications

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

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

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

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