| 21. |
- Omar, Bilal, et al.
(författare)
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Incretin hormone receptors are required for normal beta cell development and function in female mice
- 2016
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 79, s. 58-65
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Tidskriftsartikel (refereegranskat)abstract
- The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment of beta cell function both in vivo and in vitro in a process that appears to be independent of the intestinally secreted incretin hormones. We therefore conclude that the incretin hormones together significantly impact both beta-cell function and beta-cell development.
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| 22. |
- Omar, Bilal, et al.
(författare)
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Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:7, s. 2196-2202
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Tidskriftsartikel (refereegranskat)abstract
- Dipeptidyl peptidase (DPP)-4 inhibition is a glucose-lowering treatment for type 2 diabetes. The classical mechanism for DPP-4 inhibitors is that they inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, in turn increasing glucose utilization and diminishing hepatic glucose production, which, through reduction in postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but also to a limited degree in humans have found additional mechanisms for DPP-4 inhibitors that may contribute to their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which prevents inactivation of newly released GLP-1, which in turn augments GLP-1-induced activations of autonomic nerves and results in high portal GLP-1 levels, resulting in inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents inactivation of locally produced intact GLP-1 in the islets, thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation; and 3) prevention of the inactivation of other bioactive peptides apart from GLP-1, such as glucose-dependent insulinotropic polypeptide, stromal-derived factor-1α, and pituitary adenylate cyclase-activating polypeptide, which may improve islet function. These pleiotropic effects may contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.
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| 23. |
- Omar, Bilal, et al.
(författare)
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Regulation of AMP-activated protein kinase by cAMP in adipocytes: Roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis.
- 2009
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 21, s. 760-766
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Tidskriftsartikel (refereegranskat)abstract
- AMP-activated protein kinase (AMPK) is an important regulator of cellular energy status. In adipocytes, stimuli that increase intracellular cyclic AMP (cAMP) have also been shown to increase the activity of AMPK. The precise molecular mechanisms responsible for cAMP-induced AMPK activation are not clear. Phosphodiesterase 3B (PDE3B) is a critical regulator of cAMP signaling in adipocytes. Here we investigated the roles of PDE3B, PDE4, protein kinase B (PKB) and the exchange protein activated by cAMP 1 (Epac1), as well as lipolysis, in the regulation of AMPK in primary rat adipocytes. We demonstrate that the increase in phosphorylation of AMPK at T172 induced by the adrenergic agonist isoproterenol can be diminished by co-incubation with insulin. The diminishing effect of insulin on AMPK activation was reversed upon treatment with the PDE3B specific inhibitor OPC3911 but not with the PDE4 inhibitor Rolipram. Adenovirus-mediated overexpression of PDE3B and constitutively active PKB both resulted in greatly reduced isoproterenol-induced phosphorylation of AMPK at T172. Co-incubation of adipocytes with isoproterenol and the PKA inhibitor H89 resulted in a total ablation of lipolysis and a reduction in AMPK phosphorylation/activation. Stimulation of adipocytes with the Epac1 agonist 8-pCPT-2'O-Me-cAMP led to increased phosphorylation of AMPK at T172. The general lipase inhibitor Orlistat decreased isoproterenol-induced phosphorylation of AMPK at T172. This decrease corresponded to a reduction of lipolysis from adipocytes. Taken together, these data suggest that PDE3B and PDE4 regulate cAMP pools that affect the activation/phosphorylation state of AMPK and that the effects of cyclic AMP on AMPK involve Epac1, PKA and lipolysis.
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| 24. |
- Omar, Bilal, et al.
(författare)
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Regulation of the pro-inflammatory cytokine osteopontin by GIP in adipocytes - A role for the transcription factor NFAT and phosphodiesterase 3B.
- 2012
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 425:4, s. 812-817
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Tidskriftsartikel (refereegranskat)abstract
- The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and osteopontin expression in primary adipocytes. The GIP-induced increase in osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP mediated effects on osteopontin a number of strategies were used. Thus, the β3-adrenergic receptor aganist CL316,243 stimulated osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 3B knock-out mice with CL316,243 resulted in a dramatic upregulation of osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulate osteopontin in adipocytes. Given the established link between osteopontin and insulin resistance, our data suggest that GIP by stimulating osteopontin expression, also could promote insulin resistance in adipocytes.
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| 25. |
- Pacini, G., et al.
(författare)
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Methods and Models for Metabolic Assessment in Mice
- 2013
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6753 .- 2314-6745.
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Tidskriftsartikel (refereegranskat)abstract
- The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validated in vivo experimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded.
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