| 1. |
- Ahmed Khandker, Meftun, et al.
(författare)
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Mitochondrial proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic beta-cells exposed to high glucose
- 2010
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 2:5, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hyperglycemia leads to deterioration of insulin release from pancreatic beta-cells as well as insulin action on peripheral tissues. However, the mechanism underlying beta-cell dysfunction resulting from glucose toxicity has not been fully elucidated. The aim of the present study was to define a set of alterations in mitochondrial protein profiles of pancreatic beta-cell line in response to glucotoxic condition using 2-DE and tandem mass spectrometry. INS1E cells were incubated in the presence of 5.5 and 20 mM glucose for 72 hrs and mitochondria were isolated. Approximately 75 protein spots displayed significant changes (p < 0.05) in relative abundance in the presence of 20 mM glucose compared to controls. Mitochondrial proteins downregulated under glucotoxic conditions includes ATP synthase a chain and delta chain, malate dehydrogenase, aconitase, trifunctional enzyme beta subunit, NADH-cytochrome b5 reductase and voltage-dependent anion-selective channel protein (VDAC) 2. VDAC 1, 75 kDa glucose-regulated protein, heat shock protein (HSP) 60 and HSP10 were found to be upregulated. The orchestrated changes in expression of VDACs and multiple other proteins involved in nutrient metabolism, ATP synthesis, cellular defense, glycoprotein folding and mitochondrial DNA stability may explain cellular dysfunction in glucotoxicity resulting in altered insulin secretion.
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| 2. |
- Alonso-Magdalena, Paloma, et al.
(författare)
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Antidiabetic Actions of an Estrogen Receptor beta Selective Agonist
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:6, s. 2015-2025
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Tidskriftsartikel (refereegranskat)abstract
- The estrogen receptor beta (ER beta) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ER beta selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic beta-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide-induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic beta-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic beta-cell mass. We conclude that ER beta agonists should be considered as new targets for the treatment of diabetes.
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| 5. |
- Jabar Muhammed, Sarheed, et al.
(författare)
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Pancreatic β-cell dysfunction, expression of iNOS and the effect of phosphodiesterase inhibitors in human pancreatic islets of type 2 diabetes.
- 2012
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 14:11, s. 1010-1019
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Induction of iNOS in pancreatic islets leads to exaggerated NO production associated with dysfunctional β-cells. We examined insulin secretion, iNOS expression and its relation to the cAMP system in islets from human type 2 diabetes. METHODS: Insulin, glucagon and cAMP were analyzed by RIA; iNOS or PDE expression by qPCR, Western blot and confocal microscopy; cell viability by MTS. RESULTS: Diabetic islets displayed impaired insulin and glucagon responses to glucose, disturbed cAMP generation, and high iNOS mRNA and protein expression. Confocal microscopy showed iNOS protein expression in diabetic islets being confined to insulin, glucagon and somatostatin cells. Culture of diabetic islets at 5.5 mmol/l glucose with dibutyryl-cAMP (Bt(2) -cAMP) for 24 h was accompanied by marked suppression of iNOS mRNA, reduced nitrite production and increased insulin secretion. Diabetic islets displayed marked increase in PDE3A and PDE3B mRNA expression. Short-time incubation of diabetic islets showed, among the PDE inhibitors tested, cilostazol being most favourable to increase insulin secretion. Diabetic islets were most susceptible to long-term (72 h) culture at high glucose (20 mmol/l) reacting with increased apoptosis. Bt(2) -cAMP and the PDE inhibitors cilostazol, milrinone and IBMX efficiently increased cell viability at high glucose during culture. Defective glucose-stimulated insulin release upon induction of iNOS was restored by iNOS inhibitor aminoguanidine. CONCLUSION: Our results suggest that in islets from type 2 diabetes, stimulatory effects in certain cAMP-compartments induced by PDE inhibitors might play a central role in the suppression of iNOS, resulting in increased β-cell viability and improved secretory response to glucose.
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| 6. |
- Jabar Muhammed, Sarheed
(författare)
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The impact of glucotoxicity on pancreatic β-cell function
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes mellitus is connected with elevated plasma glucose levels which negatively influence β-cells and cause impaired glucose-stimulated insulin secretion (GSIS). The aim of present thesis was to investigate the impact of long-term hyperglycemia on the pancreatic islet β-cell function. The data showed abnormally increased expression of inducible nitric oxide synthase (iNOS) protein in the islets from diabetic donors as well as in the islets exposed to chronic hyperglycemia. cAMP analogue or PDE inhibitors counteract these abnormalities and restore β-cell function at least in part, by activating cyclic AMP/PKA system. Using two different diabetic animal models i.e. mild hyperlipidemic ZDF (fa/fa) and hyperglycemic GK rat, we found that chronic hyperglycemia in the absence of hyperlipidemia almost abolish GPR40 expression in the islet cells and abrogate the FFA-induced secretory effects. We suggest that this might be an important contributing factor for dysfunction of β-cells seen in human type 2 diabetes (T2D). Furthermore we also observed that prolonged exposure of INS-1E and INS-1 832/13 cells or isolated human islets to high glucose concentration are associated with increased level of VDAC1 and reduced level of VDAC2 accompanied with marked reduction of GSIS. Similar to glucose, 2-deoxy-glucose also increased the expression of VDAC1. Addition of glycogen synthase kinase 3β (GSK-3β) inhibitor reversed the alteration in VDAC1/VADC2 expression and improved GSIS. Islets of type 2 diabetic donors showed increased expression of VDAC1 and a marked reduction of VDAC2. Diabetic islets also displayed increased expression of ChREBP and TXNIP. Down-regulation of ChREBP and TXNIP in INS-1 832/13 cells cultured at high glucose suppressed high glucose-induced increase in VDAC1 expression. The cultured INS-1 832/13 cells also exhibited a reduced expression of VADC1 when resveratrol (a polyphenolic compound) was present. The data suggest that an increased expression of iNOS, increased expression of VDAC1 and reduced expression of VDAC2 are the main causative factors in the pathogenesis of glucotoxicity. The GPR40 protein is interactively modulated by both hyperlipidemia and hyperglycemia. Taken together, these contributing signaling factors are promising targets for pharmacotherapy in different variants of type 2 diabetes.
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| 7. |
- Mahdi, Taman, et al.
(författare)
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Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.
- 2012
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 16:5, s. 625-633
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Tidskriftsartikel (refereegranskat)abstract
- A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1β. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
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| 8. |
- Meidute, Sandra, et al.
(författare)
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GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats.
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 381:1-2, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- The role of islet GPR40 protein in the pathogenesis of diabetes is unclear. We explored the influence of GPR40 protein levels on hormone secretion in islets from two rat models of spontaneous type 2 diabetes displaying either hyperlipidaemia or hyperglycaemia. GPR40 expression was analysed by confocal microscopy, Western blot and qPCR in islets from preobese Zucker (fa/fa) rats, diabetic Goto-Kakizaki (GK) rats, and controls. Confocal microscopy of control islets showed expression of GPR40 protein in insulin, glucagon and somatostatin cells. GPR40 expression was strongly increased in islets of hyperlipidaemic fa/fa rats and coincided with a concentration-related increase in palmitate-induced release of insulin and glucagon and its inhibition of somatostatin release. Conversely, hyperglycaemic GK islets displayed an extremely faint expression of GPR40 as did high-glucose-cultured control islets. This was reflected in abolished palmitate-induced hormone response in GK islets and high-glucose-cultured control islets. The palmitate antagonist rosiglitazone promoted reappearance of GPR40 in high-glucose-cultured islets and served as partial agonist in glucose-stimulated insulin release. GPR40 protein is abundantly expressed in pancreatic islets and modulates stimulated hormone secretion. Mild hyperlipidaemia in obesity-prone diabetes creates increased GPR40 expression and increased risk for an exaggerated palmitate-induced insulin response and lipotoxicity, a metabolic situation suitable for GPR40 antagonist treatment. Chronic hyperglycaemia creates abrogated GPR40 expression and downregulated insulin release, a metabolic situation suitable for GPR40 agonist treatment to avoid glucotoxicity. GPR40 protein is interactively modulated by both free fatty acids and glucose and is a promising target for pharmacotherapy in different variants of type 2 diabetes.
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| 9. |
- Salehi, S Albert, et al.
(författare)
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The insulinogenic effect of whey protein is partially mediated by a direct effect of amino acids and GIP on beta-cells
- 2012
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Ingår i: Nutrition & Metabolism. - : Springer Science and Business Media LLC. - 1743-7075. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Whey protein increases postprandial serum insulin levels. This has been associated with increased serum levels of leucine, isoleucine, valine, lysine, threonine and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). We have examined the effects of these putative mediators of whey's action on insulin secretion from isolated mouse Langerhans islets. Methods: Mouse pancreatic islets were incubated with serum drawn from healthy individuals after ingestion of carbohydrate equivalent meals of whey protein (whey serum), or white wheat bread (control serum). In addition the effect of individual amino acid combinations on insulin secretion was also tested. Furthermore, the stimulatory effects of whey serum on insulin secretion was tested in vitro in the absence and presence of a GIP receptor antagonist ((Pro(3)) GIP[mPEG]). Results: Postprandial amino acids, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were higher after whey compared to white wheat bread. A stimulatory effect on insulin release from isolated islets was observed with serum after whey obtained at 15 min (+87%, P < 0.05) and 30 min (+139%, P < 0.05) postprandially, compared with control serum. The combination of isoleucine, leucine, valine, lysine and threonine exerted strong stimulatory effect on insulin secretion (+270%, P < 0.05), which was further augmented by GIP (+558% compared to that produced by glucose, P < 0.05). The stimulatory action of whey on insulin secretion was reduced by the GIP-receptor antagonist (Pro(3)) GIP[mPEG]) at both 15 and 30 min (-56% and -59%, P < 0.05). Conclusions: Compared with white wheat bread meal, whey causes an increase of postprandial insulin, plasma amino acids, GIP and GLP-1 responses. The in vitro data suggest that whey protein exerts its insulinogenic effect by preferential elevation of the plasma concentrations of certain amino acids, GIP and GLP-1.
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| 10. |
- Soriano, Sergi, et al.
(författare)
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Rapid Insulinotropic Action of Low Doses of Bisphenol-A on Mouse and Human Islets of Langerhans: Role of Estrogen Receptor beta
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic beta-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ER beta(-/-) mice to study whether ER beta is involved in the rapid regulation of K-ATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in beta-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased K-ATP channel activity, increased glucose-induced [Ca2+](i) signals and insulin release in beta-cells from WT mice but not in cells from ER beta(-/-) mice. The rapid reduction in the K-ATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ER beta and indicate that results obtained with BPA in mouse beta-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.
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