| 1. |
- Abaraviciene, S, et al.
(författare)
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Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities.
- 2008
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Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-9071 .- 1420-682X. ; 65:14, s. 2256-2265
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Tidskriftsartikel (refereegranskat)abstract
- Chronic exposure of pancreatic islets to elevated levels of palmitate leads to beta-cell dysfunction. We examined possible involvement of mitogenactivated protein kinases (MAPKs) and caspase-3 in palmitate-induced beta-cell dysfunction and tested the influence of the anti-diabetic drug rosiglitazone (ROZ). Palmitate amplified glucose-stimulated augmentation of intracellular free calcium ([Ca(2+)](i)) and insulin secretion in incubated islets. ROZ suppressed this amplification, whereas it modestly augmented glucose-induced increase in these events. ROZ suppressed short-term palmitate-induced phosphorylation of pro-apoptotic MAPKs, i.e., SAPK/JNK and p38. Long-term islet culturing with palmitate induced inducible nitric oxide synthase (iNOS) and activated SAPK/JNK-p38. ROZ counteracted these effects. Both palmitate and cytokines activated caspase-3 in MIN6c4-cells and isolated islets. ROZ suppressed palmitate- but not cytokine-induced caspase-3 activation. Finally, after palmitate culturing, ROZ reversed the inhibitory effect on glucose-stimulated insulin release. We suggest that ROZ counteracts palmitateinduced deleterious effects on beta-cell function via suppression of iNOS, pro-apoptotic MAPKs and caspase-3 activities, as evidenced by restoration of glucose-stimulated insulin release.
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| 2. |
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| 4. |
- Amisten, Stefan, et al.
(författare)
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ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice.
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; Jul 1, s. 1927-1934
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESES: To investigate the effects of extracellular purines on insulin secretion from mouse pancreatic islets. METHODS: Mouse islets and beta cells were isolated and examined with mRNA real-time quantification, cAMP quantification and insulin and glucagon secretion. ATP release was measured in MIN6c4 cells. Insulin and glucagon secretion were measured in vivo after glucose injection. RESULTS: Enzymatic removal of extracellular ATP at low glucose levels increased the secretion of both insulin and glucagon, while at high glucose levels insulin secretion was reduced and glucagon secretion was stimulated, indicating an autocrine effect of purines. In MIN6c4 cells it was shown that glucose does induce release of ATP into the extracellular space. Quantitative real-time PCR demonstrated the expression of the ADP receptors P2Y(1) and P2Y(13) in both intact mouse pancreatic islets and isolated beta cells. The stable ADP analogue 2-MeSADP had no effect on insulin secretion. However, co-incubation with the P2Y(1) antagonist MRS2179 inhibited insulin secretion, while co-incubation with the P2Y(13) antagonist MRS2211 stimulated insulin secretion, indicating that ADP acting via P2Y(1) stimulates insulin secretion, while signalling via P2Y(13) inhibits the secretion of insulin. P2Y(13) antagonism through MRS2211 per se increased the secretion of both insulin and glucagon at intermediate (8.3 mmol/l) and high (20 mmol/l) glucose levels, confirming an autocrine role for ADP. Administration of MRS2211 during glucose injection in vivo resulted in both increased secretion of insulin and reduced glucose levels. CONCLUSIONS/INTERPRETATION: In conclusion, ADP acting on the P2Y(13) receptors inhibits insulin release. An antagonist to P2Y(13) increases insulin release and could be evaluated for the treatment of diabetes.
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| 5. |
- Balhuizen, Alexander, et al.
(författare)
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Activation of G protein-coupled receptor 30 modulates hormone secretion and counteracts cytokine-induced apoptosis in pancreatic islets of female mice.
- 2010
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 320, s. 16-24
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Tidskriftsartikel (refereegranskat)abstract
- The role of the newly discovered estrogen receptor GPR30 in islet physiology and pathophysiology is unclear. We examined GPR30 expression in relation to hormone secretion and possible anti-apoptotic effects in isolated mouse islets using the synthetic GPR30 ligand G-1. The mRNA and protein expression of GPR30 was analyzed by qPCR, Western blot and confocal microscopy. Hormone secretion and cAMP content were determined with RIA and apoptosis in islet cells with the Annexin-V method. GPR30 mRNA and protein expression was markedly higher in islets from females compared to male. This gender difference was not found for the genomic estrogen receptors ERalpha and ERbeta, the ERalpha expression being 10-fold higher than ERbeta in both genders. Confocal microscopy revealed abounden GPR30 expression in insulin, glucagon and somatostatin cells. Dose-response studies of G-1 vs 17beta-estradiol in isolated islets at 1 or 12mM glucose showed an almost identical pattern in that both compounds increased insulin and inhibited glucagon and somatostatin secretion. ICI-182,780 and EM-652, potent antagonists of the 17beta-estradiol receptors (ERalpha and ERbeta) did not influence the amplifying effect of G-1 or 17beta-estradiol on cAMP content or insulin secretion from isolated islets. Cytokine-induced (IL-1beta+TNFalpha+INFgamma) apoptosis in islets, cultured for 24h at 5mM glucose, was almost abolished by G-1 or 17beta-estradiol treatment. Addition of ICI-182,780 or EM-652 did not affect this beneficial effect of G-1 or 17beta-estradiol. Taken together, our findings show that GPR30 is expressed in most islet endocrine cells. The synthetic GPR30 ligand G-1 mimics the non-genomic effects of 17beta-estradiol on islet hormone secretion, cAMP content in islets and its anti-apoptotic effects. G-1 or analogs thereof might be new potential candidates in the therapeutic strategy for type 2 diabetes in women.
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| 7. |
- Fan, Bo-Guang, et al.
(författare)
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Total parenteral nutrition influences both endocrine and exocrine function of rat pancreas
- 1997
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Ingår i: Pancreas. - 0885-3177. ; 15:2, s. 147-153
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine the effect of total parenteral nutrition (TPN) on the endocrine and exocine function of the pancreas. Endocrine function was investigated using an intravenous glucose tolerance test (IGTT) in rats with TPN for 7 or 14 days. Exocrine function was evaluated by measuring amylase secretion from isolated acini as well as pancreatic weight, water content, protein, and enzymes after 7 days of TPN. When the TPN rats were compared with the controls, the glucose tolerance curve after an IGTT was unchanged, the basal plasma insulin levels were slightly lower and the insulin secretory response to intravenous glucose was markedly impaired. No differences could be seen between the insulin response after 7 days and that after 14 days of TPN. The weight of pancreas, the total content and concentration of pancreatic protein, and the total amylase content of the pancreas were lower, whereas the total content of both chymotrypsin and trypsin was higher. The concentration of DNA remained intact, whereas the total DNA content decreased. The levels of lipolytic enzymes, except for carboxylesterlipase, were unaffected. After TPN treatment, the insulin secretory response to glucose is impaired, the exocrine pancreas is hypoplastic and the storage pattern of pancreatic exocrine enzymes is altered.
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| 8. |
- 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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| 9. |
- Jimenez, Javier, et al.
(författare)
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Abnormally decreased NO and augmented CO production in islets of the leptin-deficient ob/ob mouse might contribute to explain hyperinsulinemia and islet survival in leptin-resistant type 2 obese diabetes.
- 2011
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 170, s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islet displayed iNOS activity appearing after ~60min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.
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| 10. |
- Jimenez, Javier, et al.
(författare)
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Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway
- 2005
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 319:2, s. 221-230
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Tidskriftsartikel (refereegranskat)abstract
- We have examined the expression and activity of inducible nitric oxide synthase ( iNOS) and the activity of neuronal constitutive NOS ( ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/ protein kinase A ( cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation ( 20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction in ncNOS activity and increased insulin release. The GLP-1-induced suppression of glucose-stimulated iNOS activity and expression and its stimulation of insulin release is, at least in part, PKA dependent, since the PKA inhibitor H-89 reverses the effects of GLP-1. These observations have been confirmed by confocal microscopy showing the glucose-stimulated expression of iNOS, its suppression by GLP-1 and its reversion by H-89 in beta-cells. We have also found that the NO scavenger cPTIO and the NOS inhibitor L-NAME potentiate the insulin response to glucose, again suggesting that NO is a negative modulator of glucose-stimulated insulin release. We conclude that the induction of iNOS and the increase in ncNOS activity caused by glucose in rat islets is suppressed by the cyclic AMP/ PKA system. The inhibition of iNOS expression by the GLP-1/ cyclic AMP/ PKA pathway might possibly be of therapeutic potential in NO-mediated beta-cell dysfunction and destruction.
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