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| 2. |
- 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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| 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. |
- Eliasson, Lena, et al.
(författare)
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SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells.
- 2003
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Ingår i: Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 121:3, s. 181-197
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS–insensitive) component correlated with a rapid increase in membrane capacitance of ~80 fF that plateaued within ~200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 µM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.
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| 8. |
- 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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| 9. |
- Henningsson, Ragnar, et al.
(författare)
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Role of nitric oxide synthase isoforms in glucose-stimulated insulin release.
- 2002
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Ingår i: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 283:1, s. 296-304
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Tidskriftsartikel (refereegranskat)abstract
- The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of L-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus.
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| 10. |
- Hjalmarsson, Claes, et al.
(författare)
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Does Epidermal Growth Factor Participate in the Regulation of Glucose, Insulin and Glucagon Levels?
- 2006
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Ingår i: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 38:4, s. 377-384
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background/Aims:</i> The presence of receptors for epidermal growth factor (EGF) on β cells in the rat pancreatic islets has been established, but the physiological role remains to be settled. The aim of the present study was to evaluate the effect of EGF on glucose homeostasis. <i>Methods:</i> Fasted rats were treated with intraperitoneal injections of 10, 40 or 80 µg/kg body weight, either with EGF or 1% bovine serum albumin (controls). In a second experiment, fasted rats received an intraperitoneal injection of 1 mg glucose/kg body weight, followed by an injection of EGF or bovine serum albumin. Blood was drawn before the injections and at different time points afterwards. The plasma concentrations of glucose, insulin and glucagon were measured. <i>Results:</i>A modest elevation of the concentrations of glucose and insulin in plasma during the study was found in fasted rats in experiment 1. The increase in insulin concentration was attenuated by EGF, but after glucose injection this effect was reversed. Plasma glucagon levels were dose-dependently elevated by EGF and increased instead of decreased after glucose injection. <i>Conclusion:</i> Our data suggest that EGF might play an important role in the regulation of glucagon secretion by preventing the lowering effect of glucose on plasma glucagon levels.
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