| 1. |
- Amisten, Stefan, et al.
(författare)
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A comparative analysis of human and mouse islet G-protein coupled receptor expression
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- G-protein coupled receptors (GPCRs) are essential for islet function, but most studies use rodent islets due to limited human islet availability. We have systematically compared the GPCR mRNA expression in human and mouse islets to determine to what extent mouse islets can be used as surrogates for human islets to study islet GPCR function, and we have identified species-specific expression of several GPCRs. The A 3 receptor (ADORA3) was expressed only in mouse islets and the A 3 agonist MRS 5698 inhibited glucose-induced insulin secretion from mouse islets, with no effect on human islets. Similarly, mRNAs encoding the galanin receptors GAL 1 (GALR1), GAL 2 (GALR2) and GAL 3 GALR3) were abundantly expressed in mouse islets but present only at low levels in human islets, so that it reads (GALR3) and galanin inhibited insulin secretion only from mouse islets. Conversely, the sst1 receptor (SSTR1) was abundant only in human islets and its selective activation by CH 275 inhibited insulin secretion from human islets, with no effect on mouse islets. Our comprehensive human and mouse islet GPCR atlas has demonstrated that species differences do exist in islet GPCR expression and function, which are likely to impact on the translatability of mouse studies to the human context.
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| 2. |
- Parandeh, Fariborz, et al.
(författare)
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Uridine diphosphate (UDP) stimulates insulin secretion by activation of P2Y(6) receptors.
- 2008
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 6;370:3, s. 499-503
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Tidskriftsartikel (refereegranskat)abstract
- We examined the transcriptional expression and functional effects of receptors for the extracellular pyrimidines uridine triphosphate (UTP) and uridine diphosphate (UDP), on insulin and glucagon secretion in isolated mouse pancreatic islets and purified beta-cells. Using real-time PCR, the UDP receptor P2Y(6) was found to be highly expressed in both whole islets and beta-cells purified by repeated counter-flow elutriation, whereas no mRNA expression for UTP receptors P2Y(4) and P2Y(2) could be detected. Functional in vitro experiments revealed that the P2Y(6) agonist UDPbetaS dose-dependently enhanced insulin and glucagon release during short-term incubation (1h), while P2Y(6) activation during a longer period (24h), selectively increased insulin release, especially at high glucose levels. The corresponding EC(50) value for UDPbetaS ranged from 3.2x10(-8)M to 1.6x10(-8)M for both glucose concentrations. The P2Y(6) antagonist MRS2578 inhibited the effects of UDPbetaS, supporting a P2Y(6) specific effect. In addition to negative RT-PCR results, the lack of response to UTPgammaS a selective P2Y(2/4) agonist further rule out the involvement of P2Y(2/4) receptors in the islet hormone release. Our results suggest a modulatory role for UDP via a functional active P2Y(6) receptor in the regulation of islet hormone release.
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| 3. |
- Salehi, S Albert, et al.
(författare)
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Absence of adenosine A(1) receptors unmasks pulses of insulin release and prolongs those of glucagon and somatostatin
- 2009
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Ingår i: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 85:11-12, s. 470-476
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Extracellular ATP modulates pulsatile release of insulin, glucagon and somatostatin by activating P2Y(1) receptors. The present study examines if adenosine via A(1) receptors (A(1)R) interferes with pulsatile islet hormone release. Main methods: Pancreas was perfused in mice expressing or lacking the A(1) receptor and the hormones measured with radioimmunoassay. Cytoplasmic Ca2+ was recorded in isolated beta-cells using the fura-2 indicator. Key findings: Addition of 10 mu M adenosine removed the Ca2+ transients supposed to coordinate the insulin release pulses. This effect of adenosine was counteracted by 100 nM of the A(1)R antagonist DPCPX. In situ perfusion of the pancreas indicated two phases of islet hormone release when glucose was raised from 3.3 to 16.7 mM. The first phase was characterized by a brief dip followed by a peak which was more pronounced for insulin and somatostatin than for glucagon. The second phase was markedly affected by knock out of A(1)R. The wild-type AIR (+/+) mice, usually lacked statistically verified insulin pulses but generated antisynchronous glucagon and somatostatin pulses with half-widths of 4 min. In the A(1)R (-/-) mice time-average release of insulin during the second phase was almost three times higher than in the controls and 30% of the hormone was released as distinct pulses with half-widths of 3 min. The absence of the AIR receptor resulted in 50% prolongation of the pulse cycles of glucagon and somatostatin and loss of their antisynchronous relationship. Significance: The A(1)R receptor is important both for the amplitude (insulin) and duration (glucagon and somatostatin) of islet hormone pulses. (C) 2009 Elsevier Inc. All rights reserved.
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| 4. |
- Salehi, S Albert, et al.
(författare)
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Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses
- 1998
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Ingår i: Cellular Signalling. - 1873-3913. ; 10:9, s. 645-651
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Tidskriftsartikel (refereegranskat)abstract
- We examined the relation between the islet NO system and islet hormone secretion induced by either the non-glucose nutrient alpha-ketoisocaproic acid (KIC) or, in some experiments, glucose. KIC dose dependently stimulated insulin but inhibited glucagon secretion. In a medium devoid of any nutrient, the NO synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) induced an increase in basal insulin release but a decrease in glucagon release. These effects were evident also in K+-depolarised islets. KIC-induced insulin release was increased by L-NAME. This increase was abolished in K+-depolarised islets. In contrast, glucose- induced insulin release was potentiated by L-NAME after K+ depolarisation. The intracellular NO donor hydroxylamine dose dependently inhibited KIC-stimulated insulin release and reversed KIC-induced suppression of glucagon release. Our data suggest that islet hormone secretion in a medium devoid of nutrients is greatly affected by the islet NO system, whereas KIC-induced secretion is little affected. Glucose-induced insulin release, however, is accompanied by increased NOS activity, the NOS-activating signal being derived from the glycolytic-pentose shunt part of glucose metabolism. The observed NO effects on islet hormone release can proceed independently of membrane-depolarisation events.
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| 5. |
- Salehi, S Albert, et al.
(författare)
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The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester potentiates insulin secretion stimulated by glucose and L-arginine independently of its action on ATP-sensitive K+ channels
- 1998
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Ingår i: Bioscience Reports. - 0144-8463. ; 18:1, s. 19-28
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Tidskriftsartikel (refereegranskat)abstract
- The nature of the action of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on hormone release from isolated islets was investigated. We found that glucose-induced insulin release was potentiated by L-NAME in the absence or presence of diazoxide, a potent K+ATP channel opener, as well as in the presence of diazoxide plus a depolarizing concentration of K+. At a low, physiological glucose concentration L-NAME did not influence insulin secretion induced by K+ but inhibited glucagon secretion. L-arginine-induced insulin release was potentiated by L-NAME. This potentiation was observed also in the presence of K+ plus diazoxide. Further, glucagon release induced by L-arginine as well as by L-arginine plus K+ and diazoxide was suppressed by L-NAME. The results strongly suggest that the L-NAME-induced potentiation of insulin secretion in response to glucose or L-arginine as well as the inhibitory effects on glucagon secretion are largely mediated by L-NAME directly suppressing islet NOS activity. Hence NO apparently affects insulin and glucagon secretion independently of membrane depolarization events.
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