| 1. |
- Bennet, Hedvig, et al.
(författare)
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Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans.
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 59:4, s. 744-754
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Tidskriftsartikel (refereegranskat)abstract
- The Gq-coupled 5-hydroxytryptamine 2B (5-HT2B) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells.
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| 2. |
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| 3. |
- Dekker Nitert, Marloes, et al.
(författare)
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CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells.
- 2008
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Ingår i: Journal of Molecular Endocrinology. - 1479-6813. ; 41:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- In clonal beta-cell lines and islets from different species, a variety of calcium channels are coupled to glucose-stimulated insulin secretion. The aim of this study was to identify the voltage-gated calcium channels that control insulin secretion in insulinoma (INS)-1 832/13 cells. The mRNA level of Ca(V)1.2 exceeded that of Ca(V)1.3 and Ca(V)2.3 two-fold. Insulin secretion, which rose tenfold in response to 16.7 mM glucose, was completely abolished by 5 microM isradipine that blocks Ca(V)1.2 and Ca(V)1.3. Similarly, the increase in intracellular calcium in response to 15 mM glucose was decreased in the presence of 5 microM isradipine, and the frequency of calcium spikes was decreased to the level seen at 2.8 mM glucose. By contrast, inhibition of Ca(V)2.3 with 100 nM SNX-482 did not significantly affect insulin secretion or intracellular calcium. Using RNA interference, Ca(V)1.2 mRNA and protein levels were knocked down by approximately 65% and approximately 34% respectively, which reduced insulin secretion in response to 16.7 mM glucose by 50%. Similar reductions in calcium currents and cell capacitance were seen in standard whole-cell patch-clamp experiments. The remaining secretion of insulin could be reduced to the basal level by 5 microM isradipine. Calcium influx underlying this residual insulin secretion could result from persisting Ca(V)1.2 expression in transfected cells since knock-down of Ca(V)1.3 did not affect glucose-stimulated insulin secretion. In summary, our results suggest that Ca(V)1.2 is critical for insulin secretion in INS-1 832/13 cells.
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| 4. |
- Eliasson, Björn, et al.
(författare)
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Nationwide cardiovascular risk categorization : applying the European Society of Cardiology (ESC) guidelines to the Swedish National Diabetes Register
- 2022
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press. - 2047-4873 .- 2047-4881. ; 824
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The 2021 European Society of Cardiology (ESC) guidelines recommend that patients with type 2 diabetes (T2D) with a very high cardiovascular disease (CVD) risk receive cardiovascular (CV)-protective glucose-lowering medication (glucagon-like peptide-1 receptor agonists or sodium-glucose co-transporter-2 inhibitors). This analysis compared previous prescribing practices with the ESC recommendations.METHODS AND RESULTS: Patients in the Swedish National Diabetes Register (NDR) with T2D, aged 18-90 years, not receiving CV-protective glucose-lowering medication in 2017 were identified, and the ESC criteria for very high CVD risk was applied. The composite outcome of major adverse CV events (MACE; defined as CV death, non-fatal stroke or non-fatal myocardial infarction) during 2017 was calculated and the number of MACE avoided with semaglutide, an example of a CV-protective glucose-lowering medication, was estimated for patients within a certain CV risk score.Of the 320,028 patients in the NDR with T2D who were not receiving CV-protective glucose-lowering medication, 129,512 patients had a very high CVD risk. Patients with a very high CVD risk had a high incidence of MACE (75.4 events/1000 person-years), which was higher in those with atherosclerotic CVD (ASCVD) with and without elevated glycated haemoglobin (>9%; 136.5 and 90.8 events/1000 person-years, respectively). If patients with a very high CVD risk, according to the ESC, and ASCVD received semaglutide, 803 MACE may have been avoided in 2017.CONCLUSIONS: This analysis highlights differences between previous prescribing practices in Sweden and the 2021 ESC guidelines, and offers strategies to prioritize CV-protective glucose-lowering medication for patients who would benefit most.
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| 5. |
- Lyssenko, Valeriya, et al.
(författare)
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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 82-88
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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| 6. |
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| 7. |
- Malmgren, Siri, et al.
(författare)
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Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity.
- 2013
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 288:17, s. 11973-11987
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Tidskriftsartikel (refereegranskat)abstract
- Lipotoxicity is a presumed pathogenetic process whereby elevated circulating and stored lipids in Type 2 Diabetes cause pancreatic β-cell failure. To resolve the underlying molecular mechanisms, we exposed clonal INS-1 832/13 β-cells to palmitate for 48 h. We observed elevated basal insulin secretion but impaired glucose-stimulated insulin secretion in palmitate-exposed cells. Glucose utilization was unchanged, palmitate oxidation increased, and oxygen consumption impaired. Removal of palmitate from the clonal INS-1 832/13 β-cells largely recovered all of the lipid-induced functional changes. Metabolite profiling revealed profound but reversible increases in cellular lipids. Glucose-induced increases in tricarboxylic acid cycle intermediates were attenuated by exposure to palmitate. Analysis of gene expression by microarray showed increased expression of 982 genes and decreased expression of 1032 genes after exposure to palmitate. Increases were seen in pathways for steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids; decreases occurred in the aminoacyl-tRNA-synthesis pathway. The activity of histone-modifying enzymes and histone modifications of differentially expressed genes were reversibly altered upon exposure to palmitate. Thus, Insig1, Lss, Peci, Idi1, Hmgcs1 and Casr were subject to epigenetic regulation. Our analyses demonstrate that coordinate changes in histone modifications, mRNA levels and metabolite profiles accompanied functional adaptations of clonal β-cells to lipotoxicity. It is highly likely that these changes are pathogenetic, accounting for loss of glucose responsiveness and perturbed insulin secretion.
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| 8. |
- Mulder, Hindrik, et al.
(författare)
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Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1240-1249
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin is a circulating hormone that is primarily released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms; its levels are high during the night and low during the day. Interestingly, insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release. Indeed, both melatonin receptor 1A (MTNR1A) and MTNR1B are expressed in pancreatic islets. The role of melatonin in the regulation of glucose homeostasis has been highlighted by three independent publications based on genome-wide association studies of traits connected with type 2 diabetes, such as elevated fasting glucose, and, subsequently, of the disease itself. The studies demonstrate a link between variations in the MTNR1B gene, hyperglycaemia, impaired early phase insulin secretion and beta cell function. The risk genotype predicts the future development of type 2 diabetes. Carriers of the risk genotype exhibit increased expression of MTNR1B in islets. This suggests that these individuals may be more sensitive to the actions of melatonin, leading to impaired insulin secretion. Blocking the inhibition of insulin secretion by melatonin may be a novel therapeutic avenue for type 2 diabetes.
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| 9. |
- Nagorny, Cecilia, et al.
(författare)
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Distribution of melatonin receptors in murine pancreatic islets.
- 2011
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Ingår i: Journal of Pineal Research. - 1600-079X. ; 50, s. 412-417
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin has multiple receptor-dependent and receptor-independent functions. At the cell membrane, melatonin interacts with its receptors MT1 and MT2, which are expressed in numerous tissues. Genome-wide association studies have recently shown that the MTNR1B/MT2 receptor may be involved in the pathogenesis of type 2 diabetes mellitus. In line with these findings, expression of melatonin receptors has been shown in mouse, rat, and human pancreatic islets. MT1 and MT2 are G-protein-coupled receptors and are proposed to exert inhibitory effects on insulin secretion. Here, we show by immunocytochemistry that these membrane melatonin receptors have distinct locations in the mouse islet. MT1 is expressed in α-cells while MT2 is located to the β-cells. These findings help to unravel the complex machinery underlying melatonin's role in the regulation of islet function.
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| 10. |
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| 11. |
- Nagorny, Cecilia
(författare)
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Melatonin receptors in pancreatic islets - Linking a genetic variant to functional phenotype
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Defective insulin secretion and insulin resistance are the two hallmarks of Type 2 Diabetes (T2D). The pathophysiology of the disease is not fully understood but genetic susceptibility for the disease is a new major player in the understanding of the underlying mechanisms. T2D research has in recent years invested tremendous efforts in identifying new risk variants for the disease. It has proven to be a great success, with about 40 new risk loci identified. This thesis describes the discovery and functional phenotype of one of these risk variants: the melatonin receptor 2 (MT2; MTNR1B). The overall aim was to understand the link between this genetic variation and the functional phenotype. The initial finding of the risk variant in the MTNR1B gene was associated with increased fasting plasma glucose, impaired early insulin secretion, and increased risk of T2D. Also, risk variant carriers displayed increased mRNA expression of MTNR1B in islets, suggesting a direct inhibitory effect of melatonin on β-cells. The confirmation and further characterization of melatonin receptor expression in pancreatic islets was completed in study II. Here, we could show that murine pancreatic islets express MT2 in β-cells, whereas melatonin receptor 1 (MT1) is localized in α-cells. After an intravenous glucose challenge, glucose elimination was unaltered in MT2 whole body knock out animals. In contrast, insulin secretion was elevated, particularly the first phase of secretion. This could in part be explained by an increased amount of pancreatic islets in these animals. The two other knock out strains investigated – the MT1 knock out and the double knock out MT1/2 – displayed a more moderate phenotype. Whereas the MT1/2 mouse was very similar to wild type mice in all parameters of glucose homeostasis investigated, MT1 mice displayed a more diabetes-like phenotype, with elevated blood glucose levels after glucose challenge. Taken together, findings in the MT2 knock out mice supported the model of a gain-of-function mutation in MT2/MTNR1B in humans in T2D. This results in increased expression of the receptor in β-cells, where it exhibits a direct inhibition of insulin release. With this, we have substantiated a possible link between the genetic risk variant and the functional phenotype of MTNR1B.
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| 12. |
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| 13. |
- Nagorny, Cecilia, et al.
(författare)
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Tired of Diabetes Genetics? Circadian Rhythms and Diabetes: The MTNR1B Story?
- 2012
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Ingår i: Current Diabetes Reports. - : Springer Science and Business Media LLC. - 1539-0829 .- 1534-4827. ; 12:6, s. 667-672
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Tidskriftsartikel (refereegranskat)abstract
- Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease.
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| 14. |
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| 15. |
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| 16. |
- Spégel, Peter, et al.
(författare)
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Metabolomic analysis of a human oral glucose tolerance test reveals fatty acids as reliable indicators of regulated metabolism
- 2010
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Ingår i: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 6:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Gas chromatography/mass spectrometry-based metabolomics was applied to investigate dynamic changes in the plasma metabolome upon an oral glucose tolerance test (OGTT). The OGTT is a frequently used diagnostic test of glucose homeostasis and diabetes. Diabetes is diagnosed either when glucose levels a parts per thousand yen7.0 mM in the fasting state or a parts per thousand yen11.0 mM at 2 h after oral glucose intake. The accuracy of the OGTT would, however, most likely improve if additional variables could be identified. In the present study, plasma samples were drawn every 15 min for 2 h after an oral glucose load of 75 g preceded by an overnight fast in healthy individuals. Blood plasma levels of more than 200 putative metabolites were measured. Multivariate modelling was used to distinguish metabolic regulation due to the glucose challenge from that of other variability. Two data scaling methods were applied, yielding similar results when evaluated by appropriate diagnostic tools. Fatty acid levels were found to be strongly decreased during the OGTT. Also, the levels of amino acids were shown to decrease. However, technical and uninduced biological variations were found to affect the amino acid levels to a greater extent than the fatty acid levels, making the fatty acids more reliable as indicators of metabolic regulation. Levels of several metabolites correlated with the quadratic glucose profile and two were found having an inverse correlation. Raw data plots of all identified significantly altered metabolites confirmed the excellent performance of the multivariate models. Using this approach, a better understanding of the metabolic response to an OGTT can be achieved, paving the way for inclusion of other variables describing appropriate metabolic control.
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| 17. |
- Spégel, Peter, et al.
(författare)
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Time-resolved metabolomics analysis of beta-cells implicates the pentose phosphate pathway in the control of insulin release
- 2013
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Ingår i: Biochemical Journal. - 0264-6021. ; 450, s. 595-605
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is coupled with changes in beta-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP(+), NADPH and insulin secretion were measured within 15 mm of stimulation of clonal INS-1 832/13 beta-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the beta-cell metabolic response. This was fulfilled by the NADPH/NADP(+) ratio, which was elevated (8-fold; P < 0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P < 0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 beta-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in beta-cell stimulus-secretion coupling.
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| 18. |
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| 19. |
- Stamenkovic, Jelena, et al.
(författare)
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Regulation of core clock genes in human islets.
- 2012
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 61:7, s. 978-985
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Tidskriftsartikel (refereegranskat)abstract
- Nearly all mammalian cells express a set of genes known as clock genes. These regulate the circadian rhythm of cellular processes by means of negative and positive autoregulatory feedback loops of transcription and translation. Recent genomewide association studies have demonstrated an association between a polymorphism near the circadian clock gene CRY2 and elevated fasting glucose. To determine whether clock genes could play a pathogenetic role in the disease, we examined messenger RNA (mRNA) expression of core clock genes in human islets from donors with or without type 2 diabetes mellitus. Microarray and quantitative real-time polymerase chain reaction analyses were used to assess expression of the core clock genes CLOCK, BMAL-1, PER1 to 3, and CRY1 and 2 in human islets. Insulin secretion and insulin content in human islets were measured by radioimmunoassay. The mRNA levels of PER2, PER3, and CRY2 were significantly lower in islets from donors with type 2 diabetes mellitus. To investigate the functional relevance of these clock genes, we correlated their expression to insulin content and glycated hemoglobin levels: mRNA levels of PER2 (ρ = 0.33, P = .012), PER3 (ρ = 0.30, P = .023), and CRY2 (ρ = 0.37, P = .0047) correlated positively with insulin content. Of these genes, expression of PER3 and CRY2 correlated negatively with glycated hemoglobin levels (ρ = -0.44, P = .0012; ρ = -0.28, P = .042). Furthermore, in an in vitro model mimicking pathogenetic conditions, the PER3 mRNA level was reduced in human islets exposed to 16.7 mmol/L glucose per 1 mmol/L palmitate for 48 hours (P = .003). Core clock genes are regulated in human islets. The data suggest that perturbations of circadian clock components may contribute to islet pathophysiology in human type 2 diabetes mellitus.
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| 20. |
- Tuomi, Tiinamaija, et al.
(författare)
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Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes
- 2016
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 23:6, s. 1067-1077
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.
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