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Sökning: WFRF:(Hastoy Benoit)

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1.
  • Collins, S. C., et al. (författare)
  • Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion
  • 2016
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 0012-1797. ; 65:7, s. 1952-1961
  • Tidskriftsartikel (refereegranskat)abstract
    • The transcription factor Sox4 has been proposed to underlie the increased type 2 diabetes risk linked to an intronic single nucleotide polymorphism in CDKAL1. In a mouse model expressing a mutant form of Sox4, glucose-induced insulin secretion is reduced by 40% despite normal intracellular Ca2+ signaling and depolarization-evoked exocytosis. This paradox is explained by a fourfold increase in kiss-and-run exocytosis (as determined by single-granule exocytosis measurements) in which the fusion pore connecting the granule lumen to the exterior expands to a diameter of only 2 nm, which does not allow the exit of insulin. Microarray analysis indicated that this correlated with an increased expression of the exocytosis-regulating protein Stxbp6. In a large collection of human islet preparations (n = 63), STXBP6 expression and glucose induced insulin secretion correlated positively and negatively with SOX4 expression, respectively. Overexpression of SOX4 in the human insulin-secreting cell EndoC-beta H2 interfered with granule emptying and inhibited hormone release, the latter effect reversed by silencing STXBP6. These data suggest that increased SOX4 expression inhibits insulin secretion and increased diabetes risk by the upregulation of STXBP6 and an increase in kiss- and-run exocytosis at the expense of full fusion. We propose that pharmacological interventions promoting fusion pore expansion may be effective in diabetes therapy.
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2.
  • Vergari, Elisa, et al. (författare)
  • Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin's capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin's hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.
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3.
  • Dwivedi, Om Prakash, et al. (författare)
  • Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; , s. 1-22
  • Tidskriftsartikel (refereegranskat)abstract
    • A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
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4.
  • Latreille, Mathieu, et al. (författare)
  • MicroRNA-7a regulates pancreatic beta cell function
  • 2014
  • Ingår i: Journal of Clinical Investigation. - : Am Soc Clin Investig. - 0021-9738. ; 124:6, s. 2722-2735
  • Tidskriftsartikel (refereegranskat)abstract
    • Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic beta cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of beta cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in beta cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates beta cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in beta cells developed diabetes due to impaired insulin secretion and beta cell dedifferentiation. Interestingly, perturbation of miR-7a expression in beta cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine beta cell mass. Furthermore, we found that miR-7a levels are decreased in obese/ diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated beta cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic beta cells and support a role for miR-7 in the adaptation of pancreatic p cell function in obesity and type 2 diabetes.
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