| 1. |
- Zhang, Q., et al.
(författare)
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Na+ current properties in islet alpha- and beta-cells reflect cell-specific Scn3a and Scn9a expression
- 2014
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Ingår i: Journal of Physiology-London. - : Wiley. - 0022-3751 .- 1469-7793. ; 592:21, s. 4677-4696
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Tidskriftsartikel (refereegranskat)abstract
- - and -cells express both Na(v)1.3 and Na(v)1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in - and -cells. Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells. Islet Na(v)1.7 channels are locked in an inactive state due to an islet cell-specific factor. Mouse pancreatic - and -cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation (V-0.5) at -100mV and -50mV in - and -cells, respectively). Single-cell PCR analyses show that both - and -cells have Na(v)1.3 (Scn3) and Na(v)1.7 (Scn9a) subunits, but their relative proportions differ: -cells principally express Na(v)1.7 and -cells Na(v)1.3. In -cells, genetically ablating Scn3a reduces the Na+ current by 80%. In -cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a(-/-) islets but unaffected in Scn9a-deficient islets. Thus, Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells because Na(v)1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Na(v)1.7 sequence in brain and islets is identical and yet the V-0.5 for inactivation is >30mV more negative in -cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.
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| 2. |
- Latreille, Mathieu, et al.
(författare)
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MicroRNA-7a regulates pancreatic beta cell function
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 124:6, s. 2722-2735
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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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