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- Hamilton, A., et al.
(författare)
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Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca2+ mobilization from acidic stores in pancreatic a-Cells
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:6, s. 1128-1139
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Tidskriftsartikel (refereegranskat)abstract
- Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human a-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity, and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+]i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum. © 2018 by the American Diabetes Association.
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- Adam, J., et al.
(författare)
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Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:13, s. 3135-3148
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Tidskriftsartikel (refereegranskat)abstract
- We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1 beta KO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1 alpha or Nrf2. Progressive hyperglycemia in Fh1bKO mice led to dysregulated metabolism in b cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+](i) elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1bKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.
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- Mach, Henryk, et al.
(författare)
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Ultrafast-timing lifetime measurements in Ru-94 and Pd-96 : Breakdown of the seniority scheme in N=50 isotones
- 2017
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Ingår i: PHYSICAL REVIEW C. - : American Physical Society. - 2469-9985. ; 95:1
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Tidskriftsartikel (refereegranskat)abstract
- The advanced time-delayed gamma gamma(t) method has been applied to determine half-lives of low-lying states in the N = 50 isotones Ru-94 and Pd-96. The inferred experimental E2 strengths for the 4(+) -> 2(+) transitions in the two nuclei show a dramatic deviation with respect to the shell model predictions in the (f(5/2), p, g(9/2)) proton hole space in Sn-100. The anomalous behavior can be ascribed to a breakdown of the seniority quantum number in the pi g(9/2)(n) configuration due to particle-hole excitations across the N = Z = 50 shell as confirmed by large-scale shell model calculations.
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- van Setten, Jessica, et al.
(författare)
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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
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- Hastoy, B., et al.
(författare)
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Electrophysiological properties of human beta-cell lines EndoC-beta H1 and -beta H2 conform with human beta-cells
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-beta H1 and EndoC-beta H2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca2+](i), membrane depolarisation and increased action potential firing. Similar to human primary beta cells, K-ATP channel activity is low at 1mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the K-ATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca2+-activated K+ channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electrondense core surrounded by a thin clear halo. We conclude that the EndoC-beta H1 and -beta H2 cells share many features of primary human beta-cells and thus represent a useful experimental model.
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