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- Taddeo, EP, et al.
(författare)
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Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:2, s. 131-145
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Tidskriftsartikel (refereegranskat)abstract
- Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.
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- Navidad, Marina, et al.
(författare)
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Ordovician magmatism in the Eastern Pyrenees : Implications for the geodynamic evolution of northern Gondwana
- 2018
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Ingår i: Lithos. - : Elsevier. - 0024-4937 .- 1872-6143. ; 314-315, s. 479-496
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Tidskriftsartikel (refereegranskat)abstract
- New data on the geochemistry and geochronology of different felsic gneisses and metabasites from the Variscan massifs of Eastern Pyrenees have allowed us to shed some light on the Ordovician magmatic evolution in northern Gondwana during the opening of the Rheic Ocean. According to these data, the Ordovician magmatism represents a continuous event of anatectic melting, with limited mantle influence, that lasted 20 m.y., from Early to Late Ordovician. In the Canigó massif, peraluminous monzogranitic and granodioritic metaigneous rocks intruded a late Ediacaran-early Cambrian sequence at 464.3 ± 1.6 Ma and 461.6 ± 1.5 Ma, respectively, and leucogranitic gneisses intruded at 457.4 ± 1.6 Ma. Whole-rock geochemistry of the felsic rocks (plutonic and subvolcanic) points to a volcanic arc setting. However, the geological context and the geochemistry of the coeval metabasites are incompatible with this tectonic setting and point out to the inception of an extensional margin. Sm-Nd isotopic data suggest that the felsic rocks are derived from the anatexis of juvenile igneous rocks (probably Cadomian), mixed with older crustal components present in a late Neoproterozoic crust. We interpret that the Ordovician magmas inherited the geochemical signature of the rocks formed at the former Cadomian convergent margin. The variation of the εNd values from −2 to −4 in the Lower Ordovician rocks, to −5 in the Upper Ordovician rocks suggests a greater implication of the older component in a within-plate geodynamic context, coeval with the evolution of an extensional marginal basin linked to the opening of the Rheic Ocean. A similar isotopic evolution, more depleted first and with a greater implication of the crust in the younger sample, is shown by the studied metabasites.
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