| Autor: |
McQuaid, T S, Saleh, M C, Joseph, J W, Gyulkhandanyan, A, Manning-Fox, J E, MacLellan, J D, Wheeler, M B, Chan, C B |
| Zdroj: |
Journal of Endocrinology; July 2006, Vol. 190 Issue: 3 p669-680, 12p |
| Abstrakt: |
We investigated whether an increase in cAMP could normalize glucose-stimulated insulin secretion (GSIS) in uncoupling protein-2 (UCP2) overexpressing (ucp2-OE) β-cells. Indices of β-cell (β-TC-6f7 cells and rodent islets) function were measured after induction of ucp2, in the presence or absence of cAMP-stimulating agents, analogs, or inhibitors. Islets of ob/obmice had improved glucose-responsiveness in the presence of forskolin. Rat islets overexpressing ucp2had significantly lower GSIS than controls. Acutely, the protein kinase A (PKA) and epacpathway stimulant forskolin normalized insulin secretion in ucp2-OE rat islets and β-TC-6f7 β-cells, an effect blocked by specific PKA inhibitors but not mimicked by epacagonists. However, there was no effect of ucp2-OE on cAMP concentrations or PKA activity. In ucp2-OE islets, forskolin inhibited ATP-dependent potassium (KATP) channel currents and 86Rb+efflux, indicative of KATPblock. Likewise, forskolin application increased intracellular Ca2+, which could account for its stimulatory effects on insulin secretion. Chronic exposure to forskolin increased ucp2mRNA and exaggerated basal secretion but not GSIS. In mice deficient in UCP2, there was no augmentation of either cAMP content or cAMP-dependent insulin secretion. Thus, elevating cellular cAMP can reverse the deficiency in GSIS invoked by ucp2-OE, at least partly through PKA-mediated effects on the KATPchannel. |
| Databáze: |
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