| 1. |
- Davani, B, et al.
(författare)
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Aged transgenic mice with increased glucocorticoid sensitivity in pancreatic beta-cells develop diabetes
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 5353 Suppl 1, s. S51-S59
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids are diabetogenic hormones because they decrease glucose uptake, increase hepatic glucose production, and inhibit insulin release. To study the long-term effects of increased glucocorticoid sensitivity in β-cells, we studied transgenic mice overexpressing the rat glucocorticoid receptor targeted to the β-cells using the rat insulin I promoter. Here we report that these mice developed hyperglycemia both in the fed and the overnight-fasted states at 12–15 months of age. Progression from impaired glucose tolerance, previously observed in the same colony at the age of 3 months, to manifest diabetes was not associated with morphological changes or increased apoptosis in the β-cells. Instead, our current results suggest that the development of diabetes is due to augmented inhibition of insulin secretion through α2-adrenergic receptors (α2-ARs). Thus, we found a significantly higher density of α2-ARs in the islets of transgenic mice compared with controls, based on binding studies with the α2-AR agonist UK 14304. Furthermore, incubation of islets with benextramine, a selective antagonist of the α2-AR, restored insulin secretion in response to glucose in isolated islets from transgenic mice, whereas it had no effect on control islets. These results indicate that the chronic enhancement of glucocorticoid signaling in pancreatic β-cells results in hyperglycemia and impaired glucose tolerance. This effect may involve signaling pathways that participate in the regulation of insulin secretion via the α2-AR.
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| 2. |
- Winzell, M S, et al.
(författare)
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The expression of hormone-sensitive lipase in clonal beta-cells and rat islets is induced by long-term exposure to high glucose
- 2001
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 50:10, s. 2225-2230
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Tidskriftsartikel (refereegranskat)abstract
- Hormone-sensitive lipase (HSL) is expressed and enzymatically active in beta-cells and has been proposed to be involved in the generation of the lipid-derived signal that seems to be necessary for glucose-stimulated insulin secretion. In this study, we investigated whether the expression of HSL in INS-1 cells and in rat islets is affected by exposure to high glucose concentrations. Incubation of INS-1 cells in 25 mmol/l glucose for 16 and 32 h induced HSL protein expression twofold, whereas no effect was observed after 4 and 8 h of incubation. The HSL activity, defined as the diglyceride lipase activity inhibited by anti-rat HSL antibodies, constituted approximately 25% of total diglyceride lipase activity and was induced to a similar extent as HSL protein levels. The glucose effect at 16 h on HSL protein expression level was confirmed in freshly isolated rat islets. Exposure of INS-1 cells to different glucose concentrations for 16 h showed that the inductive effect on HSL protein levels was maximum at 20 mmol/l glucose (2- to 2.5-fold). Northern blot analysis demonstrated a more than threefold elevation of HSL mRNA levels. The induction was blocked by actinomycin D, and the half-life of the transcript seemed to be unchanged by high glucose, suggesting a transcriptional nature of the glucose effect on HSL gene expression. The nonmetabolizable glucose analog 2-deoxyglucose, which has no mitogenic effect, induced HSL approximately 1.3-fold, whereas mannose was similar to glucose, stimulating HSL expression 1.7- to 2-fold. The results suggest that HSL is involved in the beta-cell responses to hyperglycemia and also in generating the lipid signal that is needed in stimulus-secretion coupling.
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