| 1. |
- Mulder, Hindrik, et al.
(författare)
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Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion.
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:1, s. 122-128
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Tidskriftsartikel (refereegranskat)abstract
- Lipids may serve as coupling factors in KATP-independent glucose sensing in β-cells. We have previously demonstrated that β-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether β-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in KATP-independent glucose sensing has been perturbed. Thus, β-cell lipase activity is involved in GSIS, emphasizing the important role of β-cell lipid metabolism for insulin secretion.
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| 2. |
- Sörhede Winzell, Maria, et al.
(författare)
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Pancreatic beta-Cell Lipotoxicity Induced by Overexpression of Hormone-Sensitive Lipase.
- 2003
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 52:8, s. 2057-2065
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Tidskriftsartikel (refereegranskat)abstract
- Lipid perturbations associated with triglyceride overstorage in β-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in β-cells, in the development of lipotoxicity, we generated transgenic mice overexpressing hormone-sensitive lipase specifically in β-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased in transgenic compared with wild-type islets. This was reflected in significantly lower triglycerides levels in transgenic compared with wild-type islets in mice receiving the high-fat diet, whereas no difference in islet triglycerides was found between the two genotypes under low-fat diet conditions. Our results highlight the importance of mobilization of the islet triglyceride pool in the development of β-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating β-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid-activated transcription factors, which in turn alter the expression of critical genes. One such gene might be uncoupling protein-2, which was found to be upregulated in transgenic islets, a change that was accompanied by decreased ATP levels.
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| 3. |
- Sörhede Winzell, Maria, et al.
(författare)
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Beta-Cell-Targeted Expression of a Dominant-Negative Mutant of Hepatocyte Nuclear Factor-1{alpha} in Mice: Diabetes Model with {beta}-Cell Dysfunction Partially Rescued by Nonglucose Secretagogues.
- 2004
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Ingår i: Diabetes. - 1939-327X. ; 53:suppl_3, s. 92-96
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Tidskriftsartikel (refereegranskat)abstract
- We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. At age 2-3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P=0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P=0.006). In islets incubated for 60 min, the insulin response to glucose (3.3-22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose secretagogues were only partially suppressed (to GLP-1 [100 nmol/l] by 40%, to carbachol [1 micromol/l] by 20%, and to palmitate [0.5 mmol/l] by 15%), whereas the response to depolarization by KCl (50 mmol/l) was not reduced. Finally, the IVGTT data insulin sensitivity in transgenic mice was not significantly different from that of wild-type mice. Thus, mice with targeted suppression of beta-cell HNF-1alpha represent a good diabetes model exhibiting severely impaired insulin secretion after glucose with marked glucose intolerance. In contrast, the insulin responses to nonglucose stimuli are not suppressed when the islet insulin content is taken into account.
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| 4. |
- Sörhede Winzell, Maria, et al.
(författare)
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The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes.
- 2004
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Ingår i: Diabetes. - 1939-327X. ; 53:Suppl 3, s. 215-219
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Tidskriftsartikel (refereegranskat)abstract
- This study characterizes the high-fat diet-fed mouse as a model for impaired glucose tolerance (IGT) and type 2 diabetes. Female C57BL/6J mice were fed a high-fat diet (58% energy by fat) or a normal diet (11% fat). Body weight was higher in mice fed the high-fat diet already after the first week, due to higher dietary intake in combination with lower metabolic efficiency. Circulating glucose increased after 1 week on high-fat diet and remained elevated at a level of approximately 1 mmol/l throughout the 12-month study period. In contrast, circulating insulin increased progressively by time. Intravenous glucose challenge revealed a severely compromised insulin response in association with marked glucose intolerance already after 1 week. To illustrate the usefulness of this model for the development of new treatment, mice were fed an orally active inhibitor of dipeptidyl peptidase-IV (LAF237) in the drinking water (0.3 mg/ml) for 4 weeks. This normalized glucose tolerance, as judged by an oral glucose tolerance test, in association with augmented insulin secretion. We conclude that the high-fat diet-fed C57BL/6J mouse model is a robust model for IGT and early type 2 diabetes, which may be used for studies on pathophysiology and development of new treatment.
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