| 1. |
- Lindvall, Håkan, et al.
(författare)
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A novel hormone-sensitive lipase isoform expressed in pancreatic beta -cells.
- 2004
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 279:5, s. 3828-3836
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Tidskriftsartikel (refereegranskat)abstract
- Hormone-sensitive lipase (HSL) is a key enzyme in fatty acid mobilization in many cell types. Two isoforms of HSL are known to date, namely HSLadi (84 kDa in rat) and HSLtes (130 kDa in rat). These are encoded by the same gene, with exons 1-9 encoding the parts that are common to both and an additional 5'-exon encoding the additional amino acids in HSLtes. HSL of various tissues, among these the islet of Langerhans, is larger than HSLadi, but not as large as HSLtes, indicating that there may be other 5'-coding exons. Here we describe the molecular basis for a novel 89-kDa HSL isoform that is expressed in -cells, adipocytes, adrenal glands, and ovaries in the rat and that is encoded by exons 1-9 and exon A, which is spliced to exon 1 and thereby introducing an upstream start codon. The additional 5'-base pairs encode a 43-amino acid peptide, which is highly positively charged. Conglomerates of HSL molecules are in close association with the secretory granules of the -cell, as determined by immunoelectron microscopy with antibodies targeting two separate regions of HSL. We have also determined that the human genomic sequence upstream of exon A has promoter activity in INS-1 cells as well as glucose sensing capability, mediating an increase in expression at high glucose concentration. The minimal promoter is present within 170 bp from the transcriptional start site and maximal glucose responsiveness is conferred by sequence within 850 bp from the transcriptional start site.
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| 2. |
- Sörhede Winzell, Maria, et al.
(författare)
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Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50, s. 1453-1462
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA ( 300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. Results Fasting plasma glucose levels were reduced by GRA (6.0 +/- 0.2 vs 7.4 +/- 0.5 mmol/l; p= 0.017). The acute insulin response to intravenous glucose was augmented ( 1,300 +/- 110 vs 790 +/- 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA ( 1,890 +/- 160 vs 3,040 +/- 420 pmol/ l; p= 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response ( 129 +/- 12 vs 36 +/- 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 +/- 0.007 vs 0.030 +/- 0.004 pmol islet(-1) h(-1) at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.
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| 3. |
- 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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