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Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling
| Title | Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling |
| Publication Type | Journal Article |
| Year of Publication | 2006 |
| Authors | |
| Journal | Diabetologia |
| Volume | 49 |
| Issue | 9 |
| Pagination | 2120-30 |
| Date Published | Sep |
| Publication Language | eng |
| ISBN Number | 0012-186X (Print) |
| Accession Number | 16868750 |
| Key Words | Forskolin/pharmacology, Fatty Acids, Animals, Signal Transduction/drug effects, Reverse Transcriptase Polymerase Chain Reaction, Rats, Zucker, Oxidation-Reduction/drug effects, Models, Biological, Lipid Metabolism/drug effects, Lipase/metabolism, Insulin-Secreting Cells/drug effects/*metabolism, *Insulin Resistance, Insulin/*secretion, Glucose/pharmacology, Glucagon-Like Peptide 1/pharmacology, Gene Expression Regulation/drug effects, Nonesterified/metabolism/pharmacology, Binding Sites, Lipolysis/drug effects, Lactones/metabolism/pharmacology, Islets of Langerhans/cytology/drug effects/*metabolism |
| Abstract | AIMS/HYPOTHESIS: The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. MATERIALS AND METHODS: NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. RESULTS: Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. CONCLUSIONS/INTERPRETATION: The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity. |
| Notes | DK-63356/DK/NIDDK NIH HHS/United StatesDK56818/DK/NIDDK NIH HHS/United StatesIn VitroJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tGermany |
| URL | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16868750 |
| Citation Key | 460 |
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- *Insulin Resistance
- Animals
- Binding Sites
- Fatty Acids, Nonesterified/metabolism/pharmacology
- Forskolin/pharmacology
- Gene Expression Regulation/drug effects
- Glucagon-Like Peptide 1/pharmacology
- Glucose/pharmacology
- Insulin-Secreting Cells/drug effects/*metabolism
- Insulin/*secretion
- Islets of Langerhans/cytology/drug effects/*metabolism
- Lactones/metabolism/pharmacology
- Lipase/metabolism
- Lipid Metabolism/drug effects
- Lipolysis/drug effects
- Models, Biological
- Oxidation-Reduction/drug effects
- Rats
- Rats, Zucker
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects