The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets

Masiello, Pellegrino; Novelli, Michela; Bombara, M; Fierabracci, Vanna; Vittorini, Simona; Prentki, Marc; Bergamini, Ettore

doi:10.1053/meta.2002.28969

Cited by 34 publications

(32 citation statements)

References 10 publications

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“…For instance, LC-CoAs and diacylglycerol [1,6] are both lipid-derived molecules that potentially could be generated by HSL upon lipolysis. The role of lipases in insulin secretion has been emphasised by islet studies, using different pharmacological inhibitors [21,42]. Recently, a specific inhibitor of HSL, 5-(2H)-isoxazolonyl urea, was shown to significantly inhibit insulin secretion in rat islets [14].…”

Section: Discussionmentioning

confidence: 99%

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A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

et al. 2008

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Aims/hypothesis The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. Methods To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. Results We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. Conclusions/interpretation Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipidderived signal essential for normal insulin secretion.

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Section: Discussionmentioning

confidence: 99%

“…While pharmacological studies have supported the idea of a role for lipases in insulin secretion [13,42], such studies have their shortcomings. It was therefore hoped that a global KO mouse would provide clear information about the role of HSL in beta cells.…”

Section: Discussionmentioning

confidence: 99%

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

et al. 2008

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“…We [16,18] and co-workers [17] have provided genetic (Hsl knockout studies) and pharmacological (Orlistat, dimethylpyrazole) evidence that lipolysis plays a role in GSIS. This study expands that concept by providing evidence that enhanced lipolysis and, most probably, TG-FA cycling in ZF islets appear to be a mechanism for the enhanced insulin secretion that characterises beta cell compensation for their insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Lipolysis is known to be active in the beta cell, and has been implicated in both lipid signalling for insulin secretion [16][17][18] and, if dysregulated, beta cell failure [19]. However, little is known about its regulation and which lipolytic enzymes are operative.…”

Section: Introductionmentioning

confidence: 99%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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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 glucosestimulated 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/interpretationThe 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.

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“…To date, the role of endogenous TG in the regulation of insulin secretion has remained elusive, although the following evidence indicates that they may be important: 1) islet TG content correlates with the enhancement of insulin secretion in obesity (31); 2) glucose-stimulated insulin secretion is abrogated in islets depleted of TG by overexpression of the leptin gene (18); 3) pharmacological antilipolytic agents partially inhibit glucose-induced insulin secretion in vivo (16); and 4) we recently observed that the antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cAMP agonists in isolated rat islets, the inhibition being relieved by a synthetic diacylglycerol (32). Hence, our results in HSL-deficient mice provide direct support for the hypothesis that endogenous TG stores, via HSL-mediated lipolysis, normally play an important role in glucoseinduced insulin release.…”

Section: Discussionmentioning

confidence: 99%

A Role for Hormone-Sensitive Lipase in Glucose-Stimulated Insulin Secretion

et al. 2001

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Endogenous lipid stores are thought to be involved in the mechanism whereby the ␤-cell adapts its secretory capacity in obesity and diabetes. In addition, hormonesensitive lipase (HSL) is expressed in ␤-cells and may provide fatty acids necessary for the generation of coupling factors linking glucose metabolism to insulin release. We have recently created HSL-deficient mice that were used to directly assess the role of HSL in insulin secretion and action. HSL ؊/؊ mice were normoglycemic and normoinsulinemic under basal conditions, but showed an ϳ30% reduction of circulating free fatty acids (FFAs) with respect to control and heterozygous animals after an overnight fast. An intraperitoneal glucose tolerance test revealed that HSL-null mice were glucose-intolerant and displayed a lack of a rise in plasma insulin after a glucose challenge. Examination of plasma glucose during an insulin tolerance test suggested that HSL-null mice were insulin-resistant, because plasma glucose was barely lowered after the injection of insulin. Freshly isolated islets from HSL-deficient mice displayed elevated secretion at low (3 mmol/l) glucose, failed to release insulin in response to high (20 mmol/l) glucose, but had a normal secretion when challenged with elevated KCl. The phenotype of heterozygous mice with respect to the measured parameters in vitro was similar to that of wild type. Finally, the islet triglyceride content of HSL ؊/؊ mice was 2-2.5 fold that in HSL ؊/؉ and HSL ؉/؉ animals. The results demonstrate an important role of HSL and endogenous ␤-cell lipolysis in the coupling mechanism of glucose-stimulated insulin secretion. The data also provide direct support for the concept that some lipid molecule(s), such as FFAs, fatty acyl-CoA or their derivatives, are implicated in ␤-cell glucose signaling.

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The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets

Cited by 34 publications

References 10 publications

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

A Role for Hormone-Sensitive Lipase in Glucose-Stimulated Insulin Secretion

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