A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion.

Dobbins, Robert L.; Chester, Michael R.; Stevenson, B E; Daniels, M B; Stein, Daniel T.; McGarry, Julie

doi:10.1172/jci1813

Cited by 143 publications

(135 citation statements)

References 14 publications

(24 reference statements)

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“…This finding is in keeping with the previous observation that NEFA augment insulin secretion in response not only to glucose but also to all fuel and nonfuel secretagogues, including GLP-1 [13]. The present findings reinforce the concept that NEFA are not only essential for insulin secretion [23] but are also involved in enhancement of secretion in response to a wide variety of Fig. 6 Expression of genes related to lipid metabolism and signalling at the mRNA level in ZF and ZL islets.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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

et al. 2006

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“…Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release (Boden et al, 1998;Dobbins et al, 1998;McGarry and Dobbins, 1999). These results imply that physiological plasma levels of FFA are important for bcell function.…”

Section: Resultsmentioning

confidence: 95%

“…In rats deprived of food for 18-24 h, the ability of the b-cell to secrete insulin in response to a glucose load is fully dependent upon the elevated levels of circulating FFA characteristic of the fasted state (Stein et al, 1996). In fact, circulating FA are essential for an efficient glucose stimulation of insulin release after prolonged fasting in humans and rats (Dobbins et al, 1998).…”

Section: Plasma Fa and Insulin Secretionmentioning

confidence: 99%

“…This condition renders the b-cell dependent upon a high external FFA concentration to make up the deficit. Alternatively, starvation may simply deplete a critical lipid moiety that is needed to synergize with glucose for activation of hormone release and whose concentration can only be maintained under an adequate supply of FFA from the circulation (Dobbins et al, 1998).…”

Section: Plasma Fa and Insulin Secretionmentioning

confidence: 99%

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Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

148

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Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic b-cells have long been recognized. Acute exposure of the pancreatic b-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for b-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acylCoA (LC-CoA) controls several aspects of the b-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide-and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.

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“…10 LC-CoA may also directly stimulate exocytosis. 11 Thus, malonyl-CoA and LCCoA increase within minutes after glucose addition in a pancreatic b-cell line. 12 Addition of exogenous FFA may amplify this effect by providing more LC-CoA.…”

Section: Short-term Effects Of Fatty Acids On Insulin Secretionmentioning

confidence: 94%

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet

2004

Int J Obes

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Obesity is associated with increased storage of lipids in nonadipose tissues like skeletal muscle, liver, and pancreatic b cells. These lipids constitute a continuous source of long-chain fatty acyl CoA (LC-CoA) and derived metabolites like diacylglycerol and ceramide, acting as signalling molecules on protein kinases activities (in particular, the family of PKCs), ion channel, gene expression, and protein acylation. In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. This interrupts the insulin signalling pathway leading to the stimulation of glucose transport. In pancreatic b cells, short-term excess of fatty acids or LC-CoA activates PKC and also directly stimulates insulin exocytosis. Longterm exposure to free fatty acids (FFA) leads to an increased basal and blunted glucose-stimulated insulin secretion by affecting gene expression, increase in K ATP channel activity, and uncoupling of the mitochondria. In addition, the saturated FFA palmitate increases cell death by apoptosis via increase in ceramide synthesis.

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A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion.

Cited by 143 publications

References 14 publications

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

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

Pleiotropic effects of fatty acids on pancreatic β‐cells

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

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