Glucagon-like peptide 1 and fatty acids amplify pulsatile insulin secretion from perifused rat islets

Cunningham, Barbara A.; Richard, Ann-Marie; Dillon, Joseph S.; Daley, Jennifer; Civelek, Vildan N.; Deeney, Jude T.; Yaney, Gordon C.; Corkey, Barbara E.; Tornheim, Keith

doi:10.1042/bj20021196

Cited by 20 publications

(22 citation statements)

References 51 publications

(70 reference statements)

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“…These latter negative effects might simply be quantitatively unimportant or less important under physiological conditions. Another intriguing possibility is that in the context of oscillations in glycolysis, intracellular Ca 2+ and secretion [59,114,123,124,125,126], they may actually contribute to the recovery of resting cytosolic Ca 2+ after its increase, if LC-CoA oscillates out of phase with the ATP:ADP ratio. This scenario would be distinct from the incretin effects of exogenous NEFA which might be more "global" and long-lived.…”

Section: Potential Mediators and Targets Of Lc-coa Estersmentioning

confidence: 99%

“…These data provide important evidence that NEFA, their CoA derivatives or complex lipids formed from them are critical coupling factors in nutrient signalling in the beta cell. Recent evidence indicates that lipolysis of beta-cell triglyceride stores could play a central role in the action of incretins such as GLP-1 in potentiating GSIS via increased intracellular cAMP [113,114].…”

Section: Potentiation Of Gsis By Extracellular Nefamentioning

confidence: 99%

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Fatty acid metabolism and insulin secretion in pancreatic beta cells

2003

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Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acylCoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial β-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states. [Diabetologia (2003[Diabetologia ( ) 46:1297[Diabetologia ( -1312

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Section: Potential Mediators and Targets Of Lc-coa Estersmentioning

confidence: 99%

Section: Potentiation Of Gsis By Extracellular Nefamentioning

confidence: 99%

Fatty acid metabolism and insulin secretion in pancreatic beta cells

2003

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“…In addition, the potent hormone, glucagon-like peptide 1 (GLP-1), has been shown to stimulate lipolysis in clonal pancreatic ␤-cells (HIT) (16). Furthermore, its incretin effect can be inhibited in rat islets (17) by the lipase inhibitor orlistat. The proposed mechanism of GLP1Ϫinduced lipolysis is via activation of hormone-sensitive lipase (HSL) (16).…”

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confidence: 99%

Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1

et al. 2004

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We previously reported decreased glucose-stimulated insulin secretion (GSIS) in hormone-sensitive lipase؊null mice (HSL ؊/؊ ), both in vivo and in vitro. The focus of the current study was to gain further insight into the signaling role and regulation of lipolysis in islet tissue. The effect of glucagon-like peptide 1 (GLP-1) on GSIS was also studied, as GLP-1 could augment GSIS via protein kinase A activation of HSL and lipolysis. Freshly isolated islets from fasted and fed male HSL ؊/؊ and wild-type (HSL ؉/؉ ) mice were studied at ages 4 and 7 months. Neutral cholesteryl ester hydrolase activity was markedly reduced in islets from both 4-and 7-month-old male HSL ؊/؊ mice, whereas a marked deficiency in triglyceride lipase activity became evident only in the older mice. The deficiencies in lipase activities were associated with higher islet triglyceride content and reduced lipolysis at basal glucose levels. Lipolysis was stimulated by high glucose in islets of both wild-type and HSL-null mice. Severe deficiencies in GSIS were found, but only in islets from 7-month-old, fasted, male HSL ؊/؊ mice. GSIS was less affected in 4-month-old fasted male HSL ؊/؊ mice and not reduced in female mice. Exogenous delivery of free fatty acids (FFAs) rescued GSIS, supporting the view that the lack of endogenous FFA supply for lipid-signaling processes in HSL ؊/؊ mice was responsible for the loss of GSIS. GLP-1 also rescued GSIS in HSL ؊/؊ mice, indicating that signaling via HSL is not a major pathway for its incretin effect. Thus, the secretory phenotype of HSL-null mice is gender dependent, increases with age, and is influenced by the nutritional state. Under most circumstances, the major determinant of lipolytic flux in the ␤-cell involves an enzyme(s) other than HSL that is acutely activated by glucose. Our results support the view that the availability of endogenous FFA through HSL and an additional enzyme(s) is involved in providing lipid moieties for ␤-cell signaling for secretion in response to glucose.

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“…To circumvent the issue of which particular lipase accounts for hydrolysis of acylglycerides in pancreatic ␤-cells, we used an inhibitor of a wide spectrum of lipases. Our choice was tetrahydrolipstatin, or orlistat, which is a lipophilic molecule that irreversibly binds to the catalytic site of a great number of lipases (13) and which has previously been shown to inhibit cAMPinduced insulin secretion in the clonal ␤-cell line HIT-T15 (14) and glucagon-like peptide 1 (GLP-1)-stimulated secretion in rat islets (15). The drug is widely used for treatment of obesity (16); it inhibits intestinal lipases, preventing uptake of lipids and thereby restricting caloric input.…”

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confidence: 99%

Inhibition of Lipase Activity and Lipolysis in Rat Islets Reduces Insulin Secretion

et al. 2004

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Lipids may serve as coupling factors in K ATP -independent glucose sensing in ␤-cells. We have previously demonstrated that ␤-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether ␤-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 K ATP -independent glucose sensing has been perturbed. Thus, ␤-cell lipase activity is involved in GSIS, emphasizing the important role of ␤-cell lipid metabolism for insulin secretion. Diabetes 53:122-128, 2004A large body of evidence suggests that lipids are required for appropriate glucose sensing in pancreatic ␤-cells. For instance, when triglycerides in pancreatic islets are depleted by hyperleptinemia, pancreatic ␤-cells fail to release insulin (1). Along similar lines, perfused pancreas from fasted rats is unresponsive to a rise in glucose (2). Importantly, in both cases, glucose responsiveness is reinstated by the addition of exogenous fatty acids.The current view holds that lipids serve as coupling factors in glucose-stimulated insulin secretion (GSIS) that does not rely on closure of the ATP-sensitive K ϩ channel (K ATP independent) (3). These putative mechanisms presumably drive the second phase of GSIS and accordingly have been termed as amplifying (4), and the coupling factors have been proposed to emanate from intermediary metabolism in the ␤-cell (5). Against this background, lipids have become attractive candidates for coupling factors in K ATP -independent glucose sensing. In fact, a model has been proposed to delineate the combined events in metabolism of glucose and lipids that result in a dose-dependent regulation of insulin secretion, the socalled long-chain acyl-CoA hypothesis (3). This model is based on the observations that an increase in glucose metabolism in ␤-cells results in decreased oxidation of fats while esterification of lipids increases. As a consequence, the levels of complex lipids rise, perhaps acyl-CoA moieties, which then act as a signaling molecules coupling stimulus to secretion in the ␤-cell. We have previously demonstrated that different preparations of ␤-cells...

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Glucagon-like peptide 1 and fatty acids amplify pulsatile insulin secretion from perifused rat islets

Cited by 20 publications

References 51 publications

Fatty acid metabolism and insulin secretion in pancreatic beta cells

Fatty acid metabolism and insulin secretion in pancreatic beta cells

Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1

Inhibition of Lipase Activity and Lipolysis in Rat Islets Reduces Insulin Secretion

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