Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

Carpentier, André C.; Giacca, Adria; Lewis, Gary F.

doi:10.1007/s001250100002

Cited by 28 publications

(4 citation statements)

References 22 publications

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“…In contrast, Carpentier et al [23] have shown that the increase in insulin secretion observed in response to an acute (90-min) lipid infusion in healthy subjects disappears when the infusion is prolonged to 48h. The loss of insulin secretion is specific to the response to glucose, as the response to arginine remains normal [24]. The same group further showed that obese, but not diabetic, subjects are susceptible to the inhibitory effect of lipids on glucose-induced insulin secretion [25].…”

Section: Why Has Glucolipotoxicity Been Challenged?mentioning

confidence: 99%

Glucolipotoxicity of the pancreatic β-cell: myth or reality?

Poitout

2008

Biochemical Society Transactions

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The glucolipotoxicity hypothesis postulates that chronically elevated levels of glucose and fatty acids adversely affect pancreatic beta-cell function and thereby contribute to the deterioration of insulin secretion in type 2 diabetes. Whereas ample experimental evidence in in vitro systems support the glucolipotoxicity hypothesis, the contribution of this phenomenon to beta-cell dysfunction in human type 2 diabetes has been questioned. The reasons for this controversy include differences between in vitro systems and in vivo situations; time-dependent effects of fatty acids on insulin secretion (acutely stimulatory and chronically inhibitory); and the ill-defined use of the suffix “-toxicity”. In vitro, prolonged exposure of insulin-secreting cells or isolated islets to concomitantly elevated levels of fatty acids and glucose impair insulin secretion, inhibit insulin gene expression and, under certain circumstances, induce beta-cell death by apoptosis. Recent studies in our laboratory have shown that cyclical and alternate infusions of glucose and Intralipid in rats impair insulin gene expression, providing evidence that inhibition of the insulin gene under glucolipotoxic conditions is an early defect that might indeed contribute to beta-cell failure in type 2 diabetes, although this hypothesis remains to be tested in humans.

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Section: Why Has Glucolipotoxicity Been Challenged?mentioning

confidence: 99%

Glucolipotoxicity of the pancreatic β-cell: myth or reality?

Poitout

2008

Biochemical Society Transactions

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“…The effect of intravenous arginine infusion has been examined in healthy individuals [ 17 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], T2DM patients [ 42 , 43 , 44 , 45 , 47 , 48 , 49 , 50 ], and obese individuals [ 46 , 51 , 52 , 53 ] ( Supplemental Figure S4C ). All twenty studies [ 17 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ,…”

Section: Resultsmentioning

confidence: 99%

“…Glucose concentrations were increased from baseline in both healthy individuals (iAUC, 5.04 mg/dL/min) and T2DM patients (iAUC, 8.44 mg/dL/min). All four studies [ 46 , 51 , 52 , 53 ] on intravenous arginine infusion in obese individuals showed increased insulin (iAUC range, 6.10 to 22.07 µU/mL/min) and glucose concentrations (iAUC range, 1.37 to 9.08 mg/dL/min). Maccario et al [ 46 ] demonstrated that the arginine induced insulin response was higher in obese participants (iAUC, 22.07 µU/mL/min) than in healthy individuals (iAUC, 8.30 µU/mL/min).…”

Section: Resultsmentioning

confidence: 99%

The Impact of Amino Acids on Postprandial Glucose and Insulin Kinetics in Humans: A Quantitative Overview

et al. 2020

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Different amino acids (AAs) may exert distinct effects on postprandial glucose and insulin concentrations. A quantitative comparison of the effects of AAs on glucose and insulin kinetics in humans is currently lacking. PubMed was queried to identify intervention studies reporting glucose and insulin concentrations after acute ingestion and/or intravenous infusion of AAs in healthy adults and those living with obesity and/or type 2 diabetes (T2DM). The systematic literature search identified 55 studies that examined the effects of l-leucine, l-isoleucine, l-alanine, l-glutamine, l-arginine, l-lysine, glycine, l-proline, l-phenylalanine, l-glutamate, branched-chain AAs (i.e., l-leucine, l-isoleucine, and l-valine), and multiple individual l-AAs on glucose and insulin concentrations. Oral ingestion of most individual AAs induced an insulin response, but did not alter glucose concentrations in healthy participants. Specific AAs (i.e., leucine and isoleucine) co-ingested with glucose exerted a synergistic effect on the postprandial insulin response and attenuated the glucose response compared to glucose intake alone in healthy participants. Oral AA ingestion as well as intravenous AA infusion was able to stimulate an insulin response and decrease glucose concentrations in T2DM and obese individuals. The extracted information is publicly available and can serve multiple purposes such as computational modeling.

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“…The concept of “glucolipotoxicity” implies that repeated or continued exposure to high glucose and lipids (specifically to elevated free fatty acids (FAs)) impacting at the same time cause β-cell damage and dysfunction [38] , [42] , [43] . The literature data on acetylcholine mediated potentiation of insulin release in obesity and T2DM are very limited [5] , [6] , [7] . Previously, we have shown that FAs interfere acutely with acetylcholine potentiation of glucose stimulated insulin release in studies with isolated mouse islets [13] .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor

Doliba

Liu

et al. 2017

Molecular Metabolism

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ObjectivesChronic hyperlipidemia and hyperglycemia are characteristic features of type 2 diabetes (T2DM) that are thought to cause or contribute to β-cell dysfunction by “glucolipotoxicity.” Previously we have shown that acute treatment of pancreatic islets with fatty acids (FA) decreases acetylcholine-potentiated insulin secretion. This acetylcholine response is mediated by M3 muscarinic receptors, which play a key role in regulating β-cell function. Here we examine whether chronic FA exposure also inhibits acetylcholine-potentiated insulin secretion using mouse and human islets.MethodsIslets were cultured for 3 or 4 days at different glucose concentration with 0.5 mM palmitic acid (PA) or a 2:1 mixture of PA and oleic acid (OA) at 1% albumin (PA/BSA molar ratio 3.3). Afterwards, the response to glucose and acetylcholine were studied in perifusion experiments.ResultsFA-induced impairment of insulin secretion and Ca2+ signaling depended strongly on the glucose concentrations of the culture medium. PA and OA in combination reduced acetylcholine potentiation of insulin secretion more than PA alone, both in mouse and human islets, with no evidence of a protective role of OA. In contrast, lipotoxicity was not observed with islets cultured for 3 days in medium containing less than 1 mM glucose and a mixture of glutamine and leucine (7 mM each). High glucose and FAs reduced endoplasmic reticulum (ER) Ca2+ storage capacity; however, preserving ER Ca2+ by blocking the IP3 receptor with xestospongin C did not protect islets from glucolipotoxic effects on insulin secretion. In contrast, an inhibitor of casein kinase 2 (CK2) protected the glucose dependent acetylcholine potentiation of insulin secretion in mouse and human islets against glucolipotoxicity.ConclusionsThese results show that chronic FA treatment decreases acetylcholine potentiation of insulin secretion and that this effect is strictly glucose dependent and might involve CK2 phosphorylation of β-cell M3 muscarinic receptors.

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Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

Cited by 28 publications

References 22 publications

Glucolipotoxicity of the pancreatic β-cell: myth or reality?

Glucolipotoxicity of the pancreatic β-cell: myth or reality?

The Impact of Amino Acids on Postprandial Glucose and Insulin Kinetics in Humans: A Quantitative Overview

Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor

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