A 48-hour Lipid Infusion in the Rat Time-Dependently Inhibits Glucose-Induced Insulin Secretion and B Cell Oxidation Through a Process Likely Coupled to Fatty Acid Oxidation*

Sako, Yasuhiro; Grill, Valdemar

doi:10.1210/endo-127-4-1580

Cited by 350 publications

(244 citation statements)

References 29 publications

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“…The deleterious effect of high glucose is well established [2,3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6,10,33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11,12,13,14]. We also found that in-action is, at least in part, mediated by modifications in gene expression [9,17].…”

Section: Discussionsupporting

confidence: 92%

“…The marked increase in CPT-I expression induced by NEFA, and its negative correlation with GSIS suggest that CPT-I could exert a central role in the loss of beta-cell signal recognition induced by NEFA. Those results are concordant with the glucose fatty acid cycle reported in rat islets [6,7,10]. This hypothesis proposes that an increase in NEFA oxidation leads to a decrease in glucose metabolism in beta-cells, according to the Randle cycle observed in other tissues [40].…”

Section: Discussionsupporting

confidence: 90%

“…The consequence is a reduction in insulin secretion, since it is linked to glucose oxidation. This hypothesis is supported by (i) the restoration of insulin secretion by inhibition of NEFA oxidation and (ii) the specificity of the altered response to glucose, as opposed to other secretagogues [6,7,10]. We report, however, that the concomitant presence of increased glucose and NEFA also induced ACC gene expression in islets.…”

Section: Discussionmentioning

confidence: 60%

“…However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial. Some authors have shown that beta-cell failure was induced by increased glucose alone [2,9] or increased NEFA alone [6,10], while others have suggested that excess glucose or NEFA are not deleterious separately, but synergize in causing glucolipotoxicity [11,12,13,14].…”

mentioning

confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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Aims/hypothesis. Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism. Methods. Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated. Results. Non-esterified fatty acids decreased glucosestimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucosestimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2. Conclusion/interpretation. In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression. [Diabetologia (2004) 47:463-469]

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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“…94 However, after longer periods of times (418 h), Glucose sensing in metabolic diseases B Thorens free fatty acids reduce the secretory response to glucose. 95 This has been attributed to the accumulation of fatty acylCoAs that can generate various lipid species that interfere with the function of ionic channels or other proteins regulating the exocytosis of insulin granules.…”

Section: Glucose-lipid Interactionmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

et al. 1998

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Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (approximately 9 mmol l(-1)) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (approximately 4000 micromol l(-1)) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20-44% (p < 0.05) and C-peptide levels by 17-25% (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45% in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion.

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A 48-hour Lipid Infusion in the Rat Time-Dependently Inhibits Glucose-Induced Insulin Secretion and B Cell Oxidation Through a Process Likely Coupled to Fatty Acid Oxidation*

Cited by 350 publications

References 29 publications

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

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