What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes

Jd, McGarry

doi:10.1126/science.1439783

Cited by 618 publications

(447 citation statements)

References 21 publications

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“…In vivo, the normal plasma concentration of NEFA is less than 0.6 mmol/l, but could exceed 1 mmol/l in Type 2 diabetic patients [31,32]. Palmitate and oleate are the two most represented NEFA in plasma (20 to 25% each) and circulate linked to albumin.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…This condition is characterized by hyperglycemia and hyperinsulinemia, as found in type 2 diabetes and obesity (Randle et al, 1963;McGarry, 1992;Littman et al, 2000). FA are recognized to stimulate insulin secretion in vitro (Malaisse and Malaisse-Lagae, 1968;Opara et al, 1992) and to modulate the stimulatory effect of glucose on insulin release (Vara et al, 1988;Warnotte et al, 1994).…”

Section: Fa Metabolism In B-cellsmentioning

confidence: 99%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

149

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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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“…It is well documented that lipids reduce insulin sensitivity and glucose uptake in skeletal muscle cells [8]. The first theory was postulated by Randle et al, glucose-fatty acid cycle [9].…”

Section: Introductionmentioning

confidence: 99%

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

Ragheb

Shanab

Medhat

et al. 2009

Biochemical and Biophysical Research Communications

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In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine 307 phosphorylation of IRS-1. IRS-1 Serine 307 phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IκB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKα/β, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10 mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms. KeywordsFree fatty acid (FFA); Insulin resistance (IR); Skeletal muscle cell (C2C12); Protein kinase C (PKC); Insulin receptor substrate-1 (IRS-1)

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What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes

Cited by 618 publications

References 21 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

Pleiotropic effects of fatty acids on pancreatic β‐cells

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

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