Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.
Daniel T. Stein,Victoria Esser,B E Stevenson,K E Lane,J H Whiteside,M B Daniels,Songyuan Chen,Songyuan Chen,J. D. McGarry +8 more
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TLDR
The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.Abstract:
We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.read more
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The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.
J. Denis McGarry,N. F. Brown +1 more
TL;DR: Key developments of the last 20 years that have led to the current understanding of the physiology of the CPT system, the structure of theCPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population are reviewed.
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Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes
TL;DR: The primary focus of this lecture will be on the first of these issues, which is the pathophysiological basis for type 2 diabetes and why is their rate of appearance accelerating so rapidly at this particular juncture of human history.
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Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.
Yasuaki Itoh,Yuji Kawamata,Masataka Harada,Makoto Kobayashi,Ryo Fujii,Shoji Fukusumi,Kazuhiro Ogi,Masaki Hosoya,Yasuhiro Tanaka,Hiroshi Uejima,Hideyuki Tanaka,Minoru Maruyama,Rie Satoh,Shoichi Okubo,Hideki Kizawa,Hidetoshi Komatsu,Fumika Matsumura,Yuko Noguchi,Tokuyuki Shinohara,Shuji Hinuma,Yukio Fujisawa,Masahiko Fujino +21 more
TL;DR: It is shown that a G-protein-coupled receptor, GPR40, which is abundantly expressed in the pancreas, functions as a receptor for long-chain FFAs, and that long- Chain FFAs amplify glucose-stimulated insulin secretion from pancreatic β cells by activating GPR 40.
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Interplay between lipids and branched-chain amino acids in development of insulin resistance.
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Insulin action and resistance in obesity and type 2 diabetes
TL;DR: This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance and connects insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle.
References
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Regulation of hepatic fatty acid oxidation and ketone body production.
J. D. McGarry,Daniel W. Foster +1 more
TL;DR: The role of Exogenous Fatly Acids in the Control of Ketogenesis and Applications of the Model are examined.
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Hormone-fuel interrelationships during fasting.
George F. Cahill,M G Herrera,A P Morgan,J S Soeldner,Jurgen Steinke,P L Levy,G A Reichard,D M Kipnis +7 more
TL;DR: Over 50 years ago, Benedict published his extensive monograph on the metabolism of fasting in man, in which he demonstrated that carbohydrate stores provide a small but significant component of the body's fuel for only the first few days.
Journal ArticleDOI
Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships
TL;DR: A role for hyperlipacidemia in the pathogenesis of NIDDM is suggested; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invokedto explain the FFA-induced loss of GSIS.
Journal ArticleDOI
What if Minkowski had been ageusic? An alternative angle on diabetes.
TL;DR: It is suggested that the phenomena of insulin resistance and hyperglycemia might be more readily understood if viewed in the context of underlying abnormalities of lipid metabolism.
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Metabolic coupling factors in pancreatic beta-cell signal transduction.
TL;DR: Evidence supporting the idea that glucose metabolism is required for GSIS is summarized and that the GLUT-2 facilitated glucose transporter and the glucose phosphorylating enzyme glucokinase play important roles in measuring changes in extracellular glucose concentration is summarized.
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