Mechanisms decreasing glucose oxidation in diabetes and starvation: Role of lipid fuels and hormones

Randle, P. J.; Kerbey, A L; Espinal, J.

doi:10.1002/dmr.5610040702

Cited by 231 publications

(151 citation statements)

References 62 publications

(18 reference statements)

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“…26 The ability of FFA to reduce insulin-stimulated glucose disposal has been confirmed in humans and rodents. In human studies, infusion of FFA during euglycemic hyperinsulinemic clamp induced a rapid decrease in glucose oxidation, while insulin action was modified after several hours and was associated with a decrease in glucose-6-phosphate.…”

Section: Triglyceride Content and Insulin Action In Skeletal Musclementioning

confidence: 96%

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet

2004

Int J Obes

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Obesity is associated with increased storage of lipids in nonadipose tissues like skeletal muscle, liver, and pancreatic b cells. These lipids constitute a continuous source of long-chain fatty acyl CoA (LC-CoA) and derived metabolites like diacylglycerol and ceramide, acting as signalling molecules on protein kinases activities (in particular, the family of PKCs), ion channel, gene expression, and protein acylation. In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. This interrupts the insulin signalling pathway leading to the stimulation of glucose transport. In pancreatic b cells, short-term excess of fatty acids or LC-CoA activates PKC and also directly stimulates insulin exocytosis. Longterm exposure to free fatty acids (FFA) leads to an increased basal and blunted glucose-stimulated insulin secretion by affecting gene expression, increase in K ATP channel activity, and uncoupling of the mitochondria. In addition, the saturated FFA palmitate increases cell death by apoptosis via increase in ceramide synthesis.

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Section: Triglyceride Content and Insulin Action In Skeletal Musclementioning

confidence: 96%

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet

2004

Int J Obes

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“…So the PDH effect is likely to be substrate-driven, e.g. through a rise in intramitochondrial pyruvate concentration, which will inhibit PDH kinase [85]. The rapid decline in oxidation of fatty acids will also result in a decrease in the intramitochondrial acetyl-CoA\CoA ratio, which would favour dephosphorylation of PDH [85].…”

Section: Enzymes Involved In the Partitioning Of Fatty Acids Between mentioning

confidence: 99%

Role of insulin in hepatic fatty acid partitioning: emerging concepts

Zammit

1996

Biochemical Journal

114

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“…Randle and colleagues proposed many years ago that resistance may be due to a glucose-fatty acid cycle, i.e., a reciprocal relationship between the metabolism of FA and glucose in which abundance of FA decreases the uptake and metabolism of glucose (reviewed in Refs. 27,28). The pyruvate dehydrogenase (PDH) complex played a key role in this concept.…”

mentioning

confidence: 99%

“…The pyruvate dehydrogenase (PDH) complex played a key role in this concept. It was demonstrated in liver, heart, and skeletal muscle that FA decreased PDH activity through activation of PDH kinase (27,28). Evidence was presented that an ambient effect of FA on PDH kinase activity was supplemented by a timedependent one.…”

mentioning

confidence: 99%

Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

Qvigstad

Mostad

Bjerve

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Qvigstad, Elisabeth, Ingrid L. Mostad, Kristian S. Bjerve, and Valdemar E. Grill. Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects. Am J Physiol Endocrinol Metab 284: E129-E137, 2003; 10.1152/ajpendo.00114.2002.-We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol Ͼ2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A 1c (379 Ϯ 34 vs. 326 Ϯ 30 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 without Acipimox, P Ͻ 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects. insulin sensitivity; hypertriglyceridemia; lipotoxicity; Acipimox; low-fat diet AN ELEVATED PLASMA LEVEL of fatty acids (FA) is a risk factor for type 2 diabetes (8, 24). The risk has been ascribed to an insulin resistance-inducing effect of FA in skeletal muscle and in liver (3). Randle and colleagues proposed many years ago that resistance may be due to a glucose-fatty acid cycle, i.e., a reciprocal relationship between the metabolism of FA and glucose in which abundance of FA decreases the uptake and metabolism of glucose (reviewed in Refs. 27, 28). The pyruvate dehydrogenase (PDH) complex played a key role in this concept. It was demonstrated in liver, heart, and skeletal muscle that FA decreased PDH activity through activation of PDH kinase (27, 28). Evidence was presented that an ambient effect of FA on PDH kinase activity was supplemented by a timedependent one. Many data support the operation of the glucose-fatty acid cycle (27), although alternative concepts have also been put forward (17, 37).More recent evidence indicates that elevated FA can exert negative effects on pancreatic ␤-cells and that such effects add to the diabetogenicity of elevated FA. In the obese and diabetic Zucker rat, triacylglycerols accumulate in ␤-cells in conjunction with elevated plasma FA (for review see Ref. 19). Such accumulation has been associated with ␤-cell damage, with proposed implications i...

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Mechanisms decreasing glucose oxidation in diabetes and starvation: Role of lipid fuels and hormones

Cited by 231 publications

References 62 publications

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Role of insulin in hepatic fatty acid partitioning: emerging concepts

Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

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