Feedback Inhibition of Key Glycolytic Enzymes in Liver: Action of Free Fatty Acids

Weber, George; Convery, Hazel J. Hird; Lea, Michael A.; Stamm, Nancy B.

doi:10.1126/science.154.3754.1357

Cited by 168 publications

(58 citation statements)

References 29 publications

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“…Possible mechanisms based on known modulatory effects of fatty acids include acylation [29], increased gene transcription [30], increased production of long chain-CoA products, or a direct effect of fatty acid metabolites on the enzyme activity. Regarding the latter, an inhibitory effect of long chain acyl-CoA esters has been reported for glucokinase [31,32], phosphofructokinase [33], and glucose 6-phosphatase [34]: we are not aware of any reports of stimulation of a glycolytic enzyme such as that noted in this study. No attempt to address these different possibilities was made in this study.…”

Section: Discussionmentioning

confidence: 48%

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

1997

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Section: Discussionmentioning

confidence: 48%

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

1997

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“…Given the fact that islets from obese prediabetic rats have an abnormally high lipid content in vivo (14), lipid overload seems plausible. It has long been known that increased long-chain fatty acyl-CoA impedes glucose metabolism at multiple levels (25)(26)(27)(28)(29), as recently reviewed by McGarry (30). A novel additional mechanism, excessive acylation, also warrants consideration; just as unregulated overglycation resulting from hyperglycemia can modify the function of certain proteins, excessively high FFA levels causing overacylation might similarly alter protein functions (31).…”

Section: Discussionmentioning

confidence: 99%

Defective Fatty Acid-mediated β-Cell Compensation in Zucker Diabetic Fatty Rats

Hara

Lee

Inman

et al. 1996

Journal of Biological Chemistry

126

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Although obesity is associated with insulin resistance, most obese humans and rodents remain normoglycemic because of compensatory hyperinsulinemia. This has been attributed to ␤-cell hyperplasia and increased low K m glucose metabolism of islets. Since free fatty acids (FFA) can induce these same ␤-cell changes in normal islets of Wistar rats and since plasma FFA are increased in obesity, FFA could be the signal from adipocytes that elicits ␤-cell compensation sufficient to prevent diabetes. To determine if FFA-induced compensation is impaired in islets of rats with a diabetogenic mutation, the Zucker diabetic fatty (ZDF) rat, we cultured islets from 6-week-old obese (fa/fa) rats that had compensated for obesity and apparently normal islets from lean ZDF rats (fa/؉) in 0, 1, or 2 mM FFA. Low K m glucose usage rose 2.5-fold in FFA-cultured control islets from age-matched Wistar rats, but failed to rise in either the precompensated islets of ZDF rats or in islets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-fold in Wistar islets but not in islets from obese or lean ZDF rats. Insulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.01) but increased only slightly in islets from lean ZDF rats (not significant) and declined in islets from obese ZDF rats (p < 0.05). We conclude that, unlike the islets of age-matched Wistar rats, islets of 6-week-old heterozygous and homozygous ZDF rats lack the capacity for FFA-induced enhancement of ␤-cell function.Pancreatic islets from obese rodents are enlarged and exhibit a marked increase in low K m glucose metabolism (1), which may account for their high output of insulin even at low concentrations of glucose (1-3). The hyperinsulinemia is regarded as a compensatory response that prevents hyperglycemia despite the insulin resistance that invariably accompanies obesity.There is evidence that free fatty acids (FFA) 1 may be the signal from adipocytes that mediates this compensatory insulin secretion (1). Plasma FFA are elevated in obesity (4, 5) and have long been known to stimulate insulin secretion (6 -8).Moreover, the compensatory triad observed in islets from obese rats can be induced in normal islets by culturing them for 7 days in the presence of 1 or 2 mM FFA; low K m glucose metabolism rises dramatically (1), there is evidence of increased ␤-cell replication (1), and insulin secretion increases (1), confirming the earlier description of FFA-induced hyperinsulinemia (9). If the FFA-induced compensation in obesity is, at least in part, responsible for preventing diabetes, it follows that FFAinduced compensation may be impaired at or before the onset of diabetes. In this study we assess the ability of FFA to induce the compensatory triad of enhanced low K m glucose metabolism, increased ␤-cell replication, and insulin hypersecretion in islets from obese rats with a diabetogenic mutation, the Zucker diabetic fatty rat (ZDF-drt). We observe that FFA induction of these compensatory changes is impaired, not only in islets from obese homozygous r...

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“…Selective inhibition of enzymes involved in glucose dissimilation by free fatty acids under conditions where gluconeogenic enzymes were not affected had been reported for bacterial (Ferdinandus & Clark, 1969) and animal (Weber, Convery, Lea & Stamm, 1966) systems.…”

Section: Discussionmentioning

confidence: 99%

Caproic Acid Metabolism and the Production of 2-Pentanone and Gluconic Acid by Aspergillus niger

Lewis

1970

Journal of General Microbiology

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Vegetative hyphae of Aspergillus niger rapidly converted caproic acid to 2-pentanone whereas germinating spores carried out the transformation slowly and ungerminated spores not at all. Glucose stimulated ketone production by germinating spores, but suppressed it in hyphae; the degree of stimulation and suppression varied with glucose concentration. This explains earlier reports that spores but not vegetative hyphae convert fatty acids to methyl ketones, since hyphae were earlier tested with high sugar concentrations, conditions where ketone formation was inhibited. Glucose disappeared from cultures containing caproate even though ketone production was inhibited, and glucose disappearance was paralleled by gluconic acid accumulation in the medium. These findings suggest that free fatty acids may play an important role in the regulation of metabolic pathways in A . niger.

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Feedback Inhibition of Key Glycolytic Enzymes in Liver: Action of Free Fatty Acids

Cited by 168 publications

References 29 publications

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

Defective Fatty Acid-mediated β-Cell Compensation in Zucker Diabetic Fatty Rats

Caproic Acid Metabolism and the Production of 2-Pentanone and Gluconic Acid by Aspergillus niger

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