Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

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 acidtreated 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 ␤ cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences. ( J. Clin. Invest. 1996. 97:2728-2735.)

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

“…Glucolipotoxicity and beta-cells Circulating free fatty acids are required for normal glucosestimulated insulin secretion, 93 and incubation of pancreatic islets in the presence of elevated fatty acid concentrations leads to an initial increase in glucose-stimulated insulin secretion. 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.…”

Pleiotropic effects of fatty acids on pancreatic β‐cells

“…The role of FA in the process of glucoseinduced insulin secretion has been investigated by several groups (Opara et al, 1992(Opara et al, , 1994Stein et al, 1996Stein et al, , 1997Boden et al, 1998). The potency of FA to promove glucose-induced insulin release increases with the chain length and decreases with the degree of unsaturation (Opara et al, 1994;Dobbins et al, 1997).…”

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

“…The malonyl-CoA-long-chain acyl-CoA axis is implicated by observations that inhibition of CPTo with etomoxir results in the elevation of cellular acyl-CoA and activation of insulin secretion ; several insulin secretagogues raise the concentration of malonyl-CoA prior to stimulation of secretion [120]. In pancreata isolated from fasted animals, supplementation of fatty acids in the medium is essential for glucose-stimulated insulin secretion [121], raising the prospect that the depletion of β-cell TAG during 18-24 h of fasting eliminates a source of acyl-CoA that is required for secretion. In the fasted animal, plasma NEFA concentrations are high, thus enabling the pancreas to respond to refeeding with the appropriate insulin-secretory response.…”