Stimulation of insulin secretion by infusion of free fatty acids

Abstract

A B S T R A C r The acute elevation of plasma free fatty acid (FFA) levels by direct infusion of sodium oleate into the plasma of conscious dogs was accompanied by the rapid onset of a 2-to 12-fold increase in plasma immunoreactive insulin, and, subsequently, a marked fall in plasma glucose, even in dogs receiving intravenous glucose throughout the infusion. The magnitude of both the insulin and glucose responses correlated with the mean FFA level during infusion. A large increase in plasma insulin and fall in glucose also occurred when glycerol was infused with oleate in order to simulate endogenous lipolysis more closely. Insulin levels in pancreaticoduodenal vein blood rose markedly during oleate infusion, while plasma ketone levels rose only slightly.In contrast to the effects of oleate infusion, elevation of plasma FFA to correspondingly high levels by triolein ingestion and intravenous heparin produced only small increases in plasma insulin, which did not correlate well with the FFA level reached, and small increases in plasma glucose.The results indicate that under certain conditions elevated FFA levels may be a potent stimulus of insulin secretion. This response is modified under other conditions such as during chylomicron removal under the influence of heparin. This effect may play a role in the regulation of lipolysis and ketone formation, but determination of the exact mechanism of FFA stimulation of the pancreas and its physiological significance will require further investigation.

Fatty acid metabolism and insulin secretion in pancreatic beta cells

“…This effect has also been documented in vivo, where NEFA increase serum insulin concentrations in animals [81] and humans [82]. Under normal physiologic conditions the necessity for simulatory glucose can stem from the additional need for one or more of the following signals generated by glucose: (i) an increased influx of Ca 2+ , (ii) an increased ATP:ADP ratio acting distal to the K ATP channel, (iii) increased production of α-glycerol phosphate as a precursor to complex lipids, or (iv) increased malonyl-CoA required for inhibition of CPT-1.…”

“…Short-term exposure of islets or beta cells to saturated long-chain NEFA provide a powerful potentiation of GSIS, whereas long-term exposure results in increased basal secretion and a blunted response to glucose. This dichotomy in response has been shown both in vitro [26,89] and in vivo [81,82,96]. At early time points after lipid infusion (<6 h), glucose-stimulated secretion in these studies is enhanced, whereas measurements at 24 and 48 h show mostly an inhibition.…”

Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1

“…Once all islets were transferred, the plate was incubated for 3 h at 37°C in a humidified atmosphere containing 5% CO 2 , after which the sample media were collected for glycerol determination by an enzymatic luminescence detection method based on the reduction of NAD ϩ to NADH in a series of enzymatic reactions. The reactions are as follows: 1) glycerol is converted to glycerol-3-PO 4 by glycerol kinase; 2) glycerol-3-PO 4 is converted to dihydroxyacetone-PO 4 by glycerol-3-PO 4 O) for 1 h at 37°C with shaking. The conversion reaction was then stopped by placing the samples on ice and adding 0.4 ml H 2 O.…”

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

“…4,5 Administration of intralipid and heparin to raise plasma FFA results in an increased GSIS. 6,7 Experiments performed on perfused pancreas indicate that the insulinotropic action of FFA increases with their chain length and degree of saturation. 8 In contrast, long-term exposure to FFA increases basal and blunts GSIS.…”