Free fatty acids impair hepatic insulin extraction in vivo.

Abstract

Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity.

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

“…The effect is opposite to that expected from a study in normal dogs that concluded that FA impair hepatic clearance of insulin (36). Differences in experimental design and species differences, as well as the presence of diabetes in our study, could be important for the discrepancy.…”

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

“…No such differences in the C-peptide or calculated insulin secretion rate AUC were noted. The most likely explanation for this finding is a NEFA-mediated reduction of insulin extraction by the liver [28]. Although insulin extraction by the liver seems to be constant throughout the physiological range of insulin concentration at steady state insulin concentrations [29,30], it declines during dynamic (non steady state) conditions and in the presence of very high insulin concentrations, similar to those seen in our study during the second bolus infusion of arginine [31±33].…”

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

“…A direct stimulatory effect of fatty acids upon islets provides a plausible explanation for the greater insulinotropic effect with increased NEFA concentrations, as seen in this study, although in vivo, other factors, such as insulin sensitivity, hepatic insulin clearance and other stimulants have to be considered. There is evidence that both insulin sensitivity [13] and hepatic insulin clearance [9] are reduced after a short-term increase of total plasma NEFA concentrations, but it is not clear if there is a difference between the types of fatty acid. It has been reported that the insulin resistance induced by an acute increase (90 min) of plasma NEFA concentrations was precisely countered by a fatty acid-induced increase in insulin secretion [13].…”

“…Increased plasma NEFA concentrations can have adverse effects on various tissues. Excess plasma NEFA concentrations can lead to a reduced skeletal muscle glucose uptake and oxidation [4,5,6], increased hepatic glucose output [7] and a decrease in hepatic insulin clearance [8,9]. These mechanisms could lead to glucose intolerance and insulin resistance leading to Type II diabetes.…”