Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans.

TLDR

Efficient glucose‑stimulated insulin secretion in the fasted rat requires elevated circulating free fatty acids (FFAs). The study aimed to determine whether this FFA dependence of GSIS also holds in humans. Human volunteers were fasted for 24–48 h, then received either saline or nicotinic acid to deplete FFAs, with or without an Intralipid/heparin infusion to sustain FFAs, followed by intravenous glucose or a hyperglycemic clamp to assess insulin secretion. Depleting FFAs with nicotinic acid markedly reduced basal insulin and glucose‑stimulated insulin secretion after 24–48 h fasting, while maintaining FFAs restored insulin responses; in an overnight fast, FFA depletion lowered insulin AUC only in obese subjects, underscoring that post‑fasting FFA elevation is essential for GSIS in humans, particularly in obesity.

Abstract

In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either saline or nicotinic acid (NA) to deplete their plasma FFA pool, followed by an intravenous bolus of glucose. NA treatment resulted in a fall in basal insulin concentrations of 35 and 45% and in the area under the insulin response curve (area under the curve [AUC]) to glucose of 47 and 42% in the 24- and 48-h fasted individuals, respectively. The 48-h fasted subjects underwent the same procedure with the addition of a coinfusion of Intralipid plus heparin (together with NA) to maintain a high concentration of plasma FFAs throughout the study. The basal level and AUC for insulin were now completely normalized (C-peptide profiles paralleled those for insulin). To assess the effect of an overnight fast, nonobese (n = 6) and obese (n = 6) subjects received an infusion of either saline or NA, followed by a hyperglycemic clamp (200 mg/dl). The insulin AUC in response to glucose was unaffected by lowering of the FFA level in nonobese subjects, but fell by 29% in the obese group. The data clearly demonstrate that in humans, the rise in circulating FFA levels after 24 and 48 h of food deprivation is critically important for pancreatic beta-cell function both basally and during subsequent glucose loading. They also suggest that the enhancement of GSIS by FFAs in obese individuals is more prominent than that seen in their nonobese counterparts.