Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (approximately 9 mmol l(-1)) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (approximately 4000 micromol l(-1)) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20-44% (p < 0.05) and C-peptide levels by 17-25% (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45% in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion.