Glucose tolerance becomes impaired towards the evening. Increased peripheral insulin resistance may be responsible, at least in part, for this effect. The mechanism for the diurnal variation in insulin sensitivity is undefined. It is, however, possible that variations in non-esterified fatty acids (NEFA) could contribute to this variation because NEFA have been implicated in the pathogenesis of insulin resistance. Therefore, we have investigated insulin sensitivity and plasma NEFA responses to insulin at 0830 h and 2030 h in nine healthy men by measuring arterialized plasma glucose and venous plasma NEFA concentrations during a short insulin tolerance test. The studies were standardized for a period of fasting, pre-test meal and exercise. Insulin sensitivity measured KITT was greater (P < 0.05) in the morning [(20 +/- 7) x 10(-3) mmol/L/min] than in the evening [(11.6 +/- 2) x 10(-3) mmol/L/min]. Fasting NEFA levels were lower (P < 0.01) in the morning (373 +/- 84 mumol/L) than in the evening (913 +/- 122 mumol/L). Following insulin, NEFA fell more slowly (P < 0.01) in the morning (149 +/- 26 mumol/L/15 min) than in the evening (491 +/- 91 mumol/L/15 min). These results confirm diurnal variations in insulin sensitivity and plasma NEFA concentrations irrespective of feeding and exercise. We speculate that the relatively elevated plasma NEFA levels in the evening are the cause rather than the consequence of increased insulin resistance at this time.