Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men.

Aims/hypothesis: A prolonged increase of plasma NEFA impairs acute glucose-stimulated insulin secretion (GSIS) in vitro and in vivo. Our study therefore examined the combined effect of increased plasma NEFA and glucose on GSIS in humans.

Methods: We examined GSIS on four occasions in eight obese men during a 10 mmol/l hyperglycaemic clamp and after a 24-h infusion of (i) normal saline, (ii) intralipid and heparin to raise plasma NEFA about two-fold above basal, (iii) 20% dextrose to raise plasma glucose to about 7.5 mmol/l and (iv) intralipid and heparin combined with 20% dextrose to raise plasma NEFA and glucose.

Results: In study (iii) insulin sensitivity was about 20% greater than in study (i) and the disposition index was about 50% higher. Insulin sensitivity tended to be lower in study (ii) whereas the disposition index was lower than in study (i), confirming previous observations. The combination of increased plasma NEFA and glucose (study iv) reduced insulin sensitivity in comparison with study (i) and completely abolished the increase in insulin sensitivity and disposition index seen in study (iii), but did not reduce the latter to a lower value than that in the saline control study (study i).

Conclusions/interpretation: We showed that a prolonged increase of plasma NEFA completely abolishes the stimulatory effect of moderate hyperglycaemia on insulin sensitivity and beta-cell function in obese humans. This suggests that previous observations, showing that a prolonged increase of plasma NEFA impairs pancreatic beta-cell function, also apply to the hyperglycaemic state.