Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs

Aims/hypothesis A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. Methods Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A 1 adenosine receptor agonist. Results High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIR g ). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIR g with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIR g . This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. Conclusions/interpretation Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance.