The independent effect of ketone bodies on forearm glucose metabolism in normal man

Abstract

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 umol kg^-1 min^-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg^-1 min^-1) and insulin (0.01 U kg^-1 h^-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg^-1 h^-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 ± 14 and +49 ± 21 [mean ± SEM] nmol 100 ml forearm [FA]^-1 min^-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulin-aemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 ± 4 μmol/1 to a plateau of 450 ± 30 μmol/1, while control levels declined from baseline (ketone body vs control; F<0.001). Forearm ketone body uptake increased (pre-clamp, +395 ± 33vs +72 ± 22; clamp, +417 ± 42 vs +22 ± 10 nmol 100 ml FA^-1 min^-1; both P<0.001), but this failed to influence forearm glucose uptake (pre-clamp, +0.69 ± 0.15 vs +0.73 ± 0.16 and clamp, +2.41 ± 0.29 vs +2.28 ± 0.38 μmol 100 ml FA^-1 min^-1) and net forearm alanine and lactate release. In conclusion, elevated ketone body levels do not exert an independent inhibitory effect on insulin stimulated forearm glucose metabolism.

Key Words:

• acetoacetate
• forearm balance technique
• glucose-fatty acid cycle
• 3-hydroxybutyrate