Substrate metabolism during modest hyperinsulinemia in response to isolated hyperketonemia in insulin-dependent diabetic subjects

To assess the metabolic effects of moderate hyperketonemia, six young male type 1 diabetic patients received a 200-minute intravenous (IV) infusion of (1) 0.9 mmol 3-hydroxybutyrate (3-OHB)/kg/h, and (2) saline. To ensure comparable metabolic conditions, a low-dose hyperinsulinemic euglycemic glucose clamp was performed from 5 hours before and throughout 3-OHB/saline infusions. The forearm technique was employed to estimate substrate fluxes in muscle. Infusion of 3-OHB caused: (1) increases ( P < .05) in circulating levels of 3-OHB (from 112 ± 73 μmol/L to 825 ± 111 μmol/L) and forearm arteriovenous differences of 3-OHB (from 19 ± 10 μmol/L to 145 ± 46 μmol/L), as well as an eightfold increase of plasma acetoacetate. (2) Decreased ( P < .05) levels of nonesterified fatty acids (NEFA; from 466 ± 85 μmol/L to 201 ± 14 μmol/L) and glycerol (from 39 ± 7 μmol/L to 11 ± 4 μmol/L) and decreased ( P < .05) arteriovenous differences of glycerol (from −16 ± 8 μmol/L to −3 ± 2 μmol/L). (3) Increased ( P < .05) levels of serum growth hormone (GH; from 4.1 ± 1.5 μg/L to 15.9 ± 8.0 μg/L). No change was recorded in circulating concentrations of free insulin, glucagon, glucose, lactate, or alanine. Nor were arteriovenous balances of these intermediary metabolites, isotopically determined glucose turnover or amounts of exogenously administered glucose affected. In conclusion, in type 1 diabetic man, the main regulatory effect of isolated hyperketonemia appears to be a direct negative feedback inhibition of lipolysis. The following decrease in NEFA concentration may stimulate GH secretion and obscure any possible role for ketone bodies in “Randle cycle” substrate competition.