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 less than .05) in circulating levels of 3-OHB (from 112 +/- 73 mumol/L to 825 +/- 111 mumol/L) and forearm arteriovenous differences of 3-OHB (from 19 +/- 10 mumol/L to 145 +/- 46 mumol/L), as well as an eightfold increase of plasma acetoacetate. (2) Decreased (P less than .05) levels of nonesterified fatty acids (NEFA; from 466 +/- 85 mumol/L to 201 +/- 14 mumol/L) and glycerol (from 39 +/- 7 mumol/L to 11 +/- 4 mumol/L) and decreased (P less than .05) arteriovenous differences of glycerol (from -16 +/- 8 mumol/L to -3 +/- 2 mumol/L). (3) Increased (P less than .05) levels of serum growth hormone (GH; from 4.1 +/- 1.5 micrograms/L to 15.9 +/- 8.0 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)