Acetoacetate and 3-hydroxybutyrate kinetics in obese and insulin-dependent diabetic humans

Abstract

[3-14C]acetoacetate (AcAc) and beta-[3-14C]hydroxybutyrate (beta-OHB) administration, measurements of labeled AcAc and beta-OHB in blood, and kinetic modeling have been used to investigate ketone body (KB) metabolism in five normal, five obese, and eight insulin-withdrawn diabetic subjects. Diabetic subjects were divided in mildly ketotic (MKD) and highly ketotic (HKD) patients according to beta-OHB blood level. A four-compartmental model successfully described the tracer kinetic data in obese and normal subjects, whereas in diabetic patients a five-compartmental model was necessary. Obese subjects showed a significantly lower (P less than 0.05) KB de novo synthesis (R30 = 159 +/- 54 (SD) mumol X min-1 X m-2) in comparison with normal subjects (282 +/- 93), but the clearance rates of AcAc (PCR1) and beta-OHB (PCR2) were similar in the two groups. R30 was 596 +/- 534 in MKD and 1,278 +/- 445 (P less than 0.01) in HKD. PCR1 was not significantly different both in MKD and HKD in comparison with normal subjects. In contrast PCR2 was markedly reduced in HKD (0 +/- 0 ml X min-1 X m-2) in comparison with MKD (1,031 +/- 615) and normal subjects (782 +/- 278). The percentage distribution of KB among various tissues inside the organism of diabetic subjects is abnormal. Both AcAc and beta-OHB recycling and mean residence time are not normal in HKD. A significant correlation was found between C-peptide and KB production in diabetes. These results suggest that a selective defect of beta-OHB peripheral utilization is important in determining and maintaining severe diabetic ketoacidosis.