Evidence for a Role for Insulin and Growth Hormone in Overnight Regulation of 3-Hydroxybutyrate in Normal and Diabetic Adolescents

Abstract

Objective— To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. Research Design and Methods— We studied overnight changes in plasma ketones—3-hydroxybutyrate and acetoacetate—in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Results— Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 ± 5 μM), reaching a peak at 0200 (103 ± 16 μM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = −0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. Conclusions— We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.