The effects of different plasma insulin concentrations on lipolytic and ketogenic responses to epinephrine in normal and type 1 (insulin-dependent) diabetic humans.

This study was performed to verify: (1) the ability of different insulin concentrations to restrict the lipolytic and ketogenic responses to exogenous epinephrine administration; (2) whether the ability of insulin to suppress the lipolytic and ketogenic responses during epinephrine administration is impaired in Type 1 (insulin-dependent) diabetic patients. Each subject was infused on separate occasions with insulin at rates of 0.2, 0.4, and 0.8 mU.kg-1.min-1 while normoglycaemic. To avoid indirect adrenergic effects on endocrine pancreas secretions, the so-called "islet clamp" technique was used. Rates of appearance of palmitic acid, acetoacetate, and 3-hydroxybutyrate were simultaneously measured with an infusion of 13C-labelled homologous tracers. After a baseline observation period epinephrine was exogenously administered at a rate of 16 ng.kg-1.min-1. At low insulin levels (20 microU/ml) the lipolytic response of comparable magnitude was detected in normal and Type 1 diabetic patients. However, the ketogenic response was significantly higher in Type 1 diabetic patients. During epinephrine administration, similar plasma glucose increments were observed in the two groups (from 4.74 +/- 0.53 to 7.16 +/- 0.77 mmol/l (p less than 0.05) in Type 1 diabetic patients and from 4.94 +/- 0.20 to 7.11 +/- 0.38 mmol/l (p less than 0.05) in normal subjects, respectively). At intermediate insulin levels (35 microU/ml) no significant differences were found between Type 1 diabetic patients and normal subjects, whereas plasma glucose levels rose from 4.98 +/- 0.30 to 6.27 +/- 0.66 mmol/l (p less than 0.05) in Type 1 diabetic patients, and from 5.05 +/- 0.13 to 6.61 +/- 0.22 mmol/l (p less than 0.05) in normal subjects. At high insulin levels (70 microU/ml) the lipolytic response was detectable only in Type 1 diabetic patients; the ketogenic response was reduced in both groups. During the third clamp, a significant rise in plasma glucose concentration during epinephrine infusion was observed in both groups. In conclusion this study shows that at low insulin levels Type 1 diabetic patients show an increased ketogenic response to epinephrine, despite their normal nonesterified fatty acid response. Instead, high insulin levels are able to restrict the ketogenic response to epinephrine in both normal and Type 1 diabetic subjects, although there is a still detectable lipolytic response in the latter. In the presence of plasma free insulin levels that completely restrict the ketogenic response in the same group, there is still a distinct glycaemic response. Plasma insulin levels in Type 1 diabetic patients are a major determinant of the metabolic response to epinephrine.