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 C-13-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-mu-U/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 < 0.05) in Type 1 diabetic patients and from 4.94 +/- 0.20 to 7.11 +/0. 38 mmol/l (p < 0.05) in normal subjects, respectively). At intermediate insulin levels (35-mu-U/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 < 0.05) in Type 1 diabetic patients, and from 5.05 +/- 0.13 to 6.61 +/- 0.22 mmol/l (p < 0.05) in normal subjects. At high insulin levels (70-mu-U/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 non-esterified 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.