A kinetic analysis of plasma insulin disappearance and glucose-induced insulin delivery rate in diabetic and nondiabetic acromegalics

Abstract

Derangements of insulin metabolism may have a role in the pathophysiology of diabetes in acromegaly. To investigate this point, we employed a technique that allows the measurement of the degradation rate, the distribution volumes of the hormone, and the posthepatic insulin delivery rate both in the fasting state and after intravenous (i.v.) glucose. 125I-insulin was injected i.v. as a single bolus and the plasma disappearance curve of the immunoprecipitable radioactivity was sampled for 120 min. Immediately afterwards, an i.v. glucose tolerance test (GTT) was performed and both glucose and IRI levels were measured from samples taken for 90 min. By noncompartmental analysis of the plasma 125I-insulin curves were computed: (1) the initial distribution volume of insulin (IDV); (2) metabolic clearance rate (MCR); (3) basal posthepatic delivery rate (IDR); and (4) total plasma equivalent distribution volume (TDV). By deconvolution analysis of glucose-induced immunoreactive insulin (IRI) curve and plasma disappearance curve of tracer insulin, the posthepatic secretion curve of the hormone was reconstructed. Nine acromegalic patients were studied; 4 had a normal glucose tolerance (NA), and 5 were diabetic (DA). Seven normals (N) were taken as a control group. In the acromegalics the IDV was enlarged compared to normals (2.6 ± 0.2 versus 1.8 ± 0.1 liter/sq m; p < 0.01) and MCR was also greater (564 ± 24 versus 473 ± 24 ml/min × sq m; p < 0.05). In the DA the TDV was larger than in N (17.1 ± 3.4 versus 8.4 ± 0.7 liters/sq m; p < 0.05). In both NA (4.8 ± 0.7 mU/min × sq m) and DA (8.6 ± 1.9) the IDR was greater ( p < 0.01) than N (2.3 ± 0.9). Glucose-stimulated posthepatic insulin secretion showed, both in N and acromegalics, a first rapid burst secretion (Secr), which had its peak at 2–3 min and lasted for 6–10 min, and a more sustained second phase. Secr (6–90), which returned to the basal levels by the end of 90 min. In NA, Secr (0–6) was greater than in N (500 ± 93 versus 232 ± 39 mU/sq m; p < 0.05) and DA (174 ± 39; p < 0.01). Secr (6–90) was significantly greater in both NA (1707 ± 205) and DA (1752 ± 391) than N (615 ± 167 mU/sq m). When glucose-induced insulin secretion was expressed as a multiple of the basal insulin delivery the first phase of insulin secretion was superimposable in N and NA (17.7 ± 2.7 versus 17.8 ± 3.9) while it was reduced in DA (3.5 ± 0.8; p < 0.01). The second phase was not significantly different in the 3 groups. All acromegalic patients showed: (1) an enlarged IDV, (2) an increased MCR, and (3) a higher secretion rate, both in the fasting state and after i.v. glucose. These alterations of insulin kinetics and secretion seem therefore to be caused by acromegaly itself. On the other hand, an enlarged TDV, a marked decrease of the early phase of insulin secretion, and an additional factor of insulin resistance independent from GH were found in DA only, therefore they are more related to diabetes than to acromegaly.