A hyperinsulinaemic, sequentially eu- and hypoglycaemic clamp test to characterize autonomous insulin secretion in patients with insulinoma.

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyper-insulinaemic, sequentially eu- and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C-peptide during low-dose [2 pmol kg-1 min-1 (20 mU kg-1 h-1) for 90 min, plasma insulin approximately 120 pmol L-1 (20 mUL-1)] and high-dose [8 pmol kg-1 h-1 (80 mU kg-1 h-1) for 90 min, plasma insulin approximately 450 pmol L-1 (75 mU L-1)] insulin infusion under euglycaemic conditions [plasma glucose 4.4-5.0 mmol L-1 (80-90 mg dL-1)] and during high-dose insulin infusion under hypoglycaemic conditions [glucose 2-2.2 mmol L-1 (40-45 mg dL-1)] was evaluated by radioimmunoassay (RIA). Euglycaemic hyper-insulinaemia suppressed C-peptide in control subjects (P < 0.0001), whereas in insulinoma patients apparently irregular changes in C-peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyper-insulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C-peptide in normal subjects (from basal, 0.76 +/- 0.08-0.06 +/- 0.01 nmol L-1; maximum observed value 0.10 nmol L-1), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 +/- 0.16 nmol L-1; P = 0.005). In insulinoma patients, C-peptide remained elevated under all conditions (P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non-suppression of C-peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C-peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when conventional methods yield equivocal results.