Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus:: Evidence of early β-cell dysfunction

To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemiceuglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) hut significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1.766 +/- 229 pmol/L . 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) far the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory purse interval (5.8 +/- 0.2 v 5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude(133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass. Copyright (C) 2000 by W.B. Saunders Company.