Altered islet beta-cell function before the onset of type 1 (insulin-dependent) diabetes mellitus

To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 non-diabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followed-up prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2 +/- 2.0 vs 1.8 +/- 1.8 nmol/l; p less than 0.05); but lower glucose clearance (1.0 +/- 0.5 vs 1.9 +/- 0.7 %/min; p less than 0.05), first phase insulin response at 0.5 g/kg (21.1 +/- 23.2 vs 143 +/- 50 nmol/l; p less than 0.0001), and total insulin responses at 0.1 g/kg (p less than 0.05) and 0.5 g/kg (p less than 0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R2) than control subjects (p less than 0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R2 and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R2 and subnormal first phase insulin response were 67% and 58% respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.