This novel insulin secretion test elicits a distinct pattern of plasma insulin concentrations in response to the secretagogues glucose, GLP-1 and arginine and is highly reproducible and can be used for differential characterization of islet function.

The pathogenesis of Type II (non-insulin-dependent) diabetes mellitus involves a combination of impaired insulin secretion and insulin resistance [1]. Because both could be secondary to so-called ªglucose toxicityº [2] or environmental factors such as obesity, fat distribution or diet [3], it is still controversial which of these factors represents the underlying defect. One approach to narrow down the possible sites of the defect is to clinically characterise the abnormality in people who are likely to carry the genetic defect(s) but are not yet overtly hyperglycaemic. Thus, an ideal study group includes first-degree relatives of patients with Type II diabetes (prediabetic) and subjects with mildly impaired glucose tolerance (IGT). Whereas only 40 % [4] of the former group progress to manifest diabetes, the clinical penetrance Abstract Aims/hypothesis. Our studies were undertaken to characterise the defective insulin secretion of impaired glucose tolerance (IGT). Methods. We studied 13 normal glucose tolerant subjects (NGT) and 12 subjects with IGT carefully matched for age, sex, BMI and waist-to-hip ratio. A modified hyperglycaemic clamp (10 mmol/l) with a standard 2-h square-wave hyperglycaemia, an additional glucagon-like-peptide (GLP)-1 phase (1.5 pmol × kg ±1 × min ±1 over 80 min) and a final arginine bolus (5 g) was used to assess various phases of insulin secretion rate. Results. Insulin sensitivity during the second phase of the hyperglycaemic clamp was low in both groups but not significantly different (0.12 ± 0.021 in NGT vs 0.11 ± 0.013 mmol × kg ±1 × min ±1 × pmol ±1 in IGT, p = 0.61). First-phase insulin secretion was lower in IGT (1467 ± 252 vs 3198 ± 527 pmol × min ±1 , p = 0.008) whereas the second phase was not (677 ± 61 vs 878 ± 117 pmol × min ±1 , p = 0.15). The acute insulin secretory peak in response to GLP-1 was absent in IGT subjects who only produced a late phase of GLP-1-induced insulin secretion rate which was lower (2228 ± 188 pmol × min ±1) than in NGT subjects (3056 ± 327 pmol × min ±1 , p = 0.043). Insulin secretion in response to arginine was considerably although not significantly lower in IGT subjects. The relative impairment (per cent of the mean rate for NGT subjects) was greatest for the GLP-1 peak (19 ± 9 %). Conclusion/interpretation. In this Caucasian cohort a defective insulin secretion rate is essential for the development of IGT. The variable degrees of impairment of different phases of the insulin secretion rate indicate that several defects contribute to its abnormality in IGT. Defects in the incretin signalling pathway of the beta cell could contribute to the pathogenesis of beta-cell dysfunction of IGT and thus Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2000)

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In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.