Characterisation of beta-cell dysfunction of impaired glucose tolerance: Evidence for impairment of incretin-induced insulin secretion

Abstract

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)

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

“…The arginine bolus in the combined hyperglycaemic clamp produces a maximal challenge for the secretory capacity of the beta cell and can be possibly considered as a surrogate for beta cell mass [28,35]. rs10010131 did not affect this maximal insulin secretion, indicating that this variant in WFS1 might not influence beta cell mass, at least in the prediabetic state.…”

“…The participants did not take any medication known to affect glucose tolerance or insulin sensitivity. Tests were performed after an overnight fast of 12 h. Hyperglycaemic clamp Exact details of the clamping procedures have been described previously [28,35]. In brief, hyperglycaemic clamps lasted for 2 h followed by the GLP-1 and arginine stimulation (see below).…”

Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

“…Details of the study groups have been described previously [17][18][19]. In the German subgroup (n=73), the hyperglycaemic clamp was continued with an additional GLP-1 and arginine administration [15,[20][21][22].…”

Physiology of Incretins in Health and Disease

“…However, further analysis concluded that the reductions could largely be explained by differences in BMI and/or insulin sensitivity [93,107]. In terms of incretin action in impaired glucose-tolerant subjects, the insulinotropic effect of GLP-1 was found to be reduced [108], and an impaired incretin effect has been reported [107]. In another study, GIP action was normal in subjects with previous gestational diabetes [105].…”