Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

Abstract

Aims/hypothesis The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect. Methods Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function.Results After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71±3.2% and 67±4.6% (p00.4) before treatment, but decreased significantly in both groups to 58±5.2% and 32±8.8% (p<0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio. Conclusion/interpretation Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT.Trial registration: ClinicalTrials.gov NCT00784745.

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

“…The molecular explanation for the reduced incretin effects as demonstrated in the present study is unknown, but this very early beta cell defect has been found in parallel with an increased proinsulin/C-peptide ratio, reflecting increased demand for insulin [10,32]. This is in accordance with insulin resistance induced by dexamethasone in the present study.…”

“…However, few studies have examined how early in the process toward type 2 diabetes the incretin hormones lose their insulinotropic effect. In a previous study [10], we found that the incretin effect had already diminished in individuals with an increase in insulin resistance and it deteriorated further when individuals with insulin resistance also became glucose intolerant. In that study, dexamethasone-induced insulin resistance had no effect on the secretion of the incretin hormones, which excluded impaired secretion as an explanation for the loss of incretin effect.…”

“…Therefore, in the present study, we investigated in detail the effects on different measures of beta cell function of both GLP-1 and GIP in concentrations similar to those observed after oral glucose and a mixed meal in a previous study measured with the same assays [10]. We used the same protocol as in the previous study to induce insulin resistance and dysglycaemia.…”

“…Nevertheless, all insulin responses were increased after dexamethasone, suggesting that the beta cells adapted to the increase in insulin resistance, but were unable to fully compensate for this, since glucose tolerance decreased in all individuals and the amount of glucose infused was decreased during all three clamps after dexamethasone. We previously demonstrated that the incretin effect was reduced when insulin resistance was increased with dexamethasone in healthy first-degree relatives of type 2 diabetes patients, even while normal glucose tolerance was maintained [10]. When the participants developed glucose intolerance in addition to insulin resistance, a further significant decline in the incretin effect was observed.…”

“…The GLP-1 bolus was calculated as: 50 pmol/ml×0.05×body weight in kg, and the infusion rate was 0.5 pmol/(kg×min) for 120 min. The infusion rates were calculated to result in postprandial plasma concentrations, as measured in our earlier study [10]. After 80 min, the PG level was increased to 15 mmol/l (algorithm described above) and held at 15 mmol/l by means of a continuous glucose infusion, adjusted according to bedside measurements of PG level.…”