Incretin Effect in Youths with Normal and Impaired Glucose Tolerance

Background. Prediabetes includes a broad range of glucose metabolism alterations that increase the risk for diabetes in youths. Analogues of gut-derived hormones (incretins) have been paved as a promising therapeutic option for youths with diabetes. Though, we lack in vivo studies assessing the incretin effect in prediabetes and early diabetes in youths as well as longitudinal assessment of the incretin response in this age. We estimated the incretin effect in obese youths with normal and impaired glucose tolerance, by the use of the gold standard matched oral glucose tolerance test (OGTT) and iso-glycemic intravenous glucose tolerance test (iso-IVGTT). Methods. We enrolled 30 overweight/obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Each participant underwent a 180-minutes OGTT and an iso-IVGTT to quantify the incretin effect, followed by a hyperglycemic clamp to measure glucose and arginine induced insulin secretion. Seriated samples for plasma glucose, insulin, C-peptide and active GLP-1(7-36) were collected. The minimal model and deconvolution were adopted to estimate insulin secretion based on glucose and C-peptide. The hyperglycemic clamp-derived indices were A) M/I for insulin sensitivity, B) acute (0–10 min [first phase]) C-peptide response to glucose (ACPRg), C) steady-state C-peptide concentrations at plasma glucose of 11.1 mmol/L, and D) arginine-stimulated maximum C-peptide response at plasma glucose >25 mmol/L (ACPRmax). Results. We completed the three tests in 28 youths (15.9±2.4y, 14F, 13 NGT, 15 IGT). The NGT and IGT groups did not differ with respect to age, ethnicity, BMI, fasting glucose. No significant differences were observed between the two groups in either measure of β-cell function [ACPRg, steady- state C-peptide, ACPRmax, (p=0.372, p=0.478 and p=0.230)] or in insulin sensitivity [M/I] (p=0.106). The incretin effect was higher in the NGT than IGT group (+28.3%[-4, 62] and -10.3%[-34.3, 14.2], p=0.022), in spite of a lower GLP-1 secretion rate during the OGTT in the NGT group (p<0.001). Conclusion. Impairment of glucose tolerance in youths is associated with a reduced incretin effect in the absence of a significant impairment of β-cell function. The higher secretion rate of GLP-1 is suggestive for a primary incretin resistance. The incretin pathway could represent potential target for therapeutic interventions in youth onset prediabetes.