The incretin effect in obese adolescents with and without type 2 diabetes: impaired or intact?

Abstract

The incretin effect reflects the actions of enteral stimuli to promote prandial insulin secretion. Impairment of this measure has been proposed as an early marker of β-cell dysfunction and described in T2D, IGT, and even obesity without IGT. We sought to determine the effects of obesity and diabetes on the incretin effect in young subjects with short exposures to metabolic abnormalities and a few other confounding medical conditions. Subjects with T2D (n = 10; 18.0 ± 0.4 yr) or NGT, either obese (n = 11; 17.7 ± 0.4 yr) or lean (n = 8; 26.5 ± 2.3 yr), had OGTT and iso-iv. The incretin effect was calculated as the difference in insulin secretion during these tests and was decreased ∼50% in both the NGT-Ob and T2D subjects relative to the NGT-Ln group. The T2D group had impaired glucose tolerance and insulin secretion during the OGTT, whereas the lean and obese NGT subjects had comparable glucose excursions and β-cell function. During the iso-iv test, the NGT-Ob subjects had significantly greater insulin secretion than the NGT-Ln and T2D groups. These findings demonstrate that in young subjects with early, well-controlled T2D the incretin effect is reduced, similar to what has been described in diabetic adults. The lower incretin effect calculated for the obese subjects with NGT is driven by a disproportionately greater insulin response to iv glucose and does not affect postprandial glucose regulation. These findings confirm that the incretin effect is an early marker of impaired insulin secretion in persons with abnormal glucose tolerance but suggest that in obese subjects with NGT the incretin effect calculation can be confounded by exaggerated insulin secretion to iv glucose.

Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus

“…Lesser degree of reduction in incretin effect has also been observed in two other studies among non-Asian youth with T2DM. 10 37 However, the incretin effect was derived differently from all three studies making direct comparison inaccurate. The greater reduction in incretin effect in our study may be due to the poorer glycemic control among our subjects since hyperglycemia has been proposed to downregulate GLP-1 receptor expression on β-cells and cause ‘GLP-1 resistance’.…”

Targeting postprandial glycaemia in children with diabetes: Opportunities and challenges

“…Type 2 diabetes in adults is associated with a diminished incretin effect, reflecting reductions in the insulinotropic response to GIP, functioning beta cell mass and maximum insulin secretory capacity . Despite variation in the reported concentrations of GIP and GLP‐1 (both reduced and increased), meta‐analyses indicate that there is no substantial alteration in GIP or GLP‐1 secretion in type 2 diabetes . A reduced incretin effect is also seen in adolescents with impaired glucose tolerance or type 2 diabetes .…”

“…Despite variation in the reported concentrations of GIP and GLP‐1 (both reduced and increased), meta‐analyses indicate that there is no substantial alteration in GIP or GLP‐1 secretion in type 2 diabetes . A reduced incretin effect is also seen in adolescents with impaired glucose tolerance or type 2 diabetes . In type 1 diabetes, there is, predictability, a reduced incretin effect in terms of insulin response, and glucagon suppression is also impaired …”

“…88,89 A reduced incretin effect is also seen in adolescents with impaired glucose tolerance or type 2 diabetes. 85,87 In type 1 diabetes, there is, predictability, a reduced incretin effect in terms of insulin response, and glucagon suppression is also impaired. 90 GLP-1 receptor agonists (RAs), which are resistant to degradation by DPP4 and administered subcutaneously, have been developed primarily for use in type 2 diabetes.…”

An Overview of Similarities and Differences in Metabolic Actions and Effects of Central Nervous System Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2is)

“… 13 , 14 Numerous researches have reported that the function of incretin axis is impaired in T2D or metabolic syndrome, a phenomenon that causes insufficient GLP-1 production, or disrupted GLP-1 action. 15 , 16 …”