Incretin as a Pathophysiological Component and Target for Treatment in Youth Type 2 Diabetes (T2D)

Abstract

Incretin hormones have recently been considered an important pathophysiological factor for T2D in adults and youth due to their role in augmenting insulin secretion (Michaliszyn et al., 2014). It is recognized that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are glucose-dependent hormones released from the gut that stimulate insulin release from pancreatic β-cells (Muscelli et al., 2006). Thus, the insulin response to oral glucose is significantly greater than the intravenous (IV) glucose administration response; this is known as the incretin effect (Michaliszyn et al., 2014). To date, adults with T2D demonstrate a remarkable decrease in the incretin effect (Nauck et al., 1986), whereas there is lack of evidence in pediatric populations. The incretin effect is also associated with β-cell glucose sensitivity (βCGS), attesting incretins as a high-promising target for T2D treatment (Michaliszyn et al., 2014). Utilizing GLP-1 receptor agonists can be advantageous as a therapeutic option for both adults and youth (Tamborlane et al., 2019; Vanderheiden et al., 2016; Yeow et al., 2017). While metformin and insulin were the sole treatment options for Y-T2D prior to FDA approval (in 2019) for the use of GLP-1 agonists, a recent RISE (Restoring Insulin Secretion) clinical trial reported disappointing results that both metformin alone and insulin glargine for three months followed by metformin for nine months were not effective in restoring/preserving β-cell function in youth with prediabetes and T2D (RISE Consortium & RISE Consortium Investigators, 2019). On the contrary, the role of GLP-1 and the efficacy of the GLP-1 receptors in T2D signifies a strong target for potential treatment. Additional clinical trials are warranted to see if monotherapy of GLP-1 agonist vs. combined (metformin + liraglutide) therapy is effective to reserve Y-T2D to prediabetes and/or normal state. More importantly, future research should focus on disease prevention rather than treatment to avoid aggressive complications and metabolic degradations of Y-T2D (RISE Consortium & RISE Consortium Investigators, 2019). Altogether, it would be germane to investigate whether lifestyle changes (diet, physical activity, exercise medicine) can improve the incretin effect in conjunction with glycemic control in youth.