Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

Recent advances with incretin-based drugs have opened new avenues in the management of diabetes. In the clinic, we can prescribe two types of incretin-based drugs: glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 is produced from intestinal L-cells by proteolytical processing from proglucagon (ProG) and immediately degraded by DPP-4; its half-life is approximately 2 min. GLP-1RAs have been developed to avoid DPP-4-mediated cleavage of GLP-1 by introducing a mutation in the amino acid residue that DPP-4 targets. Exenatide (Exendin-4), a 39-amino-acid polypeptide isolated from the venom of the Gila monster lizard with 50% homology to human GLP-1, has been used in the clinic. Alternatively, to extend the half-life of endogenous GLP-1, DPP-4 inhibitors are prescribed. Recent clinical trials (Marso et al., 2016 (Marso et al., , 2017 Rosenstock et al., 2019) investigating the safety and efficacy of incretin-based drugs have provided diverse interpretations and provocative intellectual curiosities regarding the biology of incretin hormones and incretin-based drugs, specifically focusing on pleiotropic effects. Autophagy, the cellular mechanism that promotes cell survival during nutrient depletion, may also be relevant under basal or nutrient excess conditions. This cellular process is specified by the formation of autophagosomes, by which cytosolic components are captured and fused with lysosomes to promote the degradation and/or recycling of its contents. The autophagic process consists of four stages: initiation, nucleation, elongation, and fusion/degradation (Codogno et al., 2011) . During nutrient depletion, autophagy can provide essential components for energy production and biosynthesis. However, it also acts in a similar manner by recycling damaged organelles, unnecessary proteins, and foreign substances for the quality maintenance of these intracellular components (Ueno and Komatsu, 2017) . In circumstances of nutrient excess, autophagy plays important roles in eliminating unfolded proteins and toxic aggregates and facilitating endoplasmic reticulum (ER) homeostasis. The detailed mechanisms and biology of autophagy are summarized in subsequent sections of this issue.