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

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

GLP-1 is produced from proteolytic cleavage of the precursor polypeptide pProG (Muller et al., 2017) . The pProG gene (Gcg) is expressed in a specific population of enteroendocrine cells (L-cells) in the intestinal mucosa, islet cells in the pancreas, and some neurons within the nucleus of the solitary tract (NTS) (Han et al., 1986; Jin et al., 1988) . Regulation of the Gcg transcription process is not completely known and distinct pattern of mRNA expression has been reported in intestinal endocrine cells and in pancreatic islet α-cells (Jin, 2008; Yi et al., 2008; Chiang et al., 2012; Muller et al., 2017) . In addition to such unique transcriptional control in each cell type, posttranslational processing of prohormone plays an important role in the major cell types producing ProG peptides. In addition to glucagon and GLP-1, glucagon-like peptide-2 (GLP-2), oxyntomodulin, glicentin, glicentin-related pancreatic polypeptide (GRPP), and major proglucagon fragment (MPGF) are synthesized from ProG; however, the specific biological function of some of these fragments has not been identified (Figure 1) . Such posttranslational regulation of these ProG peptides in their respective cell types relies on tissue-specific posttranslational modification by prohormone convertases (PCs). In intestinal L-cells and neurons of the NTS, a predominance of PC1/3 expression, GLP-1, oxyntomodulin, and GLP-2 are seen as physiologically relevant (Tucker et al., 1996; Larsen et al., 1997; Vrang et al., 2007) ; in pancreatic α-cells, high PC2 levels are responsible for the predominant glucagon synthesis (Figure 1 ) (Holst et al., 1994) . PC2 is also expressed in the brain but does not colocalize with Gcg. Additionally, PC1/3 is expressed in α-cells but at lower levels than PC2, and the ratio of GLP-1 to glucagon expressed in islet cells has been shown to be increased during the progression of diabetes (O'Malley et al., 2014) . Gcg expression and ProG levels are relatively lower in the proximal gut and higher in the distal part, with the highest expression in the colon (Bryant and Bloom, 1979) .