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

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

In the stomach, gastric emptying is regulated by gastric content and neural and hormonal influences and is altered after bariatric surgery as described earlier. Accelerated gastric emptying time for liquids but slower gastric emptying time for solids have been reported after RYGB (Horowitz et al., 1982) . Kotler et al. (1985) reported faster intestinal transit time and increased enteroglucagon levels in patients with greater weight loss compared to weight-stable patients. The term "enteroglucagon" in this report did not necessarily include "glucagon" because of cross reaction with several glucagon sequence-containing polypeptides at the time of this report. The presence of extrapancreatic glucagon secretion in humans has been the focus of intense discussion for years, and even though evidence was conflicting, some investigators reported that glucagon responses after total pancreatectomy were present in animals (Sutherland and De Duve, 1948; Matsuyama and Foa, 1974; Vranic et al., 1974; Muller et al., 1978; Doi et al., 1979; Gotoh et al., 1989) and humans (Unger et al., 1966; Barnes and Bloom, 1976; Villanueva et al., 1976; Boden et al., 1980; Karesen et al., 1980; Sudo et al., 1980; Dammann et al., 1981; Holst et al., 1983; Yasui, 1983; Polonsky et al., 1984; Bajorunas et al., 1986a,b; Ohtsuka et al., 1986; Tanjoh et al., 2003) . The most challenging point was that until recently, analytical methods for glucagon have not been sufficiently sensitive or specific to justify decisive statements about the absence or presence of extrapancreatic fully processed 29amino acid glucagon (Tanjoh et al., 2003) . Recently, sandwich enzyme-linked immunosorbent assays (ELISA) utilizing a combination of C-and N-terminal antiglucagon antibodies have been emerged. Such ELISA system theoretically could eliminate cross-reactivity with truncated or elongated forms of glucagon containing polypeptides (Wewer Albrechtsen et al., 2014) . Lund et al. (2016) studied patients who underwent total pancreatectomy and analyzed plasma glucagon levels. As expected, the gastrointestinal anatomy was remarkably changed, including the removal of the pyloric sphincter and duodenum after total pancreatectomy. Therefore, following the ingestion of a meal, nutrients are rerouted and delivered directly from the stomach to the jejunum in a manner similar to bariatric surgery as previously described. The unique point of the study by Lund et al. (2016) is that they utilized not only novel sandwich enzyme-linked immunosorbent assays of plasma glucagon but also mass spectrometry-based proteomics to confirm 29-amino acid circulatory glucagon levels in patients without a pancreas. Basal glucagon levels in these patients exhibited a lower trend, and glucose challenge of the gastrointestinal tract exerted significant hyperglucagonemia in these patients. Lund et al. (2016) also confirm that the intravenous glucose infusion attenuated plasma glucagon levels, and directs focus on the gastrointestinal tract. Unfortunately, there is no direct evidence indicated the hyperglucagonemia after bariatric surgery yet, but higher glucagon release within the first 2 h and higher trend of peak level of glucagon in post RYGB patients when compared to SG or neither operation group has been recently reported (Svane et al., 2019) . These findings suggest that alteration in glucagon secretion or possibly hyperglucagonemia could be induced by bariatric surgery and be relevant in systemic physiological alterat