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    • Glucagon was described as an insulin secretagogue as early

    2022-04-08

    Glucagon was described as an insulin secretagogue as early as 1965 (Samols et al., 1965). Our studies extend these findings by demonstrating that this is a direct effect mediated by distinct receptors in the mouse pancreas. Previous experiments on isolated β Fmoc-D-Lys(Boc)-OH synthesis clearly show that glucagon is capable of directly stimulating insulin secretion, and β cells (and δ cells) have been reported to express Gcgrs (Adriaenssens et al., 2016, Huypens et al., 2000, Van Schravendijk et al., 1985). A paracrine role for glucagon in the regulation of insulin secretion is supported by observations from other groups using mouse models with Gcgr or glucagon deficiencies (Gelling et al., 2003, Gelling et al., 2009, Moens et al., 1998, Sørensen et al., 2006). Our data clearly demonstrate that glucagon can activate the GLP-1R, although with a lower potency compared with its interaction with the Gcgr. The ability of glucagon to make use of the GLP-1R in the absence of functional Gcgrs becomes apparent in Gcgrβcell−/− mice, where insulin secretion was similar to that of control mice. In Gcgr−/− mice, only high doses of glucagon were able to stimulate insulin secretion, again through the GLP-1R. Conversely, without a functional GLP-1R (whether blocked by an antagonist or in the Glp1r−/− mouse pancreas), exogenous glucagon still induced a rise in insulin secretion, although the response was slightly reduced compared with that in animals with fully functional GLP-1R and Gcgr. A role for pancreatic GLP-1 has been discussed, and studies have suggested local production of GLP-1 in islets (Marchetti et al., 2012, Taylor et al., 2013, Whalley et al., 2011). The original concept was that GLP-1 results from posttranslational processing of proglucagon via PC1/3 in intestinal L-cells, whereas proglucagon in the pancreas is cleaved by PC2, yielding glucagon and the major proglucagon fragment. Nevertheless, studies using Pdx1-Cre to control the expression of Gcg and, hence, GLP-1 in the mouse pancreas suggested that pancreas-derived GLP-1 may contribute substantially to the incretin effect following oral glucose administration in mice (Chambers et al., 2017). In contrast, our data demonstrate that the levels of active, fully processed GLP-1(7-36NH2/7-37) in perfused pancreata from control mice are very low and frequently undetectable. Indeed, a recent study based on very sensitive detection methods was unable to identify measurable amounts of GLP-1 in extracts of the normal mouse pancreas (Galsgaard et al., 2018). Hence, under normal circumstances, the secretion of active GLP-1 from the pancreas is negligible. However, we show here that GLP-1R-stimulated insulin secretion can also be elicited by glucagon and, therefore, does not require the presence of locally produced islet GLP-1. Hence, the inhibition of insulin secretion by Ex9, as demonstrated by Chambers et al. (2017) and also evident from our data, may reflect inhibition of glucagon-induced activation of the GLP-1R as well as blockade of excess GLP-1 produced in the context of selective pancreatic reactivation of Gcg expression. The Gcgr mouse has massive hyperglucagonemia associated with postnatal enlargement of the pancreas and hyperplasia of the islets, primarily α cells and, to a lesser extent, δ cells (Gelling et al., 2003). Perfusion of Gcgr−/− pancreata demonstrated significant levels of active GLP-1, showing that, in conditions with highly increased secretory activity, α cell hyperplasia, and perhaps activation of α cell Pcsk1, bioactive GLP-1 is locally produced. A recent paper showed that, under normal circumstances, islet GLP-1 is not necessary for normal insulin secretion but could play a role during metabolic stress and increased secretory demands (Traub et al., 2017). Further studies are needed to define the conditions enabling processing and secretion of bioactive GLP-1 in islet cells. The indisputable effect of the GLP-1R becomes obvious in the Gcgr−/− pancreas, where we noted an unexpected increase in insulin secretion. However, the combination of excessive glucagon secretion as well as increased levels of active GLP-1 could lead to increased activation of the GLP-1Rs in β and δ cells and, therefore, increased hormone secretion. Notably, GLP-1 blockade through Ex9 in Gcgr−/− pancreata completely abolished augmentation of insulin secretion, attesting to the importance of these two receptors for insulin secretion.