br Introduction Glucose homeostasis is
Introduction Glucose homeostasis is primarily regulated by the hormones insulin and glucagon, secreted from the pancreatic islets of Langerhans. Although insulin produced by β (E)-2-Decenoic acid is the blood glucose-lowering hormone, glucagon secreted from α cells acts as the major counter-regulatory hormone to insulin and is important for maintaining normal glucose levels. Conversely, glucagon secretion is regulated by glucose, being inhibited during hyperglycemia and stimulated during hypoglycemia, resulting in stimulation of hepatic glucose output (Gromada et al., 2007). Disturbed control of α cell function is characteristic of type 2 diabetes and, importantly, results in hyperglucagonemia, which contributes to hyperglycemia (Kahn, 2003, Kazda et al., 2016, Knop et al., 2007). The development of hyperglucagonemia would be consistent with the so-called intra-islet hypothesis stating that glucagon secretion undergoes inhibition from insulin, which, in conditions with decreased insulin secretion or α cell insulin resistance, would lead to reduced suppression of glucagon secretion (Banarer et al., 2002, Hope et al., 2004, Meier et al., 2006). On the other hand, glucagon is also known as an efficacious stimulator of insulin secretion, and the glucagon receptor is located on both pancreatic β and δ cells (Adriaenssens et al., 2016), suggesting that glucagon might have direct effects on insulin and somatostatin secretion. In this study we investigate mechanisms regulating intra-islet communication, focusing on the role of glucagon in control of insulin secretion using the perfused mouse pancreas, a model that allows investigations of the paracrine relationships within intact islets. We employed a range of complementary genetic and pharmacological approaches to disrupt local glucagon signaling. Thus, to acutely eliminate glucagon secretion from α cells, we used diphtheria toxin (DT)-induced destruction of proglucagon-producing α cells (Pedersen et al., 2013). For estimation of the importance of glucagon receptors (Gcgrs) in β cells, we used a mouse line with inducible Gcgr knockout exclusively in β cells (Gcgrβcell−/−) as well as mice with global knockout of the Gcgr (Gcgr−/−) (Gelling et al., 2003). The functional importance of the glucagon-like peptide-1 receptor (GLP-1R) was investigated using Glp1r−/− mice (Scrocchi et al., 1996) as well as the GLP-1R antagonist exendin(9-39) (Ex9).
Discussion The interplay between glucagon and insulin secretion has been the subject of many studies, and the prevailing concept reflects the “intra-islet hypothesis” that insulin inversely regulates glucagon secretion. This hypothesis would be consistent with the theory of core-to-mantle blood flow, with β cells reacting to changes first and mantle cells (α and δ cells) then responding to insulin (Bonner-Weir and Orci, 1982, Maruyama et al., 1984). However, other studies have suggested that blood flow rather perfuses the islet from one side to the other regardless of cell type, thereby providing for paracrine actions of α and δ cell secretion on downstream β cells (Kharouta et al., 2009, Liu et al., 1993, Nyman et al., 2008). Exogenous glucagon is thought to stimulate insulin secretion, but endogenous glucagon is not classically considered part of the paracrine β cell network (Kawamori et al., 2009, Leung et al., 2006, Ravier and Rutter, 2005). In this study, we revisited intra-islet paracrine relationships. An alternative approach to understanding intra-islet relationships is to use the isolated perfused pancreas preparations as opposed to the often used isolated islet or in vivo studies. This technique allows functional interrogation of islet secretory activity without interference from other organs in the body, excluding systemic factors, elimination and/or degradation of hormones, etc., which often complicates interpretation of in vivo studies. Importantly, the perfused pancreas maintains its local cytoarchitecture and microvasculature, ensuring normal flux of both substrates and products to and from the various cell types.