Glucagon antagonism in islet cell proliferation

The peptide hormones insulin and glucagon (gcg) are inextricably linked in the normal control of glucose homeostasis and in the dysregulated glucose homeostasis that defines diabetes mellitus. Pancreatic islets secrete both insulin and gcg in a manner that is tightly juxtaposed. β Cells secrete insulin, a peptide hormone that promotes the uptake and storage of carbohydrates and other nutrients in skeletal muscle and fat, while simultaneously repressing gcg secretion from pancreatic α cells and glucose efflux from the liver. Although loss of insulin function is the most conspicuous cause of both type 1 diabetes (T1D) and type 2 diabetes (T2D), hyperglucagonemia also drives hyperglycemia. Pharmacological approaches to blunt gcg action have gained some traction as a potential antidiabetic approach. In PNAS, Okamoto et al. (1, 2) present two papers evaluating gcg blockade on islet physiology. First, they examine the mechanisms of α-cell hyperplasia, a phenomenon that stands as a potential roadblock in the use of these glucagon receptor (Gcgr) antagonists (1). Second, they reveal that Gcgr antagonism when insulin action is absent can lead to normoglycemia and β-cell expansion (Fig. 1; ref. 2). Fig. 1. Pancreatic islets are composed of gcg-expressing α cells (red), insulin-expressing β cells (green), somatostatin-expressing δ cells (blue) and pancreatic polypeptide-expressing γ cells (white and red). Gcgr antagonism promotes α-cell hyperplasia possibly via amino acid-dependent mechanisms. Insr antagonism with S961 peptide can promote the expansion of β-cell mass mechanisms that may involve hepatic-derived SerpinB1. When combined, antagonism of both receptors synergistically promotes the formation of more β-cell mass. Despite five decades of biochemical, physiological, and morphological research demonstrating that aberrant gcg production correlates with diabetes and suppression of gcg corrects the hyperglycemia of diabetes, gcg is not widely accepted as the direct cause of the metabolic abnormality. Since developing the first RIA for gcg in … [↵][1]1To whom correspondence should be addressed. Email: roger.unger{at}utsouthwestern.edu. [1]: #xref-corresp-1-1