The Glucagon Receptor as a Drug Target - a Witches’ Brew of Eye of Newt (Peptides) and Toe of Frog (Receptors) (original) (raw)

Diabetes, Obesity and Metabolism

Glucagon has a noble history in the annals of metabolic disease, 1 even though, to a layperson, insulin is its more famous counterregulatory partner. For decades medical students have been taught that glucagon raises blood glucose by increasing hepatic glucose output and that alleviation of hypoglycaemia is its primary function. 2 Thus, inhibition of glucagon secretion 3 or action 4 are logical approaches to the development of therapeutics that improve glycaemic control in both type 2 and type 1 diabetes mellitus; indeed, this strategy has been pursued for nearly 4 decades. The situation, however, is complex. The preproglucagon gene product can be cleaved at various points by specific prohormone convertases to yield several bioactive peptides, including glucagon, in a tissue-selective manner. 1 Prohormone convertase 2 is expressed in pancreatic islets to generate mainly glucagon in α cells. By contrast, prohormone convertase 1/3 processes proglucagon in the gut and brain to glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glicentin and oxyntomodulin. These boundaries are not absolute, however, and the relative abundance of these peptides in a tissue, and therefore its secretory potential, can vary depending on the differential expression of the processing enzymes. 5 There is evidence that GLP-1 is expressed in pancreatic islets, 6,7 while glucagon may be secreted by enteroendocrine cells in the gut. 8 Enteroendocrine cells also express other peptides such as peptide-tyrosinetyrosine (PYY), 9,10 and it now appears that secretion can be modulated by feedback inhibition by homotypic (GLP-1 reducing GLP-1 secretion) as well as heterotypic mechanisms (GLP-1 reducing PYY secretion). 11,12 Glucagon receptor pharmacology is also multifaceted. The classic