Glucagon receptor as a drug target: A witches' brew of eye of newt (peptides) and toe of frog (receptors)

Abstract

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). 11,12Glucagon receptor pharmacology is also multifaceted. (Table 1) have uncovered good, bad and ugly aspects in humans (Table 2) 25 ; therefore, the essential question for drug development is whether these features can be separated sufficiently to open a wide therapeutic index, and allow safe long-term use. Small molecules targeting the glucagon receptor have both common structural elements and molecule-specific motifs that can confound the interpretation of adverse event profiles. Comparing the results from totally different molecular classes, small molecule-, antibody-and antisense-based approaches, therefore, allows some parsing of effects that can reasonably be attributed to mechanism-of-action vs those that may be related to moleculespecific "toxicity." Moreover, preclinical models such as glucagon

Effect of a glucagon receptor antibody (REMD‐477) in type 1 diabetes: A randomized controlled trial

“…However, several adverse effects of therapy have also been reported, including an increase in blood pressure, weight, plasma LDL-cholesterol and plasma transaminase concentrations. 11 While not measured with other compounds, a recent publication showed an increase in hepatic fat content with LY2409021, which was the first to correlate the transaminase increase with potential, underlying pathophysiology. 12 An additional concern is that chronic glucagon receptor blockade will cause pancreatic α-cell hyperplasia, which has been shown in animal models 13,14 and in case reports demonstrating α-cell hypertrophy and severe hyperglucagonaemia, without evidence of glucagonoma syndrome, in individuals with loss-of-function glucagon receptor mutations.…”

“…A series of studies have evaluated the effect of glucagon receptor blockade in humans by using small molecule antagonists, antisense oligonucleotide inhibitors of the glucagon receptor and monoclonal glucagon receptor antibodies . All of these approaches have consistently improved glycaemic control, manifested by a decrease in A1c and blood glucose concentrations.…”

“…All of these approaches have consistently improved glycaemic control, manifested by a decrease in A1c and blood glucose concentrations. However, several adverse effects of therapy have also been reported, including an increase in blood pressure, weight, plasma LDL‐cholesterol and plasma transaminase concentrations . While not measured with other compounds, a recent publication showed an increase in hepatic fat content with LY2409021, which was the first to correlate the transaminase increase with potential, underlying pathophysiology .…”

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

“…Gcgr knockout mice displayed an antidiabetogenic effect in both T1D and T2D mice 22–25. Despite numerous compounds having been developed during the last two decades, most agents were discontinued for further development due to some unexpected adverse events 3 5. Therefore, developing a safe and efficacious GCGR antagonist remains highly needed.…”

“…Glucagon acts through the glucagon receptor (GCGR), which is a G protein-coupled receptor expressed in the liver as well as multiple extrahepatic tissues, including the gastrointestinal tract 2. Accumulating evidence proves that disruption of GCGR signaling, using gene knockout, antisense oligonucleotide, antagonists or antibodies, can alleviate hyperglycemia in animals and humans 3–5. Recent data from our group and others have shown that REMD 2.59, a fully competitive antagonistic human GCGR monoclonal antibody (mAb), has a strong hypoglycemic effect in type 1 diabetic (T1D) and T2D rodents and non-human primates 6–10.…”