Miniglucagon: A Local Regulator of Islet Physiology

Abstract

Miniglucagon, or glucagon-[19-29], is partially processed from glucagon in its target tissues where it modulates the glucagon action. In the islets of Langerhans, the glucagon-producing A cells contain miniglucagon at a significant level (2-5% of the glucagon content). We studied a possible control of insulin release by miniglucagon using as a model the MIN6 cell line. Miniglucagon, in the 10(-14) to 10(-9) M range, inhibited insulin release induced by glucose, glucagon, tGLP-1, or glibenclamide by 85-100% with an IC50 close to 1 pM. While no change in the cyclic AMP content was noted, Ca2+ influx was reduced in parallel with the inhibition of insulin release. Use of pharmacological modulators of L-type voltage-sensitive Ca2+ channels and bacterial toxins indicates that miniglucagon blocks insulin release by closing this type of channel via a pertussis toxin-sensitive G protein. Miniglucagon is a novel, possibly physiologically relevant, local regulator of islet function.

Allostery and Biased Agonism at Class B G Protein-Coupled Receptors

“…Oxyntomodulin is a low-affinity agonist with dual actions at both the glucagon receptor and the GLP-1 receptor. Mini-glucagon, the C-terminal 19–29 fragment processed from glucagon, is present in pancreatic cells and is a potent inhibitor of glucagon- and GLP-1-mediated insulin secretion; however, these effects may be independent of the glucagon receptor itself. , The GLP-1 receptor agonists, GLP-1 and liraglutide are also agonists at the glucagon receptor, albeit with lower efficacy than at the GLP-1 receptor …”

“…Mini-glucagon, the C-terminal 19−29 fragment processed from glucagon, is present in pancreatic cells and is a potent inhibitor of glucagon-and GLP-1-mediated insulin secretion; however, these effects may be independent of the glucagon receptor itself. 212,213 The GLP-1 receptor agonists, GLP-1 and liraglutide are also agonists at the glucagon receptor, albeit with lower efficacy than at the GLP-1 receptor. 214 To date, there is limited information around biased agonism at the glucagon receptor, as most efforts in ligand development have focused on development of antagonists that are normally profiled in inhibition of either glucagon binding or glucagonmediated cAMP.…”

Metabolic responses of lactating dairy cows to exogenous glucagon

“…Glucagon can be further cleaved to mi ni glucagon in the pancreas or in target tissues (Carrey and Epand, 1983;Dalle et al, 1998). Glucagon and mini glucagon are mostly similar in their effect, whereas glucagon and glucagon-like peptide-1 differ in their effect (Dalle et al, 1998;Rouillé et al, 1997a, b;Sauvadet et al, 1996).…”