Attempting to further elucidate the role of glucagon and
Attempting to further elucidate the role of KW-6002 and activation of the Gcgr without the influence of GLP-1, we used DT-Gcg mice with acute knockdown of all proglucagon products. This mouse model has previously been shown previously to have a normal total islet area as well as β cell area compared with control mice (Pedersen et al., 2013). The reduced insulin secretion after glucagon knockdown suggests that glucagon may play a regulatory role in insulin secretion. Glucagon-dependent insulin secretion was only apparent at high glucose levels, indicating that intra-islet glucagon is particularly required at times with high insulin secretion demand. It could be speculated that glucose-stimulated insulin secretion also more generally depends on glucagon levels; thus, when glucagon is low, less insulin is needed to maintain appropriate blood glucose. A stimulating effect of glucagon on insulin secretion at low glucose levels would be inexpedient, if not dangerous, given glucagon’s role in the defense against hypoglycemia.
Acknowledgments We would like to thank Laurie Baggio for assistance with Gcgrβcell−/− mice. This study was supported by the Novo Nordisk Foundation, the Lundbeck Foundation (2011-9560, 2016-2394), the Carlsberg Foundation (CF16-0996), and the Danish Council for Independent Research (6110-00660). D.J.D. was supported in part by the Canada Research Chairs Program, a BBDC-Novo Nordisk Chair in Incretin Biology, and CIHR grants 136942 and 154321.
Introduction The global number of patients with diabetes was projected to increase to 366 million by 2030, while more than 80% of patients with type 2 diabetes are obese . Glucagon-like peptide-1 (GLP-1) is a potent hypoglycemic hormone, emphasized a great opportunity for the treatment of diabetes (Fig. 1) . GLP-1 has a lot of benefits in a glucose-dependent manner like promoting insulin secretion, reducing blood glucose and delaying gastric emptying via a glucagon-like peptide-1 receptor (GLP-1R) , . However, studies have found that it is difficult to further improve hypoglycemic activity if GLP-1R is activated merely when a certain point reached, meanwhile, nausea, vomiting and other adverse reactions may be caused . Derived from processing of proglucagon like GLP-1, glucagon is a 29-amino acid pancreatic hormone secreted in the islets alpha cells . Via a specific glucagon receptor(GCGR), glucagon could raise the blood glucose to be the emergency treatment of severe hypoglycaemia, but emergent possibilities of hyperglycaemia is exist . Meanwhile, glucagon has versatile effects on hepatic glucose metabolism, renal, glucagon affects the cardiovascular, pulmonary, gastrointestinal systems vascular and gastrointestinal smooth muscle , like increasing lipolysis in adipose tissue, and glucagon acts as a regulation of insulin to raise the blood glucose . Oxyntomodulin (OXM), a 37-amino acid hormones containing the entire 29-amino acid sequence of glucagon followed by other eight amino acid carboxy-terminal extension (Fig. 1), has been known as a GLP-1R/GCGR dual agonist that reduces the body weight, lowers the lipid and so on . OXM could slightly activate GLP-1R which lead to lower blood glucose . But the likelihood of hyperglycaemia is not completely erased . Meanwhile, just like the endogenous GLP-1, the half-life of OXM or glucagon is very short, which accounts for the rapid metabolic degradation and elimination by kidney filtration , . Aim to improve the GLP-1 activation, we modified the structure of glucagon, to deteriorate GCGR activation and combine good GCGR and GLP-1R activation in a single peptide so as to the activation of GCGR will induce catabolic effects which favor these on weight loss products , while GLP-1R activation will modulate glucose homeostasis , along with eliminating the possibility of hyperglycaemia. The raised hypoglycemic property of GLP-1R activation would minimize the potential diabetogenic risk of excessive GCGR activation, proper GCGR activation would help promote the lipolytic and thermogenic properties , , .