Glucagon receptor (GCGR), a 62 kDa protein, is a member of the class B G-protein coupled family of receptors. GCGR mainly exists in the liver and in the kidney. In animal models, increased GCGR signaling can improve lipid metabolism. GCGR agonists combined with glucagon-like peptide 1 receptor agonists can improve dyslipidemia and reduce hepatic steatosis. Conversely, antagonists of the GCGR can reduce hepatic glucose overproduction and show effective glucose-lowering effects in type 2 diabetes. In summary, emerging data support the essential role of GCGR in metabolism.

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a class B G-protein-coupled receptor (GPCR). GIPR activation stimulates insulin release in pancreatic beta cells, and together with its sister incretin, glucagon-like peptide-1 (GLP-1). Studies show that genetic or pharmacological blockade of GIPR protects against obesity.

GLP-1 receptor (GLP-1R) is a receptor protein that exists in beta cells of the pancreas and on neurons of the brain. It can control blood sugar levels by enhancing insulin secretion. Besides, GLP-1R can reduce neuroinflammation, promote nerve growth, improve heart function, suppress appetite, delay gastric emptying, regulate blood lipid metabolism and reduce fat deposition. GLP-1R agonists play a similar role as GLP-1. A variety of GLP-1R agonists and analogs, such as exendin-4 and Liraglutide, are effective in type 2 diabetes.

LY3437943 is a triple agonist peptide of GCGR, GIPR, and GLP-1R.

LY3437943, a 39 amino acid single peptide. In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. Meanwhile, LY3437943 increases energy expenditure through glucagon receptor activation. In obese mice, the agonist decreases body weight and improves glycemic control. What’s more, LY3437943 shows a safety and tolerability profile similar to other incretins.

All in all, LY3437943 can inhibit GCGR, GIPR, and GLP-1R and has the potential for research on obesity.


[1]. Galsgaard KD, et, al. Front Physiol. 2019 Apr 24;10:413.

[2]. Holst JJ. Physiol Rev. 2007 Oct;87(4):1409-39.