Targeting the glucagon receptor family for diabetes and obesity therapy

Hepatic β-arrestin 2 is essential for maintaining euglycemia

“…Interestingly, hepatic β-arrestin 1, in contrast with β-arrestin 2, does not play a role in regulating hepatic GCGR activity and euglycemia, indicating that the 2 β-arrestins do not have redundant functions in hepatocytes. Our findings suggest that strategies aimed at enhancing the expression or activity of hepatic β-arrestin 2 or the development of small molecule β-arrestin 2 mimetics may become clinically useful for reducing exaggerated hepatic GCGR signaling for the treatment of T2D (3,6).…”

“…HGP is modulated by the activity of several GPCRs, including hepatic glucagon receptors (GCGRs), which play a key role in maintaining euglycemia (3)(4)(5). The GCGR, which is abundantly expressed in hepatocytes, is coupled to the stimulatory G protein G s , which triggers pronounced increases in HGP through a pathway that involves cAMP-mediated activation of PKA (5,6). Importantly, glucagon levels are inappropriately elevated in patients suffering from T2D, suggesting that enhanced GCGR activity may play a central role in the pathophysiology of T2D (3)(4)(5)(6)(7).…”

Hepatic Gi signaling regulates whole-body glucose homeostasis

“…The important metabolic roles of hepatic glucagon receptors in maintaining normoglycemia under fasting conditions and in raising blood glucose levels in response to hypoglycemia are well recognized (6)(7)(8). The glucagon receptor (GCGR), which is abundantly expressed in hepatocytes, is linked to the stimulatory G protein G s , which in turn activates adenylyl cyclase to promote the generation of cAMP (6,9). This signaling pathway ultimately stimulates both glycogenolysis and gluconeogenesis (6), leading to a pronounced increase in HGP.…”

The effect of liraglutide on endothelial function in patients with type 2 diabetes

“…13 To exploit the beneficial properties of native GLP-1, which has limited therapeutic potential due to its short half-life in circulation, GLP-1 receptor agonists (RAs) with longer half-lives have been developed. 14,15 Several of these, including exenatide and liraglutide, are currently available for treating type 2 diabetes. 16,17,18 Exenatide and liraglutide have both been shown to improve markers of endothelial function in vitro and in animal models.…”