Abstract
Glucagon is secreted from the pancreatic alpha cells upon hypoglycemia and stimulates hepatic glucose production. Type 2 diabetes is associated with dysregulated glucagon secretion, and increased glucagon concentrations contribute to the diabetic hyperglycemia. Antagonists of the glucagon receptor have been considered as glucose-lowering therapy in type 2 diabetes patients, but their clinical applicability has been questioned because of reports of therapy-induced increments in liver fat content and increased plasma concentrations of low-density lipoprotein. Conversely, in animal models, increased glucagon receptor signaling has been linked to improved lipid metabolism. Glucagon acts primarily on the liver and by regulating hepatic lipid metabolism glucagon may reduce hepatic lipid accumulation and decrease hepatic lipid secretion. Regarding whole-body lipid metabolism, it is controversial to what extent glucagon influences lipolysis in adipose tissue, particularly in humans. Glucagon receptor agonists combined with glucagon-like peptide 1 receptor agonists (dual agonists) improve dyslipidemia and reduce hepatic steatosis. Collectively, emerging data support an essential role of glucagon for lipid metabolism.
Highlights
Glucagon is processed from its precursor, proglucagon, by prohormone convertase 2 and secreted from pancreatic alpha cells (Rouille et al, 1994)
Others (Gelling et al, 2003) showed a decrease in white adipose tissue mass and an increase in lean body mass in Gcgr−/− compared to wildtype mice, without changes in bodyweight, food consumption, or energy expenditure and one group (Conarello et al, 2007) found that Gcgr−/− mice had lower amounts of white adipose tissue when fed both a high fat diet (HFD) and a low fat diet compared to wild-type mice, and seemed to be resistant to dietinduced obesity
In diet-induced obese (DIO) mice, a once-weekly treatment with 70 nmol/kg glucagon/GLP-1 receptor co-agonist resulted in loss of fat mass, which in the same study was found, less pronounced in GLP-1 receptor knockout mice, and improved hepatic lipid metabolism and steatosis within 4 weeks (Day et al, 2009)
Summary
Type 2 diabetes is associated with dysregulated glucagon secretion, and increased glucagon concentrations contribute to the diabetic hyperglycemia. Antagonists of the glucagon receptor have been considered as glucoselowering therapy in type 2 diabetes patients, but their clinical applicability has been questioned because of reports of therapy-induced increments in liver fat content and increased plasma concentrations of low-density lipoprotein. In animal models, increased glucagon receptor signaling has been linked to improved lipid metabolism. Glucagon acts primarily on the liver and by regulating hepatic lipid metabolism glucagon may reduce hepatic lipid accumulation and decrease hepatic lipid secretion. Glucagon receptor agonists combined with glucagon-like peptide 1 receptor agonists (dual agonists) improve dyslipidemia and reduce hepatic steatosis. Emerging data support an essential role of glucagon for lipid metabolism
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