Abstract
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.
Highlights
In the 1920s, Kimball and Murlin reported the existence of a pancreatic factor other than insulin with effects on glucose homeostasis (GLUCose-AGONist [1]) [2]
The complexity of glucagonsuggested diabetogenic effect is greater than anticipated, as antagonizing its actions affects fasting but not postprandial blood glucose levels [11]. This is in contrast to what one may have suspected, as the ‘hyperglucagonemia’ observed in some type 2 diabetes patients has been reported to be pronounced in the postprandial state [12,13,14]
We provide an overview of the three major biological areas of glucagon receptor signaling: glucose homeostasis, amino acid metabolism, and lipid metabolism
Summary
In the 1920s, Kimball and Murlin reported the existence of a pancreatic factor other than insulin with effects on glucose homeostasis (GLUCose-AGONist [1]) [2]. The complexity of glucagonsuggested diabetogenic effect is greater than anticipated, as antagonizing its actions affects fasting but not postprandial blood glucose levels [11]. This is in contrast to what one may have suspected, as the ‘hyperglucagonemia’ observed in some type 2 diabetes patients has been reported to be pronounced in the postprandial state (the lack of glucose-induced suppression of alpha cell secretion, which we will come back to later) [12,13,14]. Investigating the physiological actions of glucagon on glucose homeostasis but, importantly, on lipid and amino acid metabolism is needed for understanding glucagon biology at fasting and prandial conditions. We begin this review by introducing the production, secretion, and measurement of glucagon before turning towards glucagon receptor signaling in regards to glucose, amino acid, and lipid metabolism
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