Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

Abstract

Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic b-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (a) cells under certain conditions can transdifferentiate into insulin (b) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

“…The liver is the prime target of glucagon signaling, but WAT is a sensitive and active metabolic endocrine organ that can affect insulin sensitivity and systemic metabolism (55). GRA treatment may cause a change in the liver and other organs that leads to secondary changes in WAT (56), in particular the up-regulation of angptl4 expression, or it can act directly on WAT because gcgr is lowly expressed in WAT. The putative liver-secreted α-cell proliferative factor may induce angptl4 in WAT and/or affect α-cells by separate mechanisms (21,36,50).…”

Glucagon and heart in type 2 diabetes: new perspectives

“…They may be found also, at a lesser degree, in the endocrine pancreas (β- and α-cells), heart, adipocytes, gastrointestinal (GI) tract, brain, adrenal glands, lymphoblasts, retina and placenta [1, 2, 8]. Intense physical exercise, hypercorticism and stimulation of the ventro-medial hypothalamus determine an increase of glucagon secretion [6].…”

“…Today, besides its actions on glucose metabolism, glucagon is known to have other relevant effects [2, 3, 8]:On lipid metabolism: decreased plasma cholesterol, total esterified fatty acids, decreased hepatic synthesis of triglycerides and apolipoproteins. In addition, glucagon determines lipolysis in white adipose tissue.…”

Endocrine And Metabolic Adaptations Of Calves To Extra-Uterine Life

“…There is a lot of evidence that proves that glucagon by itself is ineffective in triggering neonatal liver glycogenolisys [44,45]. The partial resistance to glucagon stimulation by neonatal (and also fetal) hepatocytes could be due to (a) the lower number of high affi nity receptors, or (b) an impaired coupling of the receptor with adenilate cyclase [46]. The essential role of glucagon postnatal rise is stimulation of gluconeogenesis.…”