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Lack of Glucagon Receptor Signaling and Its Implications Beyond Glucose Homeostasis

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Lack of Glucagon Receptor Signaling and Its Implications Beyond Glucose Homeostasis M J CHARRON and P M VUGUIN Glucagon beyond glucose 224:3 R123–R130 Review Lack of glucagon receptor signaling and its implications beyond glucose homeostasis Correspondence 1,2,3 4 Maureen J Charron and Patricia M Vuguin should be addressed to P M Vuguin or M J Charron Departments of 1Biochemistry, 2Obstetrics and Gynecology and Women’s Health, and 3Medicine, Albert Einstein Emails College of Medicine, 1300 Morris Park Avenue, F312, Bronx, New York 10461, USA [email protected] or 4Department of Pediatrics, Hofstra School of Medicine, Cohen Children’s Medical Center, 1991 Marcus Avenue, Lake maureen.charron@ Success, New York 11402, USA einstein.yu.edu Abstract Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, Key Words intestinal smooth muscle, brain, adipose tissue, heart, pancreatic b-cells, and placenta. " pancreas Genetically modified animal models have provided important clues about the role of " glucagon cells 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; Journal of Endocrinology 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. Journal of Endocrinology (2015) 224, R123–R130 Introduction Glucagon is a 29-amino acid polypeptide secreted by the a contaminant of pancreatic extracts with glucogenic a or glucagon cell of the islet of Langerhans in response to properties or properties that mobilize glucose in 1923. hypoglycemia, arginine, gastric inhibitory polypeptide It took more than 20 years for Sutherland and de Duve to (during ambient reduced glucose levels), gastrin, and establish that glucagon is secreted by pancreatic a-cells. potassium chloride. Glucagon was initially discovered as Between 1959 and 1962, Unger et al. developed a RIA http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0614 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 02:47:24AM via free access Review M J CHARRON and P M VUGUIN Glucagon beyond glucose 224:3 R124 making it possible to investigate the physiology of have been identified from genetically modified animal glucagon and its role in various disorders (Unger et al. models with altered Gcgr expression is provided in Fig. 1. 1959, 1962, Gromada et al. 2007). As a counter-regulatory hormone, glucagon main- Role of glucagon on pregnancy maintenance tains blood glucose levels by activating glycogenolysis and fetal growth and gluconeogenesis. In addition, glucagon reduces triglyceride, very LDL release, and cholesterol levels Disruption of the glucagon receptor gene (Gcgr) during and stimulates fatty acid oxidation (Eaton 1973, Longuet pregnancy is associated with maternal hypoglycemia, et al. 2008). Beyond glucose homeostasis, glucagon elicits hyperglucagonemia, abnormalities of placentation, poor significant extra-hepatic effects in tissues such as kidney, fetal growth, and increased fetal and early postnatal K K heart, adipose tissue (white and brown), gastrointestinal death. Gcgr / placentas are characterized by extensive tract, thyroid, and CNS (Lefebvre 1995, Burcelin et al. mineralization, fibrinoid necrosis, narrowing of the vas- 1996, Porte et al. 1998, Kieffer&Habener1999, cular channels, and a thickened interstitium associated Kinoshita et al. 2014). with trophoblast hyperplasia. In addition, lack of gluca- Glucagon action is transduced by a G protein-coupled gon placental signaling down-regulates genes that receptor (GCGR/Gcgr) that is a member of the class II control growth, adrenergic signaling, vascularization, GCGR superfamily of seven transmembrane spanning oxidative stress, and G protein-coupled receptors (Ouhilal receptors that are coupled via GTP-binding proteins to et al. 2012). adenylyl cyclase resulting in an increase in cAMP production. cAMP activates signaling pathways that Role of glucagon in pancreatic development cause an increase in gluconeogenesis, glycogenolysis, and pancreatic islet morphology and fatty acid oxidation. In addition, glucagon controls glucose, energy, and lipid metabolism at least in part via During fetal development, glucagon is required for early AC/cAMP-independent signals including p38MAPK, insulin or b-cell differentiation and to mature a subset of IP3/DAG/Ca, peroxisome proliferator-activated receptor glucagon cells (Vuguin et al. 2006). In rodent models, alpha (PPARa), and fibroblast growth factor 21 (FGF21)- disruption of the Gcgr gene is associated with an increase dependent pathways (Berglund et al. 2010, Habegger et al. in the number of pancreatic islets and an increase in the 2010, 2013, Rodgers 2012, Cyphert et al. 2014). number of somatostatin cells without altering insulin cell Journal of Endocrinology Binding sites for glucagon have been identified in mass. Lack of glucagon signaling is also associated with liver, kidney, intestinal smooth muscle, brain, adipose a profound glucagon cell hyperplasia. A subset of those tissue, heart, pancreatic islet b-cells, and placenta (Ouhilal glucagon cells coexpress markers of immature islet et al. 2012). Gcgr gene expression is positively regulated by endocrine cells such as insulin, PDX1, and glucose K K glucose and negatively regulated by glucagon and agents transporter 2 (Vuguin et al. 2006). Similar to the Gcgr / that increase intracellular cAMP (Quesada et al. 2008). model, glucagon cell expansion is observed in the majority This review will focus on the role of glucagon and of the models in which there is reduced or absent Gcgr glucagon signaling in fetal growth, pancreatic develop- receptor signaling, such as inactivation or a reduction in ment, and glucose and lipid homeostasis in genetically glucagon and/or its receptor by genetic manipulation, modified animal models that have been demonstrated to immuno-blockade, or treatment with antisense oligonu- provide important clues about the role of glucagon in cleotides (Gelling et al. 2003, Sloop et al. 2004, Conarello health and disease. Animal models provide an invaluable et al. 2007, Winzell et al. 2007, Gu et al. 2009, Hayashi et al. tool to study the underlying mechanisms associated with 2009, Lee et al. 2011, Longuet et al. 2013). In those studies, glucagon action; however, they have the disadvantage a or glucagon cell expansion is accompanied by elevated that genetic manipulation could lead to lifelong adap- plasma glucagon levels. One exception has been the study tations that can skew results. Thus, some of the findings by Liang et al. (2004), which demonstrated that may not necessarily translate into human disease. a reduction in Gcgr expression using an antisense The PubMed database was searched for articles oligonucleotide is not accompanied by changes in a or published between 1995 and 2014 using the key terms glucagon cell number; however, glucagon levels were glucagon, glucagon receptor, and animal models. Articles nonetheless significantly increased. obtained from this search are discussed in this review. Interestingly, specific inactivation of the Gcgr gene in A brief summary of all the known metabolic changes that the hepatocyte recapitulates the phenotype observed in http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0614 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 02:47:24AM via free access Review M J CHARRON and P M VUGUIN Glucagon beyond glucose 224:3 R125 Food intake Fat mass Meal side Lypolisis Placenta Retinal function Altered placentation Fetal growth Fetal demise Hepatic glucose Insulin production Glucagon Glucagon to insulin cell Hepatocyte survival Glucagon transdifferentiation GLP1 Corticosterone Gastric emptying Heart rate Intestinal length Journal of Endocrinology Figure 1 Studies using the Gcgr knockout mouse model (GcgrK/K) have revealed important insights into the role of glucagon signaling in pancreatic and extra- pancreatic tissues. K K K K Gcgr / mice. Specifically, both Gcgr / mice and the peripheral and central actions (Heppner et al. 2010). K K liver-specific Gcgr / mice have similar reductions in Consistent with a role in modulating food intake, fasting glucose and improved
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