Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: the Liver–A-Cell Axis

Diabetes Volume 66, February 2017 235 Jens J. Holst,1,2 Nicolai J. Wewer Albrechtsen,1,2 Jens Pedersen,1,2 and Filip K. Knop2,3 Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver–a-Cell Axis Diabetes 2017;66:235–240 | DOI: 10.2337/db16-0994 Glucagon is usually viewed as an important counter- glucagon’s actions on the cAMP system and its interac- regulatory hormone in glucose metabolism, with actions tions with the glucagon receptor provided substrates for opposing those of insulin. Evidence exists that shows the Nobel prizes of Earl Sutherland, Christian de Duve, glucagon is important for minute-to-minute regulation and Martin Rodbell (2). With the development of the ra- of postprandial hepatic glucose production, although dioimmunoassay for glucagon (3), delineation of its phys- PERSPECTIVES IN DIABETES conditions of glucagon excess or deficiency do not iological role became possible, and Akira Ohneda working cause changes compatible with this view. In patients with Roger Unger, the nestor of modern glucagon re- with glucagon-producing tumors (glucagonomas), the search, demonstrated the reciprocal regulation of gluca- most conspicuous signs are skin lesions (necrolytic gon secretion by glucose (4). In elegant studies in both migratory erythema), while in subjects with inactivating experimental animals and humans, typically involving mutations of the glucagon receptor, pancreatic swelling blockade of glucagon (and insulin) secretion by the hor- may be the first sign; neither condition is necessarily mone somatostatin (5,6), it was demonstrated that he- associated with disturbed glucose metabolism. In glucagonoma patients, amino acid turnover and ureagen- patic glucose production, and thereby the regulation of esis are greatly accelerated, and low plasma amino acid blood glucose in the fasting state, is maintained in a bal- levels are probably at least partly responsible for the ance between the inhibitory actions of insulin and the necrolytic migratory erythema, which resolves after stimulatory actions of glucagon, with each hormone being amino acid administration. In patients with receptor approximately equally important for the regulation (7). mutations (and in knockout mice), pancreatic swelling In further studies, inappropriate secretion of glucagon is due to a-cell hyperplasia with gross hypersecretion of was observed in various forms of diabetes (8), and pio- glucagon, which according to recent groundbreaking neering studies by Gerich et al. (9) pointed to an essential research may result from elevated amino acid levels. role for glucagon in the development of the hyperglyce- Additionally, solid evidence indicates that ureagenesis, mia and ketoacidosis of type 1 diabetes, leading Unger and and thereby amino acid levels, is critically controlled by Orci (10) to suggest that inappropriate glucagon secretion glucagon. Together, this constitutes a complete endo- underlies all forms of diabetic hyperglycemia. This hy- crine system; feedback regulation involving amino acids pothesis spurred attempts to develop glucagon receptor regulates a-cell function and secretion, while glucagon, antagonists, which on one hand would allow conclusive in turn, regulates amino acid turnover. studies about the essentiality of glucagon for diabetic hyperglycemia and, on the other hand, might be useful ther- apeutic agents for diabetes therapy (11). Eventually, the Glucagon was discovered in 1923 as a hyperglycemic pharmaceutical industry managed to develop small mole- substance (1), and subsequent research documented its cule, orally available glucagon receptor antagonists (12,13), actions on glycogenolysis and gluconeogenesis. Indeed, which have demonstrated excellent glucose-lowering efficacy 1Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Received 15 August 2016 and accepted 31 October 2016. University of Copenhagen, Copenhagen, Denmark © 2017 by the American Diabetes Association. Readers may use this article as 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health long as the work is properly cited, the use is educational and not for profit, and the and Medical Sciences, University of Copenhagen, Copenhagen, Denmark work is not altered. More information is available at http://www.diabetesjournals 3 Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, .org/content/license. Hellerup, Denmark Corresponding author: Jens J. Holst, [email protected]. 236 A New Perspective on Glucagon Biology Diabetes Volume 66, February 2017 in clinical studies in patients with type 2 diabetes, in fact knockout mice (31). These animals have similar plasma providing convincing proof for the importance of (inap- glucose levels as those treated with antibodies and also propriate?) secretion of glucagon for the hyperglycemia of do not develop hypoglycemia, although they show pro- type 2 diabetes (13). nounced changes in levels of the enzymes thought be In the delineation of the physiological role of a hor- to be regulated by glucagon: pyruvate carboxylase, glyco- mone, it may be useful to study conditions of hormone gen phosphorylases, phosphoenolpyruvate carboxykinase, excess and hormone deficiency. Among endocrinologists fructose 1,6-bisphosphatase, and glucose 6-phosphatase. with an interest in glucagon, such conditions were eagerly Obviously, life-long global deletion of the glucagon recep- searched for, employing radioimmunoassays to reveal tor may be associated with important adaptive changes, hyper- and hyposecretion. The latter turned out to be dif- but the similarity with the immunoneutralization results ficult because the glucagon concentrations in plasma are and with results from further studies employing acute low and measurements, therefore, challenging in terms of small interfering RNA–induced downregulation of the assay sensitivity (14). In addition, there were specificity glucagon receptor (32) was reassuring. Two important problems, caused by (as it turned out) gut-derived, alter- lessons emerged from these studies: 1) glucagon is not native products of proglucagon, the glucagon precursor essential for the maintenance of fasting glucose levels (15,16), so conditions with glucagon deficiency were (for this, cortisol/corticosterone is more important be- not easily identified. Regarding hyperglucagonemia, pa- cause it provides gluconeogenic substrates for gluco- tients with a glucagon-secreting tumor were eventually neogenesis [33]) and, as a consequence, 2)glucagon described (17), and with more cases being collected, it antagonism does not cause hypoglycemia. The latter was became possible to define a “glucagonoma syndrome” of course of particular interest to those trying to develop (18,19). Some glucagonoma patients did indeed show hy- glucagon receptor antagonists for diabetes therapy, and perglycemia, but not all, and overt diabetes is not the subsequent studies of the antagonists confirmed that rule. It was assumed that this might reflect what is seen they do not cause hypoglycemia (unless combined with after prolonged infusion of glucagon, where the initial inappropriate amounts of insulin) (11,13). Note that elevation of plasma glucose rapidly wanes (20,21). This these conclusions are not incompatible with a role for evanescent glucose response to glucagon was much de- glucagon in the regulation of normal and diabetic post- bated and may be due to the simultaneous stimulation prandial and fasting glucose levels, as indicated from of insulin secretion, whereby hepatic glucose production studies with glucagon antagonism and deletions of the is reduced (21). The possible consequences of glucagon glucagon receptor (34). deficiency remained enigmatic, but because of the interest Thus, neither glucagon deficiency nor glucagon excess in the development of glucagon receptor antagonists had quite the expected consequences for plasma glucose for possible clinical use, it was important to identify the regulation. In contrast, there were other, unexpected con- consequences of glucagon lack. Intensive research from sequences of the hyperglucagonemia of the glucagon- several groups had identified glucagon secretion as the producing tumors. The main features of the glucagonoma first-in-line defense against hypoglycemia in humans syndrome include a characteristic skin rash termed (22), and subcutaneous glucagon injections were used to necrolytic migratory erythema, which is observed in most treat insulin-induced hypoglycemia in patients with type cases (82% of patients), often with painful glossitis and 1 diabetes. Therefore, the expected outcome of glucagon angular stomatitis (35). Other characteristics are nor- antagonism was severe hypoglycemia. Surgical glucagon mochromic normocytic anemia (61%), weight loss deficiency brought about by experimental pancreatectomy (90%), deep vein thrombosis (50%), and depression turned out not to solve the problem because of apparent (50%). Mild hyperglycemia is seen in many (80%), but production of glucagon from sites outside of the pancreas overt diabetes is only observed in about 30% and is re- (as had been suspected since 1948 [23] and subsequently lated to pancreatic damage. The skin disease is charac- confirmed in humans [24,25]). The development of a terized by superficial epidermal necrosis, fragile blister high-affinity monoclonal neutralizing antibody against formation, crusting, and healing with hyperpigmentation glucagon enabled Brand et al. (26) to bring about a state (36). The histological appearance is quite unique and

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