glucagon receptor function

J. Physiol. 1998;275(Pt 2):R1674–R1682. These studies described a lipid-mobilizing effect for glucagon in a range of species 41). A lack of effect of glucagon on the free plasma pool of FFA and glycerol, does therefore not rule out that glucagon has a direct effect on lipid metabolism in adipocytes and hepatocytes (Figure 1). (1990). By increasing AC activity glucagon increase the AMP/ATP ratio sufficient to activate AMP-activated kinase (AMPK), which phosphorylates ACC, leading to transcriptional activation of peroxisome proliferator-activated receptor-α (PPARα). J. Med. The effect of a high-MUFA, low-glycaemic index diet and a low-fat diet on appetite and glucose metabolism during a 6-month weight maintenance period. Cell Metab. Science 259, 1614–1616. Studies of glucagon resistance in large rat adipocytes: 125I-labeled glucagon binding and lipolytic capacity. doi: 10.1042/bj2690409, Raben, A., Holst, J. J., Madsen, J., and Astrup, A. A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. Design of novel exendin-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists. Mechanistically, glucagon is known to stimulate the activity of hormone-sensitive lipase in adipocytes, resulting in an increase of nonesterified fatty acids in the circulation 67). Brito NA, Brito MN, Bartness TJ. CPT-1 catalyzes the attachment of carnitine to fatty acyl-CoA, forming acyl-carnitine. doi: 10.1371/journal.pone.0186586. It is important to note that FFA and glycerol in plasma are not only determined by release from adipocytes, but also by rate of uptake and re-esterification in other tissues. Invest. Effects of exogenous glucagon on lipids in lipoproteins and liver of lactating dairy cows. You should know what to do if symptoms of low blood sugar occur. Taken together, the contribution of glucagon receptor agonism to liver steatosis has yet to be conclusively described. Pharmacological concentrations of glucagon also stimulate secretion of catecholamines and growth hormone, both of which have powerful lipolytic effects (Mitchell et al., 1969; Stallknecht et al., 1995), possibly as part of a generalized sympathetic nervous system discharge (Paschoalini and Migliorini, 1990). Diabetes 23, 725–731. 2000;141:174–180, Postprandial Suppression of Glucagon Secretion: A Puzzlement. Furthermore, infusion with saline only gave the same increase in FFA as compared to glucagon infusion. Caren R, Corbo L. Glucagon and plasma arachidonic acid. As an example, one study reported localization of the glucagon receptor in rat adipocytes using a monoclonal antibody (Iwanij and Vincent, 1990) whereas another using autoradiography, glucagon receptors were not found to be expressed (Watanabe et al., 1998), and no studies have demonstrated presence of glucagon receptors on human adipocytes (Carranza et al., 1993). doi: 10.1016/j.cmet.2006.01.001, Wu, M. S., Jeng, C. Y., Hollenbeck, C. B., Chen, Y. D., Jaspan, J., and Reaven, G. M. (1990). One form of stored energy is fat and glycogen is another. 13(Suppl. (1993). Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes. (2011). Interestingly, these studies used genetically modified null mice generated in an identical manner and of the same background (C57B6). Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver - alpha-cell axis. In addition to glucose, several other physiological parameters are known regulators of glucagon secretion, including GLP-1 35), GLP-2 36), fatty acids 37), the autonomic nervous system 38) and circulating amino acids 39). 138, 1158–1169. To date, glucagon-binding sites have been identified in multiple tissues, including liver, brain, pancreas, kidney, intestine, and adipose tissues 20) . doi: 10.2337/db13-1609, Collins, S. C., Salehi, A., Eliasson, L., Olofsson, C. S., and Rorsman, P. (2008). doi: 10.1021/acs.jmedchem.7b00174, Faerch, K., Vistisen, D., Pacini, G., Torekov, S. S., Johansen, N. B., Witte, D. R., et al. (2016). doi: 10.1530/acta.0.1120100, Gu, W., Lloyd, D. J., Chinookswong, N., Komorowski, R., Sivits, G. Jr., Graham, M., et al. Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. 1973;14:312–318, Guettet C, Mathé D, Riottot M, Lutton C. Effects of chronic glucagon administration on cholesterol and bile acid metabolism. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Furthermore, Gcgr−/− mice showed increased hepatic TG secretion and increased plasma concentrations of TG and FFA after a 16 h fasting period, but not after 5 h of fasting (Longuet et al., 2008). J. Biol. 581(Pt 2), 431–444. Some clinical studies found a suppression of glucagon secretion at increased FFA concentrations (Madison et al., 1968; Edwards and Taylor, 1970; Luyckx and Lefebvre, 1970; Gerich et al., 1974) whereas isolated alpha cells were shown to secrete glucagon in response to FFA stimulation (Gross and Mialhe, 1986; Collins et al., 2008). (2009). Glucagon-early breakthroughs and recent discoveries. Intravenous infusions similarly produced a dose-related decrease in eating 106). Diabetes 24, 502–509. PKA phosphorylates (hence activates) hormone sensitive lipase (HSL) and P. The phosphorylation of P results in dissociation of the protein CGI-58. Peptides 16, 1163–1166. Charbonneau A, Couturier K, Gauthier MS, Lavoie JM. 260, 15130–15138. G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. References. 1991;13:1126–1130. The mechanism by which glucagon-induced thermogenesis is regulated is probably complex and may involve the sympathetic nervous system. 62) also demonstrated the importance of glucagon signaling in the adaptive response to fasting. 4, 193–199. Biomarkers Med 2016;10:1141–1151, Gosmanov NR, Gosmanov AR, Gerich JE. (2009). Hepatology. These symptoms may develop in a very short time and may result from: Unless corrected, hypoglycemia will lead to unconsciousness, convulsions (seizures), and possibly death. Glycogen may be released by the liver for a number of reasons, including: In these situations, when the body feels extra glucose is needed in the blood, the pancreas will release the hormone glucagon which triggers the conversion of glycogen into glucose for release into the bloodstream. Guettet et al. (2004). For an overview of glucagon action, see the section on the Glucagon receptor. 97, 721–766. This effect was mirrored by a report in human study participants, in whom infusion of a pharmacological dose of glucagon increased resting energy expenditure during acute insulin deficiency produced by the additional infusion of somatostatin 84). 573(Pt 3), 611–625. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. J. Biol. Diabetes May 2017, 66 (5) 1123-1125; DOI: 10.2337/dbi16-0075 http://diabetes.diabetesjournals.org/content/66/5/1123, De Oya M, Prigge WF, Swenson DE, Grande F. Role of glucagon on fatty liver production in birds. N Engl J Med 288:700-703, 1973, Gerich J, Davis J, Lorenzi M, Rizza R, Bohannon N, Karam J, Lewis S, Kaplan R, Schultz T, Cryer P: Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. Regulation of fatty-acid metabolism by pancreatic hormones in cultured human hepatocytes. 14, 312–318. Furthermore, although glucagon injection in ducklings was associated with an increase in norepinephrine, blockade of catecholamines via guanethidine sympathectomy (the interruption of the transmission of sympathetic nerve impulses by a chemical agent that blocks the secretion of epinephrine and norepinephrine at postganglionic nerve endings) decreased metabolic rate compared to nonsympathectomized birds treated with glucagon or saline 94). Glucagon may cause some patients to vomit and this position will reduce the possibility of choking. Lancet 1:73-75, 1974, Rocha DM, Santeusanio F, Faloona GR, Unger RH: Abnormal pancreatic alpha-cell function in bacterial infections. 112, 100–104. Furthermore, through PKA-dependent phosphorylation, glucagon receptor signaling inactivates acetyl-CoA carboxylase, the enzyme catalyzing the formation of malonyl-CoA. 284, E671–E678. J. Physiol. A caveat of this study is that it involved supraphysiological concentrations of glucagon administered over a 4-day period. doi: 10.1210/er.2006-0007. doi: 10.1080/19420862.2016.1189050. Chem. 311, E302–E309. Once the glucagon has been given, contact your doctor. Patients with diabetes should be aware of the symptoms of hypoglycemia (low blood sugar). J. Physiol. B., Kirk, O., and Schwartz, T. W. (1994). A. Energy can be stored by the body in different forms. S8). (1988). Once you complete your exercise session, your muscles will replenish their glycogen stores. Am. Chem. The biology of glucagon and the consequences of hyperglucagonemia. Effects of glucagon and noradrenaline on the blood flow through brown adipose tissue in temperature-acclimated rats. 12:281. doi: 10.1186/1471-2164-12-281, Zhang, F., Xu, X., Zhou, B., He, Z., and Zhai, Q. Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. 266, 11341–11346. 2004;53:1443–1448, Ahrén B. Autonomic regulation of islet hormone secretion—implications for health and disease. In vivo, a decrease in plasma glucose of 1 to 2 mmol/L increases plasma glucagon 28). Metab. Glucagon is processed from its precursor, proglucagon, by prohormone convertase 2 and secreted from pancreatic alpha cells (Rouille et al., 1994). Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice Graphical Abstract Highlights d REMD 2.59 restores euglycemia, glucose tolerance, and insulin action d REMD 2.59 suppresses hepatic gluconeogenesis by improving insulin signaling to Akt d REMD 2.59 enhances AMPK-induced lipid oxidation in liver, … Am. 535(Pt 2), 519–532. Sci. If it becomes necessary to inject glucagon, a family member or friend should know the following: Keep your doctor informed of any hypoglycemic episodes or use of glucagon even if the symptoms are successfully controlled and there seem to be no continuing problems. Lipolytic effect of TSH, glucagon and hydrocortisone on the adipose tissue of newborns and adults in vitro. Consistent with this, glucagon inhibited synthesis and secretion of TGs in cultured hepatocytes (Longuet et al., 2008), in perfused rat livers (Penhos et al., 1966; Heimberg et al., 1969), and decreased the synthesis of hepatic VLDL in rats (Eaton, 1973). doi: 10.1016/j.tips.2012.03.014, Hansen, L. H., Abrahamsen, N., and Nishimura, E. (1995). Biophys. Glucagon can be expected to take about 10-15 minutes to raise blood glucose back to safer levels. Physiol. The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. 302, E1560–E1568. Glucagon ensures energy supply by mobilizing lipids. One of the first human studies reporting a lipolytic effect of glucagon, demonstrated that an injection of 7.5 μg glucagon into the branchial artery resulted in a rapid increase in FFA plasma concentrations in the corresponding vein (Pozza et al., 1971) but this was not replicated in a similar study with mean increases of glucagon plasma concentrations by 237 pM in overnight fasted subjects (Pozefsky et al., 1976). }); Glucagon-mediated lipolysis and ketogenesis, Glucagon and regulation of glucose metabolism. Integr. Given that no direct measure of bile acid synthesis or secretion was available, the direct result on bile acid metabolism remains unknown. Metabolism 17, 301–304. Science 259: 1614–1616, 1993. J. Med. Glucagon might also have a direct effect on thermogenesis, as glucagon incubation of brown adipocytes of rat and mice, but not those of Syrian hamsters, markedly increased oxygen consumption 95). J. Lipid Res. 1989;10:333–335. Lancet 2, 415–416. Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. In addition, you should carry an ID card that lists your medical condition and medicines. GPR119 as a fat sensor. tell your doctor and pharmacist if you are allergic to glucagon, any other drugs, or beef or pork products. Another study observed that a meal rich in mono-unsaturated fatty acids resulted in a larger glucagon response when compared to a control meal (Sloth et al., 2009). Acad. In response to an appropriate stimuli, e.g., epinephrine and possibly glucagon, AC found in the plasma membrane of the adipocyte is activated, leading to increased intracellular concentrations of cAMP stimulating protein kinase A (PKA) activity. Glycogen is mainly stored in the liver and the muscles and provides the body with a readily available source of energy if blood glucose levels decrease. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models–association with liver and adipose tissue effects. Braz. Clin. (2007). GCGR glucagon receptor [ (human)] A combined activation mechanism for the glucagon receptor. Valuable insights into GLP‐1 structure and function, as well as potential anti‐obesity compounds, have come from studying the features that govern the selectivity between GLP‐1 and glucagon at their related receptors. Metab. General Function Glucagon receptor activity Specific Function This is a receptor for glucagon-like peptide 2. (1997). Studies in rats confirmed that glucagon administration increased whole-body oxygen consumption, core body temperature, blood flow 87), as well as temperature and mass of brown adipose tissue 88). doi: 10.2337/db09-0278, Pozefsky, T., Tancredi, R. G., Moxley, R. T., Dupre, J., and Tobin, J. D. (1976). cAMP-dependent protein kinase and lipolysis in rat adipocytes. Early studies by Davidson et al. Diabetologia 20, 616–621. 60, 4293–4303. Hepatic mitochondrial function in ketogenic states. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. doi: 10.3181/00379727-133-34511, Madison, L. L., Seyffert, W. A. Jr., Unger, R. H., and Barker, B. Specifically, exercise training in rats was used to increase plasma glucagon levels and improve fatty liver. doi: 10.1016/j.metabol.2004.06.011, Briant, L. J. J. Physiol. Chem. Diabetes 25, 128–135. Chem. The main physiological role of glucagon is to stimulate liver glucose output, thereby leading to increases in glycemia. Nutritional effects of fat on carbohydrate metabolism. Glucagon receptor mRNA has been detected in rat adipocytes (Svoboda et al., 1994; Hansen et al., 1995), but to determine the physiological relevance of glucagon receptor mRNA expression, it is necessary to investigate whether the mRNA is actually translated into a functional receptor.

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