Metab. Furthermore, as for several other peripheral signals that control eating, vagal afferents relay the signal to the brain 111). Others also observed an increase in glucagon concentrations upon fat-enriched meals (Radulescu et al., 2010; Niederwanger et al., 2014). Comp. In isolated rat pancreatic islets, palmitate stimulated glucagon secretion (Gremlich et al., 1997; Dumonteil et al., 2000). (2014). (1990). 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. Die Existenz des Pankreashormons Glucagon als hyperglykämischem Faktor wurde 1923 zum ersten Mal von John Raymund Murlin postuliert. It is very important that all patients have a household member who knows the symptoms of low blood sugar and how to administer glucagon. Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Endocrinol. This would suggest that glucagon receptor antagonism, if developed as a glucose-lowering agent, might deteriorate insulin secretion in type 2 diabetes, thus counterbalancing its beneficial effects. This will prevent hypoglycemia from occurring again before the next meal or snack. Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. 2006;43:117–125. Jump to: navigation, search. Acad. Lancet 1:73-75, 1974, Rocha DM, Santeusanio F, Faloona GR, Unger RH: Abnormal pancreatic alpha-cell function in bacterial infections. Participation of the CNS in the control of FFA mobilization during fasting in rabbits. Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion. J. Med. Evaluation of the lipoproteins indicated a decline in levels of apolipoprotein E (ApoE) and an increase in ApoB 52). Although these studies suggest hepatic lipoprotein metabolism as the site of such regulation, the molecular mechanism by which glucagon achieved this result remained elusive. Metab. J. Physiol. A caveat of this study is that it involved supraphysiological concentrations of glucagon administered over a 4-day period. Glucagon is for use when someone is suffering severe hypoglycemia and is unable to treat themselves. The investigators found that glucagon administra tion to rats resulted in a dose-dependent increase in binding of LDL cholesterol to the receptor, with no apparent effect on receptor mRNA expression. (. ) doi: 10.1152/ajpgi.00145.2011, Clemmensen, C., Chabenne, J., Finan, B., Sullivan, L., Fischer, K., Kuchler, D., et al. doi: 10.1210/en.2005-1132, Pegorier, J. P., Garcia-Garcia, M. V., Prip-Buus, C., Duee, P. H., Kohl, C., and Girard, J. doi: 10.1210/jcem-72-2-308, Jiang, G., and Zhang, B. J. Med. doi: 10.1016/j.ejmech.2017.07.046, Keywords: glucagon, lipid, liver, adipose tissue, alpha cell, Citation: Galsgaard KD, Pedersen J, Knop FK, Holst JJ and Wewer Albrechtsen NJ (2019) Glucagon Receptor Signaling and Lipid Metabolism. Am. J. Physiol. Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Diabetes 58, 2258–2266. A lipolytic effect of glucagon, if any, on human adipocytes may therefore only be physiologically relevant when insulin secretion is low. 2006;90:2641–2650. Edwards, J. C., and Taylor, K. W. (1970). The effects of glucagon during restoration of euglycemia involves both glycogenolysis and gluconeogenesis, predominantly the former 18). PPARα stimulates the transcription of genes involved in beta-oxidation including CPT-1, CPT-2, and acetyl-CoA oxidase (Patsouris et al., 2006), and the transcription of fibroblast growth factor 21, which is produced in the liver in response to glucagon (Xu et al., 2009; Cyphert et al., 2014). Biochim. doi: 10.1016/0014-5793(88)80799-3, Gelling, R. W., Du, X. Q., Dichmann, D. S., Romer, J., Huang, H., Cui, L., et al. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. doi: 10.1016/S0140-6736(75)92375-2, Vajda, E. G., Logan, D., Lasseter, K., Armas, D., Plotkin, D. J., Pipkin, J. D., et al. Chem. Burcelin R, Katz EB, and Charron MJ. Of notice, C57BL/6J mice do not consistently develop steatosis upon HFD feeding (Charlton et al., 2011), and this might have influenced the results. Physiological effect of glucagon in human isolated adipocytes. (2009). Glucagon G protein-coupled receptor. Metabolism. 5, 245–250. Trends Pharmacol. Interrupted glucagon signaling reveals hepatic alpha-cell axis and role for l-glutamine in alpha-cell proliferation. Endocrinology 147, 1508–1516. J. Clin. Acad. Henderson, S. J., Konkar, A., Hornigold, D. C., Trevaskis, J. L., Jackson, R., Fritsch Fredin, M., et al. J. Biol. Metab. 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. Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. J. Physiol. Glucagon receptor expression has been reported in rat adipocytes (Svoboda et al., 1994; Hansen et al., 1995), where a lipolytic effect of glucagon may be of physiological relevance. In vivo, a decrease in plasma glucose of 1 to 2 mmol/L increases plasma glucagon 28). Rudling and Angelin 56) extended these findings by the direct study of glucagon’s effects on LDL receptors (LDLRs). Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. doi: 10.2337/db09-0278, Pozefsky, T., Tancredi, R. G., Moxley, R. T., Dupre, J., and Tobin, J. D. (1976). Am. Nat. In the case of glucagon, the hepatic branch of the abdominal vagus is critical 112), consistent with the hepatic site of action. The regulation of plasma lipids by glucagon was first highlighted in studies which suggested that glucagon acts to decrease plasma cholesterol, total esterified fatty acids and arachidonic acid levels 42). (1993). Natl. If a meal is not scheduled soon (1 hour or less), you should also eat a light snack, such as crackers and cheese or half a sandwich or drink a glass of milk to keep your blood sugar from going down again. Instructions for mixing and giving the injection are in the package. }); Glucagon-mediated lipolysis and ketogenesis, Glucagon and regulation of glucose metabolism. There is a chance that he or she could choke from not swallowing correctly. 20, 2608–2616. Endocrinol. This report thus indicated that chronic glucagon pharmacology was neither transient nor detrimental to glucose homeostasis 50). Metab. In contrast, a 2-h glucagon infusion at 1.3 ng/kg × min, during a mean insulin plasma concentration of 65 pM, increased the rate of appearance of labeled FFA and glycerol by 40 and 36%, respectively (Carlson et al., 1993). Res. Improved glucose status with decreased nonesterified fatty acids and β-hydoxybutyrate was also reported 59). Int. doi: 10.1194/jlr.M900176-JLR200. U.S.A. 89, 8537–8541. Taken together, the work of Guettet et al. Glucagon was not found to have any lipolytic effects in clinical studies using glucagon concentrations ranging from 19 to 64 pM (Wu et al., 1990; Jensen et al., 1991; Gravholt et al., 2001; Xiao et al., 2011). Pegorier et al. When challenged with a high fat diet (HFD) for 8 weeks, Gcgr−/− mice did not increase the amount of inguinal and epididymal fat, whereas the amount of both doubled in wild-type mice (Longuet et al., 2008). (2001). Endocrinol. Given that no direct measure of bile acid synthesis or secretion was available, the direct result on bile acid metabolism remains unknown. (2018). Zonation of fatty acid metabolism in rat liver. 1984;247(Pt 2):R827–R832. Peptides 16, 1163–1166. Converse to the inhibition of insulin secretion by hypoglycemia, low levels of blood glucose directly stimulate the pancreatic alpha (α) cells to secrete glucagon 25). Endocrinol. Song and Chiang86 further showed that glucagon’s regulation of CYP7A1 expression is mediated via PKA signaling to HNF-4α. Activation of two signal-transduction systems in hepatocytes by glucagon. CYP7A1 is the rate-limiting enzyme in bile acid synthesis, and its expression is tightly regulated as a means to control flux through the pathway 80). Effects of glucagon and noradrenaline on the blood flow through brown adipose tissue in temperature-acclimated rats. Longuet, C., Sinclair, E. M., Maida, A., Baggio, L. L., Maziarz, M., Charron, M. J., et al. Glucagon activates Ca2+ and Cl- channels in rat hepatocytes. Methods Enzymol. Glucagon is a pancreatic peptide hormone that, as a counterregulatory hormone for insulin, stimulates glucose release by the liver and maintains glucose homeostasis. Restoration of normal blood glucose is due to a compensatory increase in hepatic glucose production. Insulin’s main actions are (1) In the liver, insulin promotes glycolysis and storage of glucose as glycogen (glycogenesis), as well as conversion of glucose to triglycerides, (2) In muscle, insulin promotes the uptake of glucose and its storage as glycogen, and (3) in adipose tissue, insulin promotes uptake of glucose and its conversion to triglycerides for storage. doi: 10.1080/19420862.2016.1189050. Sci. Biol. FFAs are under certain circumstances insulin secretagogs (Boden and Carnell, 2003) but their ability to stimulate glucagon secretion remains debated (Gerich et al., 1974; Bollheimer et al., 2004; Gromada et al., 2007). (2011). Diabetes 66, 235–240. Behav. Glucagon and glucagon-like peptides in fishes. Supporting a role for glucagon in the regulation of keto-genesis, suppression of glucagon secretion via somatostatin prevented the development of ketoacidosis in patients with type 1 diabetes mellitus 69). 9, 425–433. Chiang JY. Eur. J. Clin. doi: 10.1016/j.celrep.2018.10.018, Svoboda, M., Tastenoy, M., Vertongen, P., and Robberecht, P. (1994). doi: 10.1152/ajpendo.1995.269.6.E1059, Stephens, F. B., Constantin-Teodosiu, D., and Greenhaff, P. L. (2007). Int Rev Cytol. Amatuzio DS, Grande F, Wada S. Effect of glucagon on the serum lipids in essential hyperlipemia and in hypercholesterolemia. Eaton, R. P. (1973). 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. Nutr. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. doi: 10.1111/dom.13440, Kim, J., Okamoto, H., Huang, Z., Anguiano, G., Chen, S., Liu, Q., et al. Endocrinol. Physiol., 24 April 2019 Anim Sci J 80:686-690, 2009. Modulation of fatty acid metabolism by glucagon in man. enable_page_level_ads: true Metab. doi: 10.1074/jbc.273.1.215, Aromataris, E. C., Roberts, M. L., Barritt, G. J., and Rychkov, G. Y. Studies in rats suggest that mediatory, paracrine signaling from the β cell is essential for the inhibition of glucagon secretion by elevated glucose levels 31). (2016). Bence Sipos, Jan Sperveslage, Martin Anlauf, Maike Hoffmeister, Tobias Henopp, Stephan Buch, Jochen Hampe, Achim Weber, Pascal Hammel, Anne Couvelard, Walter Höbling, Wolfgang Lieb, Bernhard O. Boehm, Günter Klöppel, Glucagon Cell Hyperplasia and Neoplasia With and Without Glucagon Receptor Mutations, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 5, 1 May … Type 2 diabetes is associated with dysregulated glucagon secretion, and increased glucagon concentrations contribute to the diabetic hyperglycemia. Le Sauter J, Noh U, Geary N. Hepatic portal infusion of glucagon antibodies increases spontaneous meal size in rats. This medicine comes with patient instructions together with the kit provided with the package. Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. Exp. doi: 10.1016/j.tips.2012.03.014, Hansen, L. H., Abrahamsen, N., and Nishimura, E. (1995). doi: 10.1073/pnas.0237106100, Gerich, J. E., Langlois, M., Schneider, V., Karam, J. H., and Noacco, C. (1974). Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses. The glucagon signaling pathway refers to the sum of a series of proteins and regulatory factors involved in the function of glucagon. Chem. Longuet C, et al. Regul. 1983;31:391–394. Proc. Diabetes 60, 383–390. Glucagon may cause some patients to vomit and this position will reduce the possibility of choking. NNF Tandem Programme (31526), NNF Project support in Endocrinology and Metabolism – Nordic Region (34250), and Excellence Emerging Investigator Grant – Endocrinology and Metabolism (NNF19OC0055001). 112, 100–104. J. Clin. doi: 10.2337/diab.15.10.740, Perea, A., Clemente, F., Martinell, J., Villanueva-Penacarrillo, M. L., and Valverde, I. How the loss of glucagon action affects body composition remains to be determined but possible explanations may include effects on leptin, sympathetic nervous system, and brown adipose tissue thermogenesis and white adipose tissue lipolysis 101). 53, 190–197. These effects were suggested to be driven by a fall in the sensitivity of CPT1 to malonyl-CoA, releasing the inhibition of this rate-limiting enzyme in the transport of fatty acids across the mitochondrial membranes 71). α, pancreatic α-cell (glucagon); β, pancreatic β-cell (insulin); δ, pancreatic δ-cell (somatostatin); arrows, stimulatory inputs; T-ends, inhibitory inputs. The actions of glucagon are mediated via the glucagon receptor, a seven transmembrane receptor coupled to Gαs- and Gq-proteins, which regulate adenylate cyclase (AC) and phospholipase C activities when activated (Wakelam et al., 1986; Jelinek et al., 1993; Aromataris et al., 2006). doi: 10.1152/physrev.00025.2016, Niederwanger, A., Ciardi, C., Tatarczyk, T., Khan, M. I., Hermann, M., Mittermair, C., et al. doi: 10.1097/00000658-199108000-00007, Dumonteil, E., Magnan, C., Ritz-Laser, B., Ktorza, A., Meda, P., and Philippe, J. Metab. Am. This process is reversible in the absence of glucagon (and thus, the presence of insulin). doi: 10.1093/ajcn/73.2.177, Radulescu, A., Gannon, M. C., and Nuttall, F. Q. 269, 409–415. doi: 10.1016/j.metabol.2004.06.011, Briant, L. J. (2012). J. Biol. Insulin secretion depends on intra-islet glucagon signaling. doi: 10.1042/bj2640107, Hansen, H. S., Rosenkilde, M. M., Holst, J. J., and Schwartz, T. W. (2012). 278, 11303–11311. Metabolism of isolated fat cells. Soc. In addition to regulating glucose metabolism, glucagon also seems important for minute-to-minute regulation of amino acid metabolism as part of the recently described liver-alpha cell axis (Solloway et al., 2015; Dean et al., 2017; Galsgaard et al., 2017; Holst et al., 2017b; Kim et al., 2017), in which amino acids stimulate glucagon secretion and glucagon in turn stimulates hepatic amino acid uptake and metabolism (ureagenesis) and, thus, circulating amino acid concentrations as well as increased hepatic NADH/NAD+ ratio. Endocrinol. After 10 to 20 minutes, check your blood sugar again to make sure it is not still too low. Tell your doctor if any of these symptoms are severe or do not go away: If you experience any of the following symptoms, call your doctor immediately: Other side effects not listed may also occur in some patients. 287, R524–R533. Following exposure to a prolonged fasting period, Gcgr−/− mice showed increased levels of plasma triglycerides and free fatty acids 63). Furthermore, a decrease in synthesis of hepatic lipoprotein apoproteins was observed 48), complementing earlier studies that described depression of triglyceride synthesis in livers treated with glucagon. Hepatic mitochondrial function in ketogenic states. During beta-oxidation the fatty acids are degraded into acetate, which ultimately enters the citric acid cycle (DiMarco and Hoppel, 1975). (2017). Rev. Epinephrine will then travel to the liver, where it will bind to β-adrenergic receptors. doi: 10.1113/jphysiol.2006.121954, Charlton, M., Krishnan, A., Viker, K., Sanderson, S., Cazanave, S., McConico, A., et al. Glucagon should be administered and the patient’s doctor should be called at once. U.S.A. 91, 3242–3246. Chem. J. Physiol. doi: 10.2337/db10-0763, Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., et al. Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation. GCGR glucagon receptor [ (human)] A combined activation mechanism for the glucagon receptor. J. Med. Invest. 573(Pt 3), 611–625. Greenberg, A. S., Egan, J. J., Wek, S. A., Garty, N. B., Blanchette-Mackie, E. J., and Londos, C. (1991). 3. Metab. Physiol. Glucagon exerts two primary actions on your liver: (1) glycogenolysis, the breakdown of glycogen into glucose; and (2) gluconeogenesis, the synthesis of glucose from fats and proteins. Front. Furthermore, infusion with saline only gave the same increase in FFA as compared to glucagon infusion. doi: 10.3181/00379727-133-34511, Madison, L. L., Seyffert, W. A. Jr., Unger, R. H., and Barker, B. Invest. 28, 325–331. It promotes the synthesis of glycogen, fat, and protein, thereby promoting the storage of excess nutrients for later use and enhancing cellular growth and differentiation. (2013). Metab. Metab. 55) revealed that increased glucagon signaling may directly regulate lipid catabolism. (2009). To date, glucagon-binding sites have been identified in multiple tissues, including liver, brain, pancreas, kidney, intestine, and adipose tissues 20). Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues. doi: 10.2337/diab.23.9.725, Paschoalini, M. A., and Migliorini, R. H. (1990). J. 338, 70–81. tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. low) plasma insulin concentrations, there is considerable evidence that glucagon acts in the defense against hypoglycemia by antagonizing the effects of excess plasma insulin 12). In addition, Gcgr−/− mice may be prone to steatosis when challenged with a high fat diet (HFD) for 8 weeks (Longuet et al., 2008). Biol. (2014). In line with this, others (Gelling et al., 2003) showed a decrease in white adipose tissue mass and an increase in lean body mass in Gcgr−/− compared to wild-type mice, without changes in bodyweight, food consumption, or energy expenditure and one group (Conarello et al., 2007) found that Gcgr−/− mice had lower amounts of white adipose tissue when fed both a HFD and a low fat diet compared to wild-type mice, and thus seemed to be resistant to diet-induced obesity. 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). 19, 24–32. Diabetes. cAMP-dependent protein kinase and lipolysis in rat adipocytes. Kurose Y, et al. (2000). G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. The release of epinephrine is stimulated by sympathetic activation, which occurs during stress. During the last two decades, significant progress has been made in understanding the biological function of glucagon, the regulation of expression and secretion of glucagon, the interaction of glucagon with its G protein-coupled receptor, and the role of glucagon in modulating key transcription factors and metabolic enzymes.
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