Nutrient regulation of glucagon secretion: Involvement in metabolism and diabetes

Nutrition Research Reviews

Volumn 27, Issue 1, 2014, Pages 48-62

  Marroquí, Laura ^a,b   Alonso Magdalena, Paloma ^a,c   Merino, Beatriz ^a,c   Fuentes, Esther ^a,c   Nadal, Angel ^a,c   Quesada, Ivan ^a,c  

^a MIGUEL HERNÁNDEZ UNIVERSITY   (Spain)

^b UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

Diabetes; Glucagon secretion; Pancreatic cells

Indexed keywords

AMINO ACID; FATTY ACID; GLUCAGON; GLUCAGON RECEPTOR; GLUCOSE; GLUCOSE BLOOD LEVEL; INSULIN; LIPID;

BODY WEIGHT; DIABETES MELLITUS; DIABETIC PATIENT; ENERGY METABOLISM; FOOD INTAKE; GLUCAGON RELEASE; GLUCOSE HOMEOSTASIS; HUMAN; METABOLISM; NONHUMAN; NUTRIENT; OBESITY; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET CELL FUNCTION; REVIEW; DIET; GLUCOSE BLOOD LEVEL; HOMEOSTASIS; HYPERGLYCEMIA; LIPID METABOLISM; SECRETION (PROCESS); ADIPOSE TISSUE; CELL SURVIVAL; ENDOCRINE CELL; HORMONE SYNTHESIS; NUTRITION; PANCREAS ISLET BETA CELL; SMALL INTESTINE;

BLOOD GLUCOSE; DIABETES MELLITUS; DIET; ENERGY METABOLISM; GLUCAGON; GLUCAGON-SECRETING CELLS; HOMEOSTASIS; HUMANS; HYPERGLYCEMIA; LIPID METABOLISM; OBESITY; RECEPTORS, GLUCAGON;

EID: 84903891485     PISSN: 09544224     EISSN: 14752700     Source Type: Journal    
DOI: 10.1017/S0954422414000031     Document Type: Review

References (204)

1. Brissova M, Fowler MJ, Nicholson WE, et al. (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53, 1087-1097. (Pubitemid 41262977)
2. Cabrera O, Berman DM, Kenyon NS, et al. (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103, 2334-2339. (Pubitemid 43271670)
3. Nadal A, Quesada I & Soria B (1999) Homologous and heterologous asynchronicity between identified a-, b-And d-cells within intact islets of Langerhans in the mouse. J Physiol 517, 85-93. (Pubitemid 29243473)
4. Quesada I, Todorova MG & Soria B (2006) Different metabolic responses in a-, b-, and d-cells of the islet of Langerhans monitored by redox confocal microscopy. Biophys J 90, 2641-2650.
5. Smith FE, Rosen KM, Villa-Komaroff L, et al. (1991) Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas. Proc Natl Acad Sci U S A 88, 6152-6156. (Pubitemid 21914904)
6. Unger RH & Orci L (2010) Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A 107, 16009-16012.
7. Ahren B (2000) Autonomic regulation of islet hormone secretion- implications for health and disease. Diabetologia 43, 393-410. (Pubitemid 30237947)
8. Taborsky GJ Jr & Mundinger TO (2012) Minireview: the role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology 153, 1055-1062.
9. Quesada I, Tuduri E, Ripoll C, et al. (2008) Physiology of the pancreatic a-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 199, 5-19.
10. Unger RH, Aguilar-Parada E, Muller WA, et al. (1970) Studies of pancreatic a cell function in normal and diabetic subjects. J Clin Invest 49, 837-848.
11. Arafat AM, Kaczmarek P, Skrzypski M, et al. (2013) Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis? Diabetologia 56, 588-597.
12. Bertin E, Arner P, Bolinder J, et al. (2001) Action of gluca-gon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo. J Clin Endocrinol Metab 86, 1229-1234. (Pubitemid 32323009)
13. Longuet C, Sinclair EM, Maida A, et al. (2008) The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab 8, 359-371.
14. Xiao C, Pavlic M, Szeto L, et al. (2011) Effects of acute hyperglucagonemia on hepatic and intestinal lipoprotein production and clearance in healthy humans. Diabetes 60, 383-390.
15. Cryer PE (2012) Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology 153, 1039-1048.
16. Gerich JE, Lorenzi M, Schneider V, et al. (1974) Effect of somatostatin on plasma glucose and insulin responses to glucagon and tolbutamide in man. J Clin Endocrinol Metab 39, 1057-1060.
17. Ohneda A, Aguilar-Parada E, Eisentraut AM, et al. (1969) Control of pancreatic glucagon secretion by glucose. Diabetes 18, 1-10.
18. Salehi A & Vieira E (2006) Gylfe E Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes 55, 2318-2323. (Pubitemid 44743630)
19. Vieira E & Salehi A (2007) Gylfe E Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic a cells. Diabetologia 50, 370-379.
20. Gopel S, Zhang Q, Eliasson L, et al. (2004) Capacitance measurements of exocytosis in mouse pancreatic a-, band d-cells within intact islets of Langerhans. J Physiol 556, 711-726. (Pubitemid 38660309)
21. Gopel SO, Kanno T, Barg S, et al. (2000) Regulation of glucagon release in mouse a-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528, 509-520.
22. Tuduri E, Marroqui L, Soriano S, et al. (2009) Inhibitory effects of leptin on pancreatic a-cell function. Diabetes 58, 1616-1624.
23. Taborsky GJ Jr, Ahren B & Havel PJ (1998) Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired a-cell responses in type 1 diabetes. Diabetes 47, 995-1005. (Pubitemid 28294539)
24. Thorens B (2011) Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obes Metab 13, Suppl. 1, 82-88.
25. Rorsman P, Salehi SA, Abdulkader F, et al. (2008) K(ATP)-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab 19, 277-284.
26. MacDonald PE, De Marinis YZ, Ramracheya R, et al. (2007) A KATP channel-dependent pathway within a cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5, e143.
27. Gylfe E (2013) Glucose control of glucagon secretion: there is more to it than KATP channels. Diabetes 62, 1391-1393.
28. Liu YJ, Vieira E & Gylfe E (2004) A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic a-cell. Cell Calcium 35, 357-365. (Pubitemid 38351204)
29. Quoix N, Cheng-Xue R & Mattart L (2009) Glucose and pharmacological modulators of ATP-sensitive K+ channels control [Ca2+]c by different mechanisms in isolated mouse a-cells. Diabetes 58, 412-421.
30. Le Marchand SJ & Piston DW (2010) Glucose suppression of glucagon secretion: metabolic and calcium responses from a-cells in intact mouse pancreatic islets. J Biol Chem 285, 14389-14398.
31. Ravier MA & Rutter GA (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic a-cells. Diabetes 54, 1789-1797. (Pubitemid 40770769)
32. Detimary P, Dejonghe S, Ling Z, et al. (1998) The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in b cells but not in a cells and are also observed in human islets. J Biol Chem 273, 33905-33908. (Pubitemid 29008852)
33. Gorus FK, Malaisse WJ & Pipeleers DG (1984) Differences in glucose handling by pancreatic A-And B-cells. J Biol Chem 259, 1196-1200. (Pubitemid 14193273)
34. Heimberg H, De Vos A, Pipeleers D, et al. (1995) Differences in glucose transporter gene expression between rat pancreatic a-And b-cells are correlated to differences in glucose transport but not in glucose utilization. J Biol Chem 270, 8971-8975.
35. Schuit F, De Vos A, Farfari S, et al. (1997) Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in b cells. J Biol Chem 272, 18572-18579. (Pubitemid 27318196)
36. Sekine S, Ito Y, Hashimoto M, et al. (1994) Characterization of monoclonal antibodies to chitinase A1 and enhancement of chitinase A1 activity by monoclonal antibodies. Biochem Biophys Res Commun 204, 7-16. (Pubitemid 24335254)
37. Zhao C, Wilson MC, Schuit F, et al. (2001) Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50, 361-366. (Pubitemid 32127293)
38. Allister EM, Robson-Doucette CA, Prentice KJ, et al. (2013) UCP2 regulates the glucagon response to fasting and starvation. Diabetes 62, 1623-1633.
39. Cheng-Xue R, Gomez-Ruiz A, Antoine N, et al. (2013) Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both a-cells and d-cells. Diabetes 62, 1612-1622.
40. da Silva Xavier G, Farhan H, Kim H, et al. (2011) Per-Arnt-sim (PAS) domain-containing protein kinase is down-regulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia 54, 819-827.
41. Leclerc I, Sun G, Morris C, et al. (2011) AMP-Activated protein kinase regulates glucagon secretion from mouse pancreatic a cells. Diabetologia 54, 125-134.
42. Vieira E, Marroquí L, Figueroa AC, et al. (2013) Involvement of the clock gene Rev-erb a in the regulation of glucagon secretion in pancreatic a-cells. PLOS ONE 8, e69939.
43. Ellingsgaard H, Ehses JA, Hammar EB, et al. (2008) Interleu-kin-6 regulates pancreatic a-cell mass expansion. Proc Natl Acad Sci U S A 105, 13163-13168.
44. Dumonteil E, Magnan C, Ritz-Laser B, et al. (2000) Glucose regulates proinsulin and prosomatostatin but not progluca-gon messenger ribonucleic acid levels in rat pancreatic islets. Endocrinology 141, 174-180. (Pubitemid 32260357)
45. Kuhara T, Ikeda S, Ohneda A, et al. (1991) Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep. Am J Physiol 260, E21-E26.
46. Pipeleers DG, Schuit FC, Van Schravendijk CF, et al. (1985) Interplay of nutrients and hormones in the regulation of glucagon release. Endocrinology 117, 817-823. (Pubitemid 15019998)
47. Ostenson CG (1985) Grebing C Evidence for metabolic regulation of pancreatic glucagon secretion by l-glutamine. Acta Endocrinol (Copenh) 108, 386-391.
48. Li XC, Liao TD & Zhuo JL (2008) Long-term hyperglucago-naemia induces early metabolic and renal phenotypes of type 2 diabetes in mice. Clin Sci (Lond) 114, 591-601. (Pubitemid 351589059)
49. Gannon MC, Nuttall JA & Nuttall FQ (2002) The metabolic response to ingested glycine. Am J Clin Nutr 76, 1302-1307. (Pubitemid 35416566)
50. Leclercq-Meyer V, Marchand J, Woussen-Colle MC, et al. (1985) Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas. Endocrinology 116, 1168-1174. (Pubitemid 15136980)
51. Bode HP, Weber S, Fehmann HC, et al. (1999) A nutrient-regulated cytosolic calcium oscillator in endocrine pancreatic glucagon-secreting cells. Pflugers Arch 437, 324-334. (Pubitemid 29071930)
52. Collins SC, Luan J, Thompson AJ, et al. (2007) Adiponectin receptor genes: mutation screening in syndromes of insulin resistance and association studies for type 2 diabetes and metabolic traits in UK populations. Diabetologia 50, 555-562. (Pubitemid 46215498)
53. Hong J, Abudula R, Chen J, et al. (2005) The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro. Metabolism 54, 1329-1336. (Pubitemid 41262590)
54. Olofsson CS, Salehi A, Gopel SO, et al. (2004) Palmitate stimulation of glucagon secretion in mouse pancreatic a-cells results from activation of l-type calcium channels and elevation of cytoplasmic calcium. Diabetes 53, 2836-2843. (Pubitemid 39425908)
55. Bollheimer LC, Landauer HC, Troll S, et al. (2004) Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. Metabolism 53, 1443-1448. (Pubitemid 39410384)
56. Flodgren E, Olde B, Meidute-Abaraviciene S, et al. (2007) GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochem Biophys Res Commun 354, 240-245. (Pubitemid 46123225)
57. Wang L, Zhao Y, Gui B, et al. (2011) Acute stimulation of glucagon secretion by linoleic acid results from GPR40 activation and [Ca2+]i increase in pancreatic islet a-cells. J Endocrinol 210, 173-179.
58. Fujiwara K, Maekawa F, Dezaki K, et al. (2007) Oleic acid glucose-independently stimulates glucagon secretion by increasing cytoplasmic Ca2+ via endoplasmic reticulum Ca2+ release and Ca2+ influx in the rat islet a-cells. Endocrinology 148, 2496-2504. (Pubitemid 46997058)
59. Hong J, Jeppesen PB, Nordentoft I, et al. (2007) Fatty acid-induced effect on glucagon secretion is mediated via fatty acid oxidation. Diabetes Metab Res Rev 23, 202-210. (Pubitemid 46437845)
60. Piro S, Maniscalchi ET, Monello A, et al. (2010) Palmitate affects insulin receptor phosphorylation and intracellular insulin signal in a pancreatic a-cell line. Endocrinology 151, 4197-4206.
61. Gremlich S, Bonny C, Waeber G, et al. (1997) Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 272, 30261-30269. (Pubitemid 27512230)
62. Bourlon PM, Faure-Dussert A, Billaudel B, et al. (1996) Relationship between calbindin-D28K levels in the A and B cells of the rat endocrine pancreas and the secretion of insulin and glucagon: influence of vitamin D3 deficiency and 1, 25-dihydroxyvitamin D3. J Endocrinol 148, 223-232.
63. Orwoll E & Riddle M (1994) Prince M Effects of vitamin D on insulin and glucagon secretion in non-insulin-dependent diabetes mellitus. Am J Clin Nutr 59, 1083-1087.
64. Chertow BS, Driscoll HK, Blaner WS, et al. (1994) Effects of vitamin A deficiency and repletion on rat glucagon secretion. Pancreas 9, 475-484. (Pubitemid 24191715)
65. Chertow BS, Driscoll HK, Primerano DA, et al. (1996) Retinoic acid receptor transcripts and effects of retinol and retinoic acid on glucagon secretion from rat islets and glucagon-secreting cell lines. Metabolism 45, 300-305. (Pubitemid 26102633)
66. Klandorf H & Clarke BL (1987) Brown J Altered glucagon release in biotin deficiency. Gen Comp Endocrinol 65, 133-140. (Pubitemid 17208479)
67. Wilkes LC, Bailey CJ, Thompson B, et al. (1990) Effect of gastrin-releasing peptide on the secretion of mouse islet hormones in vitro. J Endocrinol 127, 335-340. (Pubitemid 20370581)
68. Winzell MS (2007) Ahren B Role of VIP and PACAP in islet function. Peptides 28, 1805-1813. (Pubitemid 47361423)
69. Miralles P, Peiro E, Degano P, et al. (1990) Inhibition of insulin and somatostatin secretion and stimulation of glucagon release by homologous galanin in perfused rat pancreas. Diabetes 39, 996-1001. (Pubitemid 20233735)
70. De Marinis YZ, Salehi A, Ward CE, et al. (2010) GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N-And L-type Ca2+ channel-dependent exocytosis. Cell Metab 11, 543-553.
71. Cabrera O, Jacques-Silva MC, Speier S, et al. (2008) Glutamate is a positive autocrine signal for glucagon release. Cell Metab 7, 545-554. (Pubitemid 351729201)
72. Rodriguez-Diaz R, Dando R, Jacques-Silva MC, et al. (2011) a Cells secrete acetylcholine as a non-neuronal paracrine signal priming b cell function in humans. Nat Med 17, 888-892.
73. Miki T, Liss B, Minami K, et al. (2001) ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4, 507-512. (Pubitemid 32397188)
74. Leibiger B, Moede T, Muhandiramlage TP, et al. (2012) Glucagon regulates its own synthesis by autocrine signaling. Proc Natl Acad Sci U S A 109, 20925-20930.
75. Tuduri E, Filiputti E, Carneiro EM, et al. (2008) Inhibition of Ca2+ signaling and glucagon secretion in mouse pancreatic a-cells by extracellular ATP and purinergic receptors. Am J Physiol Endocrinol Metab 294, E952-E960.
76. Ma X, Zhang Y, Gromada J, et al. (2005) Glucagon stimulates exocytosis in mouse and rat pancreatic a-cells by binding to glucagon receptors. Mol Endocrinol 19, 198-212. (Pubitemid 40065970)
77. Dunning BE & Foley JE (2005) Ahren B a Cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 48, 1700-1713. (Pubitemid 41317822)
78. Ding WG, Renstrom E, Rorsman P, et al. (1997) Glucagon-like peptide I and glucose-dependent insulinotropic poly-peptide stimulate Ca2+-induced secretion in rat a-cells by a protein kinase A-mediated mechanism. Diabetes 46, 792-800. (Pubitemid 27188256)
79. de Heer J, Rasmussen C, Coy DH, et al. (2008) Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabeto-logia 51, 2263-2270.
80. Opara EC, Burch WM, Taylor IL, et al. (1991) Pancreatic hormone response to neuropeptide Y (NPY) perifusion in vitro. Regul Pept 34, 225-233.
81. Gosmain Y, Cheyssac C, et al. (2011) Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in a-cell differentiation, glucagon biosynthesis and secretion. Diabetes Obes Metab 13, Suppl. 1, 31-38.
82. Jin T (2008) Mechanisms underlying proglucagon gene expression. J Endocrinol 198, 17-28. (Pubitemid 352038181)
83. Mojsov S, Heinrich G, Wilson IB, et al. (1986) Preprogluca-gon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 261, 11880-11889. (Pubitemid 17206117)
84. Dey A, Lipkind GM, Rouille Y, et al. (2005) Significance of prohormone convertase 2, PC2, mediated initial cleavage at the proglucagon interdomain site, Lys70-Arg71, to generate glucagon. Endocrinology 146, 713-727. (Pubitemid 40129827)
85. Patzelt C & Schiltz E (1984) Conversion of proglucagon in pancreatic a cells: the major endproducts are glucagon and a single peptide, the major proglucagon fragment, that contains two glucagon-like sequences. Proc Natl Acad Sci U S A 81, 5007-5011. (Pubitemid 14008870)
86. Patzelt C, Tager HS, Carroll RJ, et al. (1979) Identification and processing of proglucagon in pancreatic islets. Nature 282, 260-266. (Pubitemid 10198523)
87. Furuta M, Zhou A, Webb G, et al. (2001) Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J Biol Chem 276, 27197-27202.
88. Dumonteil E, Ritz-Laser B, Magnan C, et al. (1999) Chronic exposure to high glucose concentrations increases proglu-cagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells. Endocrinology 140, 4644-4650. (Pubitemid 30666131)
89. McGirr R, Ejbick CE, Carter DE, et al. (2005) Glucose dependence of the regulated secretory pathway in aTC1-6 cells. Endocrinology 146, 4514-4523. (Pubitemid 41324050)
90. Grzeskowiak R, Amin J, Oetjen E, et al. (2000) Insulin responsiveness of the glucagon gene conferred by interactions between proximal promoter and more distal enhancer-like elements involving the paired-domain transcription factor Pax6. J Biol Chem 275, 30037-30045.
91. Philippe J (1989) Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. J Clin Invest 84, 672-677.
92. Schinner S, Barthel A, Dellas C, et al. (2005) Protein kinase B activity is sufficient to mimic the effect of insulin on glucagon gene transcription. J Biol Chem 280, 7369-7376. (Pubitemid 40341295)
93. Yamato E, Noma Y, Tahara Y, et al. (1990) Suppression of synthesis and release of glucagon by glucagon-like peptide-1 (7-36 amide) without affect on mRNA level in isolated rat islets. Biochem Biophys Res Commun 167, 431-437. (Pubitemid 20113197)
94. Paul GL, Waegner A, Gaskins HR, et al. (1998) Histidine availability alters glucagon gene expression in murine aTC6 cells. J Nutr 128, 973-976. (Pubitemid 28280196)
95. Mayo KE, Miller LJ, Bataille D, et al. (2003) International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55, 167-194. (Pubitemid 36268402)
96. Weinstein LS, Yu S, Warner DR, et al. (2001) Endocrine manifestations of stimulatory G protein a-subunit mutations and the role of genomic imprinting. Endocr Rev 22, 675-705. (Pubitemid 32955250)
97. Kimball SR, Siegfried BA & Jefferson LS (2004) Glucagon represses signaling through the mammalian target of rapa-mycin in rat liver by activating AMP-Activated protein kinase. J Biol Chem 279, 54103-54109. (Pubitemid 40053145)
98. Chen J, Ishac EJ, Dent P, et al. (1998) Effects of ethanol on mitogen-Activated protein kinase and stress-Activated protein kinase cascades in normal and regenerating liver. Biochem J 334, 669-676. (Pubitemid 28457216)
99. Svoboda M, Tastenoy M, Vertongen P, et al. (1994) Relative quantitative analysis of glucagon receptor mRNA in rat tissues. Mol Cell Endocrinol 105, 131-137. (Pubitemid 24313980)
100. Kedees MH, Grigoryan M, Guz Y, et al. (2009) Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic a and b cells in two models of a cell hyperplasia. Mol Cell Endocrinol 311, 69-76.
101. Kieffer TJ, Heller RS, Unson CG, et al. (1996) Distribution of glucagon receptors on hormone-specific endocrine cells of rat pancreatic islets. Endocrinology 137, 5119-5125. (Pubitemid 26403357)
102. Gelling RW, Du XQ, Dichmann DS, et al. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic a cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100, 1438-1443. (Pubitemid 36184020)
103. Conarello SL, Jiang G, Mu J, et al. (2007) Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated b cell loss and hyperglycaemia. Diabetologia 50, 142-150. (Pubitemid 46035862)
104. Lee Y, Wang MY, Du XQ, et al. (2011) Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60, 391-397.
105. Sorensen H, Winzell MS, Brand CL, et al. (2006) Glucagon receptor knockout mice display increased insulin sensitivity and impaired b-cell function. Diabetes 55, 3463-3469. (Pubitemid 44923606)
106. Vuguin PM, Kedees MH, Cui L, et al. (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147, 3995-4006. (Pubitemid 44268351)
107. Gelling RW, Vuguin PM, Du XQ, et al. (2009) Pancreatic b-cell overexpression of the glucagon receptor gene results in enhanced b-cell function and mass. Am J Physiol Endocrinol Metab 297, E695-E707.
108. Berglund ED, Lustig DG, Baheza RA, et al. (2011) Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver. Diabetes 60, 2720-2729.
109. Jones BJ, Tan T & Bloom SR (2012) Minireview: glucagon in stress and energy homeostasis. Endocrinology 153, 1049-1054.
110. Yoon JC, Puigserver P, Chen G, et al. (2001) Control of hepatic gluconeogenesis through the transcriptional coacti-vator PGC-1. Nature 413, 131-138. (Pubitemid 32867868)
111. Hjorth SA, Adelhorst K, Pedersen BB, et al. (1994) Gluca-gon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes. J Biol Chem 269, 30121-30124. (Pubitemid 24376475)
112. Herzig S, Long F, Jhala US, et al. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179-183. (Pubitemid 32867880)
113. Band GC & Jones CT (1980) Functional activation by gluca-gon of glucose 6-phosphatase and gluconeogenesis in the perfused liver of the fetal guinea pig. FEBS Lett 119, 190-194. (Pubitemid 11212474)
114. De Oya M, Prigge WF & Grande F (1971) Suppression by hepatectomy of glucagon-induced hypertriglyceridemia in geese. Proc Soc Exp Biol Med 136, 107-110.
115. Penhos JC, Wu CH, Daunas J, et al. (1966) Effect of gluca-gon on the metabolism of lipids and on urea formation by the perfused rat liver. Diabetes 15, 740-748.
116. Aubry F, Marcel YL & Davignon J (1974) Effects of glucagon on plasma lipids in different types of primary hyperlipopro-teinemia. Metabolism 23, 225-238.
117. Eaton RP (1973) Hypolipemic action of glucagon in experimental endogenous lipemia in the rat. J Lipid Res 14, 312-318.
118. Charbonneau A, Couturier K, Gauthier MS, et al. (2005) Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Int J Sports Med 26, 432-441. (Pubitemid 41117061)
119. Charbonneau A, Melancon A, Lavoie C, et al. (2005) Alterations in hepatic glucagon receptor density and in Gsa and Gia2 protein content with diet-induced hepatic steatosis: effects of acute exercise. Am J Physiol Endocrinol Metab 289, E8-E14. (Pubitemid 40874928)
120. Han S, Akiyama TE, Previs SF, et al. (2013) Effects of siRNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice. J Lipid Res 54, 2615-2622.
121. Cynober LA (2002) Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18, 761-766. (Pubitemid 35286391)
122. Hoosein NM & Gurd RS (1984) Identification of glucagon receptors in rat brain. Proc Natl Acad Sci U S A 81, 4368-4372. (Pubitemid 14052446)
123. Cockram CS, Kum W, Ho SK, et al. (1995) Binding and action of glucagon in cultured mouse astrocytes. Glia 13, 141-146.
124. Inokuchi A, Oomura Y & Nishimura H (1984) Effect of intracerebroventricularly infused glucagon on feeding behavior. Physiol Behav 33, 397-400. (Pubitemid 14010066)
125. Amir S (1986) Central glucagon-induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings. Physiol Behav 37, 563-566. (Pubitemid 16056619)
126. Geary N & Smith GP (1983) Selective hepatic vagotomy blocks pancreatic glucagon's satiety effect. Physiol Behav 31, 391-394.
127. Geary N & Smith GP (1982) Pancreatic glucagon and postprandial satiety in the rat. Physiol Behav 28, 313-322. (Pubitemid 12110684)
128. Martin JR & Novin D (1977) Decreased feeding in rats following hepatic-portal infusion of glucagon. Physiol Behav 19, 461-466. (Pubitemid 8317175)
129. Penick SB & Hinkle LE Jr (1961) Depression of food intake induced in healthy subjects by glucagon. N Engl J Med 264, 893-897.
130. Woods SC, Lutz TA, Geary N, et al. (2006) Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond B Biol Sci 361, 1219-1235. (Pubitemid 44882937)
131. Langhans W, Zeiger U, Scharrer E, et al. (1982) Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon. Science 218, 894-896. (Pubitemid 13201183)
132. Jensen PB, Blume N, Mikkelsen JD, et al. (1998) Transplan-table rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus. J Clin Invest 101, 503-510. (Pubitemid 28067349)
133. Arafat AM, Perschel FH, Otto B, et al. (2006) Glucagon suppression of ghrelin secretion is exerted at hypothalamus-pituitary level. J Clin Endocrinol Metab 91, 3528-3533. (Pubitemid 44402132)
134. Mighiu PI, Yue JT, Filippi BM, et al. (2013) Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19, 766-772.
135. Davidson IW, Salter JM & Best CH (1957) Calorigenic action of glucagon. Nature 180, 1124.
136. Nair KS (1987) Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J Clin Endocrinol Metab 64, 896-901. (Pubitemid 17067417)
137. Calles-Escandon J (1994) Insulin dissociates hepatic glucose cycling and glucagon-induced thermogenesis in man. Metabolism 43, 1000-1005. (Pubitemid 24249402)
138. Tan TM, Field BC, McCullough KA, et al. (2013) Coadministration of glucagon-like peptide-1 during gluca-gon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62, 1131-1138.
139. Billington CJ, Briggs JE, Link JG, et al. (1991) Glucagon in physiological concentrations stimulates brown fat thermo-genesis in vivo. Am J Physiol 261, R501-R507.
140. Joel CD (1966) Stimulation of metabolism of rat brown adipose tissue by addition of lipolytic hormones in vitro. J Biol Chem 241, 814-821.
141. Yahata T & Kuroshima A (1982) Influence of endocrine and chemical factors on glucagon induced thermogenesis in brown adipocytes. Jpn J Physiol 32, 303-307. (Pubitemid 12025483)
142. Billington CJ, Bartness TJ, Briggs J, et al. (1987) Glucagon stimulation of brown adipose tissue growth and thermo-genesis. Am J Physiol 252, R160-R165.
143. Filali-Zegzouti Y, Abdelmelek H, Rouanet JL, et al. (2005) Role of catecholamines in glucagon-induced thermogen-esis. J Neural Transm 112, 481-489.
144. Dicker A, Zhao J, Cannon B, et al. (1998) Apparent thermogenic effect of injected glucagon is not due to a direct effect on brown fat cells. Am J Physiol 275, R1674-R1682.
145. Schulman JL, Carleton JL, Whitney G, et al. (1957) Effect of glucagon on food intake and body weight in man. J Appl Physiol 11, 419-421.
146. Chan EK, Mackey MA, Snover DC, et al. (1984) Suppression of weight gain by glucagon in obese Zucker rats. Exp Mol Pathol 40, 320-327. (Pubitemid 14083859)
147. Habegger KM, Stemmer K, Cheng C, et al. (2013) Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453-1463.
148. Liu Z, Kim W, Chen Z, et al. (2011) Insulin and glucagon regulate pancreatic a-cell proliferation. PLoS ONE 6, e16096.
149. Moens K, Heimberg H, Flamez D, et al. (1996) Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45, 257-261. (Pubitemid 26048675)
150. Mery PF, Brechler V, Pavoine C, et al. (1990) Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 345, 158-161.
151. Gonzalez-Munoz C, Nieto-Ceron S, Cabezas-Herrera J, et al. (2008) Glucagon increases contractility in ventricle but not in atrium of the rat heart. Eur J Pharmacol 587, 243-247.
152. Harney JA & Rodgers RL (2008) Insulin-like stimulation of cardiac fuel metabolism by physiological levels of glucagon: involvement of PI3K but not cAMP. Am J Physiol Endocrinol Metab 295, E155-E161.
153. Heckemeyer CM, Barker J, Duckworth WC, et al. (1983) Studies of the biological effect and degradation of glucagon in the rat perifused isolated adipose cell. Endocrinology 113, 270-276. (Pubitemid 13045148)
154. Perea A, Clemente F, Martinell J, et al. (1995) Physiological effect of glucagon in human isolated adipocytes. Horm Metab Res 27, 372-375.
155. Gravholt CH, Moller N, Jensen MD, et al. (2001) Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. J Clin Endocrinol Metab 86, 2085-2089. (Pubitemid 32472924)
156. Lefebvre P, Luyckx A & Bacq ZM (1973) Effects of denerva-tion on the metabolism and the response to glucagon of white adipose tissue of rats. Horm Metab Res 5, 245-250.
157. Ahloulay M, Bouby N, Machet F, et al. (1992) Effects of glucagon on glomerular filtration rate and urea and water excretion. Am J Physiol 263, F24-F36.
158. Yano Y, Cesar KR, Araujo M, et al. (2009) Aquaporin 2 expression increased by glucagon in normal rat inner medullary collecting ducts. Am J Physiol Renal Physiol 296, F54-F59.
159. Gutzeit A, Binkert CA, Koh DM, et al. (2012) Evaluation of the anti-peristaltic effect of glucagon and hyoscine on the small bowel: comparison of intravenous and intramuscular drug administration. Eur Radiol 22, 1186-1194.
160. Mochiki E, Suzuki H, Takenoshita S, et al. (1998) Mechanism of inhibitory effect of glucagon on gastrointestinal motility and cause of side effects of glucagon. J Gastroen-terol 33, 835-841. (Pubitemid 29271545)
161. Amanda B, Manuela M, Antonia M, et al. (2010) Posturogra-phy measures and efficacy of different physical treatments in somatic tinnitus. Int Tinnitus J 16, 44-50.
162. Larsson H (2000) Ahren B Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care 23, 650-657. (Pubitemid 30321546)
163. Reaven GM, Chen YD, Golay A, et al. (1987) Documentation of hyperglucagonemia throughout the day in nonob-ese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 64, 106-110. (Pubitemid 17015886)
164. Sherwin R, Wahren J & Felig P (1976) Evanescent effects of hypo-And hyperglucagonemia on blood glucose homeo-stasis. Metabolism 25, 1381-1383.
165. Gastaldelli A, Baldi S, Pettiti M, et al. (2000) Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49, 1367-1373. (Pubitemid 30627434)
166. Siafarikas A, Johnston RJ, Bulsara MK, et al. (2012) Early loss of the glucagon response to hypoglycemia in adolescents with type 1 diabetes. Diabetes Care 35, 1757-1762.
167. Dinneen S, Alzaid A, Turk D, et al. (1995) Failure of glucagon suppression contributes to postprandial hypergly-caemia in IDDM. Diabetologia 38, 337-343.
168. Shah P, Vella A, Basu A, et al. (2000) Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 85, 4053-4059. (Pubitemid 32055352)
169. Eldor R, Glaser B, Fraenkel M, et al. (2011) Glucagonoma and the glucagonoma syndrome-cumulative experience with an elusive endocrine tumour. Clin Endocrinol (Oxf) 74, 593-598.
170. Bolli G, De Feo P, Perriello G, et al. (1984) Mechanisms of glucagon secretion during insulin-induced hypoglycemia in man. Role of the bcell and arterial hyperinsulinemia. J Clin Invest 73, 917-922. (Pubitemid 14132819)
171. Zhou H, Zhang T, Harmon JS, et al. (2007) Zinc, not insulin, regulates the rat a-cell response to hypoglycemia in vivo. Diabetes 56, 1107-1112. (Pubitemid 46525066)
172. Zhou H, Zhang T, Oseid E, et al. (2007) Reversal of defective glucagon responses to hypoglycemia in insulin-dependent autoimmune diabetic BB rats. Endocrinology 148, 2863-2869. (Pubitemid 46984800)
173. Deng S, Vatamaniuk M, Huang X, et al. (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53, 624-632. (Pubitemid 38270631)
174. Henquin JC & Rahier J (2011) Pancreatic a cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720-1725.
175. Yoon KH, Ko SH, Cho JH, et al. (2003) Selective b-cell loss and a-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88, 2300-2308. (Pubitemid 36549911)
176. Charlton MR, Adey DB & Nair KS (1996) Evidence for a catabolic role of glucagon during an amino acid load. J Clin Invest 98, 90-99. (Pubitemid 26243824)
177. Tessari P, Inchiostro S, Barazzoni R, et al. (1996) Hyper-glucagonemia stimulates phenylalanine oxidation in humans. Diabetes 45, 463-470. (Pubitemid 26110252)
178. Roth E, Muhlbacher F, Karner J, et al. (1987) Free amino acid levels in muscle and liver of a patient with glucago-noma syndrome. Metabolism 36, 7-13. (Pubitemid 17025305)
179. Charlton MR & Nair KS (1998) Role of hyperglucagonemia in catabolism associated with type 1 diabetes: effects on leucine metabolism and the resting metabolic rate. Diabetes 47, 1748-1756. (Pubitemid 28476249)
180. Boden G, Rezvani I & Owen OE (1984) Effects of glucagon on plasma amino acids. J Clin Invest 73, 785-793. (Pubitemid 14156861)
181. Slavin BG, Ong JM & Kern PA (1994) Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. J Lipid Res 35, 1535-1541. (Pubitemid 24291214)
182. Guettet C, Rostaqui N, Mathe D, et al. (1991) Effect of chronic glucagon administration on lipoprotein composition in normally fed, fasted and cholesterol-fed rats. Lipids 26, 451-458.
183. Guettet C, Rostaqui N, Navarro N, et al. (1991) Effect of chronic glucagon administration on the metabolism of triacylglycerol-rich lipoproteins in rats fed a high sucrose diet. J Nutr 121, 24-30.
184. Beylot M, Picard S, Chambrier C, et al. (1991) Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans. Metabolism 40, 1138-1146.
185. Miles JM, Haymond MW, Nissen SL, et al. (1983) Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest 71, 1554-1561. (Pubitemid 13056760)
186. Okuda Y, Kawai K & Yamashita K (1987) Age-related change in ketone body metabolism: diminished glucagon effect on ketogenesis in adult rats. Endocrinology 120, 2152-2157. (Pubitemid 17069254)
187. Taborsky GJ Jr (2010) The physiology of glucagon. J Diabetes Sci Technol 4, 1338-1344.
188. Wahid M, Naveed AK & Hussain I (2006) Insulin and gluca-gon ratio in the patho-physiology of diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes. J Coll Physicians Surg Pak 16, 11-14.
189. Hancock AS, Du A, Liu J, et al. (2010) Glucagon deficiency reduces hepatic glucose production and improves glucose tolerance in adult mice. Mol Endocrinol 24, 1605-1614.
190. Lee Y, Berglund ED, Wang MY, et al. (2012) Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc Natl Acad Sci U S A 109, 14972-14976.
191. Sinclair EM, Yusta B, Streutker C, et al. (2008) Glucagon receptor signaling is essential for control of murine hepato-cyte survival. Gastroenterology 135, 2096-2106.
192. Parker JC, McPherson RK, Andrews KM, et al. (2000) Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes. Diabetes 49, 2079-2086.
193. Petersen KF & Sullivan JT (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 44, 2018-2024. (Pubitemid 33124047)
194. Sloop KW, Cao JX, Siesky AM, et al. (2004) Hepatic and glu-cagon-like peptide-1-mediated reversal of diabetes by glu-cagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113, 1571-1581. (Pubitemid 39071680)
195. Winzell MS, Brand CL, Wierup N, et al. (2007) Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. Diabetologia 50, 1453-1462. (Pubitemid 46879005)
196. Miller RA, Chu Q, Xie J, et al. (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256-260.
197. Day JW, Ottaway N, Patterson JT, et al. (2009) A new gluca-gon and GLP-1 co-Agonist eliminates obesity in rodents. Nat Chem Biol 5, 749-757.
198. Pocai A, Carrington PE, Adams JR, et al. (2009) Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258-2266.
199. Parker JA, McCullough KA, Field BC, et al. (2013) Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala. Int J Obes (Lond) 37, 1391-1398.
200. Nauck MA, Heimesaat MM, Behle K, et al. (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87, 1239-1246. (Pubitemid 36121094)
201. Dupre J, Behme MT & McDonald TJ (2004) Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab 89, 3469-3473. (Pubitemid 38951922)
202. Edgerton DS, Johnson KM & Cherrington AD (2009) Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. Front Biosci 14, 1169-1181.
203. Balas B, Baig MR, Watson C, et al. (2007) The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab 92, 1249-1255. (Pubitemid 46556394)
204. Lebovitz HE (2010) Adjunct therapy for type 1 diabetes mel-litus. Nat Rev Endocrinol 6, 326-334.