Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover

Journal of Clinical Investigation

Volumn 122, Issue 1, 2012, Pages 4-12

  Unger, Roger H ^a,b   Cherrington, Alan D ^c  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b VA NORTH TEXAS HEALTH CARE SYSTEM   (United States)

^c VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCAGON; INSULIN; KETONE;

DIABETES MELLITUS; HUMAN; HYPERGLUCAGONEMIA; HYPERGLYCEMIA; INSULIN DEFICIENCY; INSULIN DEPENDENT DIABETES MELLITUS; PARACRINE SIGNALING; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW;

ANIMALS; DIABETES MELLITUS, TYPE 1; GLUCAGON; GLYCOGENOLYSIS; HUMANS; INSULIN; LIVER; MICE; PANCREAS;

EID: 84855459920     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI60016     Document Type: Review

References (96)

1. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J. 1922; 12(3):141-146.
2. Kimball CP, Murlin JR. Aqueous extracts of pancreas. III. Some precipitation reactions of insulin. J Biol Chem. 1923;58(1):337-346.
3. Cherrington A, Vranic M. Role of glucagon and insulin in control of glucose turnover. Metabolism. 1971;20(6):625-628.
4. Keller U, Chiasson JL, Liljenquist JE, Cherrington AD, Jennings AS, Crofford OS. The roles of insulin, glucagon, and free fatty acids in the regulation of ketogenesis in dogs. Diabetes. 1977;26(11):1040-1051. (Pubitemid 8229936)
5. Cherrington AD, Chiasson JL, Liljenquist JE, Lacy WW, Park CR. Control of hepatic glucose output by glucagon and insulin in the intact dog. Biochem Soc Symp. 1978;43(43):31-45. (Pubitemid 9134364)
6. Exton JH, et al. The hormonal control of hepatic gluconeogenesis. Recent Prog Horm Res. 1970;26:411-461.
7. Sutherland JP, McKinley B, Eckel RH. The metabolic syndrome and inflammation. Metab Syndr Relat Disord. 2004;2(2):82-104. (Pubitemid 39545406)
8. Bromer WW, Sinn LG, Staub A, Behrens OK. The amino acid sequence of glucagon. Diabetes. 1957;6(3):234-238.
9. Unger RH. The Banting Memorial Lecture 1975. Diabetes and the alpha cell. Diabetes. 1976;25(2):136-151.
10. Unger RH, Eisentraut AM, McCall MS, Keller S, Lanz HC, Madison LL. Glucagon antibodies and their use for immunoassay for glucagon. Proc Soc Exp Biol Med. 1959;102:621-623.
11. Unger RH, Eisentraut AM, McCall MS, Madison LL. Glucagon antibodies and an immunoassay for glucagon. J Clin Invest. 1961;40:1280-1289.
12. Unger RH. Glucagon physiology and pathophysiology. N Engl J Med. 1971;285(8):443-449.
13. Gelling RW, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003;100(3):1438-1443. (Pubitemid 36184020)
14. Longuet C, et al. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 2008;8(5):359-371.
15. Yang J, et al. Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes. BMC Genomics. 2011;12:281.
16. Cherrington AD, Liljenquist JE, Shulman GI, Williams PE, Lacy WW. Importance of hypo-glycemia- induced glucose production during isolated glucagon deficiency. Am J Physiol. 1979; 236(3):E263-E271. (Pubitemid 9166381)
17. Cherrington AD, Williams PE, Shulman GI, Lacy WW. Differential time course of glucagon's effect on glycogenolysis and gluconeogenesis in the conscious dog. Diabetes. 1981;30(3):180-187. (Pubitemid 11026311)
18. Stevenson RW, et al. Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo. Diabetes. 1987;36(3):382-389. (Pubitemid 18028432)
19. Cherrington AD. Control of glucose production in vivo by insulin and glucagon,. In: Jefferson LS, Cherrington AD, Goodman HM, eds. The Handbook of Physiology: The Endocrine Pancreas and Metabolic Regulation. Vol. 2. New York, New York, USA: Oxford Press; 2001:759-785.
20. Stevenson RW, Williams PE, Cherrington AD. Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog. Diabetologia. 1987;30(10):782-790. (Pubitemid 17163004)
21. Davis MA, Williams PE, Cherrington AD. Effect of glucagon on hepatic lactate metabolism in the conscious dog. Am J Physiol. 1985;248(4 pt 1):E463-E470. (Pubitemid 15065698)
22. Fradkin J, Shamoon H, Felig P, Sherwin RS. Evidence for an important role of changes in rather than absolute concentrations of glucagon in the regulation of glucose production in humans. J Clin Endocrinol Metab. 1980;50(4):698-703. (Pubitemid 10009134)
23. Magnusson I, Rothman DL, Gerard DP, Katz LD, Shulman GI. Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration. Diabetes. 1995;44(2):185-189.
24. Muller MJ, Moring J, Seitz HJ. Regulation of hepatic glucose output by glucose in vivo. Metabolism. 1988; 37(1):55-60. (Pubitemid 18057196)
25. Nielsen MF, Wise S, Dinneen SF, Schwenk WF, Basu A, Rizza RA. Assessment of hepatic sensitivity to glucagon in NIDDM: use as a tool to estimate the contribution of the indirect pathway to nocturnal glycogen synthesis. Diabetes. 1997;46(12):2007-2016. (Pubitemid 27512088)
26. Wada M, Connolly CC, Tarumi C, Neal DW, Cherrington AD. Hepatic denervation does not significantly change the response of the liver to glucagon in conscious dogs. Am J Physiol. 1995; 268(2 pt 1):E194-E203.
27. Dobbins RL, Davis SN, Neal DW, Cobelli C, Jaspan J, Cherrington AD. Compartmental modeling of glucagon kinetics in the conscious dog. Metabolism. 1995; 44(4):452-459.
28. Liljenquist JE, Bloomgarden ZT, Cherrington AD, Perry JM, Rabin D. Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man. Diabetologia. 1979;17(3):139-143. (Pubitemid 10225687)
29. Liljenquist JE, et al. An important role for glucagon in the regulation of glucose production in vivo. Metabolism. 1976;25(11 suppl 1):1371-1373.
30. Liljenquist JE, et al. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J Clin Invest. 1977;59(2):369-374. (Pubitemid 8055697)
31. Holste LC, Connolly CC, Moore MC, Neal DW, Cherrington AD. Physiological changes in circulating glucagon alter hepatic glucose disposition during portal glucose delivery. Am J Physiol. 1997;273(3 pt 1):E488-E496. (Pubitemid 27418754)
32. Shulman GI, Liljenquist JE, Williams PE, Lacy WW, Cherrington AD. Glucose disposal during insulinopenia in somatostatin-treated dogs. The roles of glucose and glucagon. J Clin Invest. 1978;62(2):487-491. (Pubitemid 8393319)
33. Roden M, et al. The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans. J Clin Invest. 1996;97(3):642-648. (Pubitemid 26057081)
34. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109(9):1125-1131. (Pubitemid 34496588)
35. Charlton MR, Adey DB, Nair KS. Evidence for a catabolic role of glucagon during an amino acid load. J Clin Invest. 1996;98(1):90-99. (Pubitemid 26243824)
36. Foa PP, Weinstein HR, Smith JA. Secretion of insulin and of a hyperglycemic substance studied by means of pancreatic-femoral cross-circulation experiments. Am J Physiol. 1949;157(2):197-204.
37. Ferner H. The A- and B-cells of the pancreatic islets as sources of the antagonistic hormones glucagon and insulin; the shift of the AB-relation in diabetes mellitus. Am J Dig Dis. 1953;20(10):301-306.
38. Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 1985;28(8):574-578. (Pubitemid 15017391)
39. Baum J, Simons BE Jr, Unger RH, Madison LL. Localization of glucagon in the alpha cells in the pancreatic islet by immunofluorescent technics. Diabetes. 1962;11:371-374.
40. Muller WA, Faloona GR, Unger RH. Hyperglucagonemia in diabetic ketoacidosis. Its prevalence and significance. Am J Med. 1973;54(1):52-57.
41. Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975;1(7897):14-16.
42. Samols E, Tyler J, Marks V. Glucagon insulin interrelationships. In: Lefebvre PJ, Unger RH, eds. Glucagon: Molecular Physiology, Clinical and Therapeutic Implications. Oxford, United Kindgom: Pergamon Press; 1972:157-174.
43. Braaten JT, Faloona GR, Unger RH. The effect of insulin on the alpha-cell response to hyperglycemia in long-standing alloxan diabetes. J Clin Invest. 1974;53(4):1017-1021.
44. Le Marchand SJ, Piston DW. Glucose suppression of glucagon secretion: metabolic and calcium responses from alpha-cells in intact mouse pancreatic islets. J Biol Chem. 2010;285(19):14389-14398.
45. Meier JJ, Ueberberg S, Korbas S, Schneider S. Diminished glucagon suppression after beta-cell reduction is due to impaired alpha-cell function rather than an expansion of alpha-cell mass. Am J Physiol Endocrinol Metab. 2011;300(4):E717-E723.
46. Flattem N, Igawa K, Shiota M, Emshwiller MG, Neal DW, Cherrington AD. Alpha- and beta-cell responses to small changes in plasma glucose in the conscious dog. Diabetes. 2001;50(2):367-375. (Pubitemid 32127294)
47. Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes. 1982;31(10):883-889. (Pubitemid 12013792)
48. Bosco D, et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes. 2010;59(5):1202-1210.
49. Meda P, Kohen E, Kohen C, Orci L. [Heterocellular coupling in cultures of endocrine pancreatic cells]. C R Seances Acad Sci III. 1981;293(10):607-610.
50. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A. 2006;103(7):2334-2339. (Pubitemid 43271670)
51. Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A. 2010;107(37):16009-16012.
52. Sherrington CS. Further experimental note on the correlation of action of antagonistic muscles. Br Med J. 1893;1:1218.
53. Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest. 1984;74(6):2296-2299. (Pubitemid 15197376)
54. Paranjape SA, et al. Chronic reduction of insulin receptors in the ventromedial hypothalamus produces glucose intolerance and islet dysfunction in the absence of weight gain. Am J Physiol. Endocrinol Metab. 2011;301(5):E978- E983.
55. Paranjape SA, et al. Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo. Diabetes. 2010;59(6):1521-1527.
56. Koerker DJ, et al. Somatostatin: hypothalamic inhibitor of the endocrine pancreas. Science. 1974;184(135):482-484.
57. Brazeau P, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179(68):77-79.
58. Dobbs R, et al. Glucagon: role in the hyperglycemia of diabetes mellitus. Science. 1975;187(4176):544-547.
59. Gerich JE, et al. Prevention of human diabetic ketoacidosis by somatostatin. Evidence for an essential role of glucagon. N Engl J Med. 1975;292(19):985-989.
60. Raskin P, Unger RH. Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. N Engl J Med. 1978;299(9):433-436. (Pubitemid 9011327)
61. Barnes AJ, Bloom SR. Pancreatectomised man: A model for diabetes without glucagon. Lancet. 1976;1(7953):219-221.
62. Blazquez E, Munoz-Barragan L, Patton GS, Orci L, Dobbs RE, Unger RH. Gastric A-cell function in insulin-deprived depancreatized dogs. Endocrinology. 1976;99(5):1182-1188. (Pubitemid 8001930)
63. Mashiter K, et al. Persistent pancreatic glucagon but not insulin response to arginine in pancreatectomized dogs. Endocrinology. 1975;96(3):678-693.
64. Muller WA, Girardier L, Seydoux J, Berger M, Renold AE, Vranic M. Extrapancreatic glucagon and glucagonlike immunoreactivity in depancreatized dogs. A quantitative assessment of secretion rates and anatomical delineation of sources. J Clin Invest. 1978;62(1):124-132. (Pubitemid 8367344)
65. Ravazzola M, Baetens D, Engerman R, Kovacevic N, Vranic M, Orci L. Endocrine cells in oxyntic mucosa of a dog 5 years after pancreatectomy. Horm Metab Res. 1977;9(6):480-483. (Pubitemid 8247979)
66. Munoz-Barragan L, Blazquez E, Patton GS, Dobbs RE, Unger RH. Gastric A-cell function in normal dogs. Am J Physiol. 1976;231(4):1057-1061.
67. Nakabayashi H, Dobbs RE, Unger RH. The role of glucagon deficiency in the Houssay phenomenon of dogs. J Clin Invest. 1978;61(5):1355-1362. (Pubitemid 8324161)
68. Bringer J, et al. Glucagon immunoreactivity and antidiabetic action of somatostatin in the totally duodeno-pancreatectomized and gastrectomized human. Diabetes. 1981;30(10):851-856. (Pubitemid 11020059)
69. Thorel F, et al. Normal glucagon signaling and {beta}- cell function after near-total {alpha}-cell ablation in adult mice. Diabetes. 2011;60(11):2872-2882.
70. Derr R, Garrett E, Stacy GA, Saudek CD. Is HbA(1c) affected by glycemic instability? Diabetes Care. 2003;26(10):2728-2733.
71. Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes. 2011;60(2):391-397.
72. Altarejos JY, Montminy M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12(3):141-151.
73. Brand CL, Jorgensen PN, Svendsen I, Holst JJ. Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic, and alloxan-induced diabetic rabbits. Diabetes. 1996;45(8):1076-1083. (Pubitemid 26260161)
74. Brand CL, Rolin B, Jorgensen PN, Svendsen I, Kristensen JS, Holst JJ. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia. 1994;37(10):985-993. (Pubitemid 24300455)
75. Rivera N, et al. A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther. 2007;321(2):743-752. (Pubitemid 46624501)
76. Cascieri MA, et al. Characterization of a novel, nonpeptidyl antagonist of the human glucagon receptor. J Biol Chem. 1999;274(13):8694-8697. (Pubitemid 29164665)
77. Parker JC, et al. Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes. Diabetes. 2000;49(12):2079-2086.
78. Petersen KF, Sullivan JT. Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia. 2001;44(11):2018-2024. (Pubitemid 33124047)
79. Qureshi SA, et al. A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes. 2004;53(12):3267-3273. (Pubitemid 39564504)
80. Unson CG, Gurzenda EM, Merrifield RB. Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides. 1989;10(6):1171-1177. (Pubitemid 20037265)
81. Ali S, Lamont BJ, Charron MJ, Drucker DJ. Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis. J Clin Invest. 2011;121(5):1917-1929.
82. Edgerton DS, Cherrington AD. Glucagon as a critical factor in the pathology of diabetes. Diabetes. 2011;60(2):377-380.
83. Bruning JC, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2(5):559-569. (Pubitemid 128379082)
84. Charron MJ, Gorovits N, Laidlaw JS, Ranalletta M, Katz EB. Use of GLUT-4 null mice to study skeletal muscle glucose uptake. Clin Exp Pharmacol Physiol. 2005;32(4):308-313. (Pubitemid 40586067)
85. Cherrington AD, Lacy WW, Chiasson JL. Effect of glucagon on glucose production during insulin deficiency in the dog. J Clin Invest. 1978;62(3):664-677. (Pubitemid 9006437)
86. Levetan C, et al. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care. 2003;26(1):1-8. (Pubitemid 36928987)
87. Buse JB, Weyer C, Maggs DG. Amylin replacement with pramlintide in type 1 1nd type 2 diabetes: a physiological approach to overcome barriers with insulin therapy. Clin Diabetes. 2002;20(3):137-144.
88. Nyholm B, et al. The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus. Metabolism. 1999;48(7):935-941. (Pubitemid 29310053)
89. Orskov L, Nyholm B, Yde Hove K, Gravholt CH, Moller N, Schmitz O. Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects. Diabet Med. 1999;16(10):867-874. (Pubitemid 29498227)
90. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372(6505):425-432. (Pubitemid 24365442)
91. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A. 2010;107(40):17391-17396.
92. Wang MY, et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A. 2010;107(11):4813-4819.
93. Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A. 2008; 105(37):14070-14075.
94. Kalra SP. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Peptides. 2009;30(10):1957-1963.
95. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. 2007;28(1):84-116. (Pubitemid 46220851)
96. Cherrinton AD. Control of glucose production in vivo by insulin and glucagon. In: Handbook of Physiology. Vol. 2. 2011:759-785.