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Glucagon and Ketogenesis

  • Chapter
Glucagon I

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 66 / 1))

Abstract

Although suspected to exist as a pancreatic hyperglycemic factor as early as 1923, isolated and crystallized by 1953, and measurable by radioimmunoassay since 1959, only in the last decade has glucagon become firmly established as a critical hormone in the minute-to-minute regulation of the blood glucose concentration. This aspect of glucagon physiology has been discussed in detail elsewhere in this volume. The purpose of the present chapter is to review a second area of fuel homeostasis in which the A-cell hormone has again emerged as a central regulatory factor, namely, the control of hepatic fatty acid metabolism and ketone body production. From an historical standpoint, the function of glucagon in this area gained recognition even more recently than its role in the regulation of glucose metabolism, most of the significant advances having been made only in the last 15 years or so. Not surprisingly, a number of interesting parallelisms between the two systems have begun to evolve. Thus, it now appears that the same bihormonal mechanism (reciprocal changes in the levels of insulin and glucagon), instrumental in permitting the liver to respond smoothly to periods of food deprivation with accelerated release of glucose, also induces production of ketone bodies to support the energy needs of the brain and peripheral tissues. By the same token, severe imbalance between the two hormones, such as occurs in uncontrolled diabetes, is now recognized as a primary factor in the etiology of the two major metabolic derangements associated with this disorder, namely, hyperglycemia and ketoacidosis.

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References

  • Alberti KGMM, Christensen NJ, Iversen J, Orskov H (1975) Role of glucagon and other hormones in development of diabetic ketoacidosis. Lancet 1: 1307–1311

    Article  PubMed  CAS  Google Scholar 

  • Bewsher PD, Ashmore J (1966) Ketogenic and lipolytic effects of glucagon on liver. Biochem Biophys Res Commun 24: 431–436

    Article  PubMed  CAS  Google Scholar 

  • Bewsher PD, Tarrant ME, Ashmore J (1966) Effect of fat mobilization on liver acetate metabolism. Diabetes 15: 346–350

    PubMed  CAS  Google Scholar 

  • Beynen AC, Vaartjes WJ, Geelen MJH (1979) Opposite effects of insulin and glucagon in acute hormonal control of hepatic lipogenesis. Diabetes 28: 828–835

    Article  PubMed  CAS  Google Scholar 

  • Beynen AC, Geelen MJH, Van den Bergh SG (1980) Short-term control of hepatic lipogenesis by insulin. Trends Biochem Sci 5: 288–290

    Article  CAS  Google Scholar 

  • Boden G, Owen OE, Rezvani I, Elfenbein BI, Quickel KE (1977) An islet cell carcinoma containing glucagon and insulin. Diabetes 26: 128–137

    Article  PubMed  CAS  Google Scholar 

  • Boyd ME, Albright EB, Foster DW, McGarry JD (1981) In vitro reversal of the fasting state of liver metabolism in the rat. Reevaluation of the roles of insulin and glucose. J Clin Invest 68: 142–152

    Article  PubMed  CAS  Google Scholar 

  • Clark DG, Rognstad R, Katz J (1974) Lipogenesis in rat hepatocytes. J Biol Chem 249: 2028–2036

    PubMed  CAS  Google Scholar 

  • Cook GA, Otto DA, Cornell NW (1980) Differential inhibition of ketogenesis by malonyl-CoA in mitochondria from fed and starved rats. Biochem J 192: 955–958

    PubMed  CAS  Google Scholar 

  • Davidson MB, Berliner JH (1974) Acute effects of insulin on carbohydrate metabolism in rat liver slices: independence from glucagon. Am J Physiol 227: 79–87

    PubMed  CAS  Google Scholar 

  • DeFronzo RA, Ferrannini E, Hendler R, Wahren J, Felig P (1978) Influence of hyperinsu- linemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 75: 5173–5177

    Article  PubMed  CAS  Google Scholar 

  • DiMarco JP, Hoppel C (1975) Hepatic mitochondrial function in ketogenic states. Diabetes, starvation and after growth hormone administration. J Clin Invest 55: 1237–1244

    Article  PubMed  CAS  Google Scholar 

  • Exton JH, Park CR (1972) Interaction of insulin and glucagon in the control of liver metabolism. In: Geiger SR (ed) Handbook of physiology, vol 1. American Physiological Society, Washington DC, pp 437–455

    Google Scholar 

  • Exton JH, Mallette LE, Jefferson LS, Wong EHA, Friedmann N, Miller TB Jr, Park CR (1970) The hormonal control of hepatic gluconeogenesis. Recent Prog Horm Res 26: 411–461

    PubMed  CAS  Google Scholar 

  • Feliu JE, Hue L, Hers HG (1976) Hormonal control of pyruvate kinase activity and of glu-coneogenesis in isolated hepatocytes. Proc Natl Acad Sci USA 73: 2762–2766

    Article  PubMed  CAS  Google Scholar 

  • Fritz IB (1961) Factors influencing the rates of long-chain fatty acid oxidation and synthesis in mammalian systems. Physiol Rev 41: 52–129

    PubMed  CAS  Google Scholar 

  • Furuya E, Uyeda K (1980) An activation factor of liver phosphofructokinase. Proc Natl Acad Sci USA 77: 5861–5864

    Article  PubMed  CAS  Google Scholar 

  • Geelen MJH (1977) Restoration of glycogenesis in hepatocytes from starved rats. Life Sci 20: 1027–1034

    Article  PubMed  CAS  Google Scholar 

  • Geelen MJH, Gibson DM (1975) Lipogenesis in maintenance cultures of rat hepatocytes. FEBS Lett 58: 334–339

    Article  PubMed  CAS  Google Scholar 

  • Geelen MJH, Harris RA, Beynen AC, McCune SA (1980) Short-term hormonal control of hepatic lipogenesis. Diabetes 29: 1006–1022

    PubMed  CAS  Google Scholar 

  • Gerich JE, Lorenzi M, Bier DM, Schneider V, Tsalikian E, Karam JH, Forsham PH (1975) Prevention of human diabetic ketoacidosis by somatostatin - evidence for an essential role of glucagon. N Engl J Med 292: 985–989

    Article  PubMed  CAS  Google Scholar 

  • Guynn RW, Veloso D, Veech RL (1972) The concentration of malonyl-Coenzyme A and the control of fatty acid synthesis in vivo. J Biol Chem 247: 7325–7331

    PubMed  CAS  Google Scholar 

  • Harano Y, Ohgaku S, Shimizu Y, Izumi K, Takahashi J, Shichiri M, Fukuchi M, Shigeta Y, Abe H (1977) Ketogenic action of glucagon in insulin-dependent diabetic subjects. Endocrinol Jpn 24: 121–128

    Article  PubMed  CAS  Google Scholar 

  • Harris RA, Mapes JP, Ochs RS, Crabb DW, Stropes L (1979) Hormonal control of hepatic lipogenesis. Adv Exp Med Biol 111: 17

    PubMed  CAS  Google Scholar 

  • Heimberg M, Weinstein I, Kohout M (1969) The effects of glucagon, dibutyryl cyclic adenosine 3’,5’-monophosphate, and concentration of free fatty acid on hepatic lipid metabolism. J Biol Chem 244: 5131–5139

    PubMed  CAS  Google Scholar 

  • Hems DA (1977) Short-term hormonal control of hepatic carbohydrate and lipid catabolism. FEBS Lett 80: 237–245

    Article  PubMed  CAS  Google Scholar 

  • Hems DA, Whitton PD, Taylor EA (1972) Glycogen synthesis in the perfused liver of the starved rat. Biochem J 129: 529–538

    PubMed  CAS  Google Scholar 

  • Hers HG (1976) The control of glycogen metabolism in the liver. Annu Rev Biochem 45:167 Katz J, Golden S, Wals PA (1976) Stimulation of hepatic glycogen synthesis by amino acids. Proc Natl Acad Sci USA 73: 3433–3437

    Google Scholar 

  • Katz J, Golden S, Wals PA (1979) Glycogen synthesis by rat hepatocytes. Biochem J 180: 389–402

    PubMed  CAS  Google Scholar 

  • Keller U, Chiasson JL, Liljenquist JE, Cherrington AD, Jennings AS, Crofford OB (1977) The roles of insulin, glucagon, and free fatty acids in the regulation of ketogenesis in dogs. Diabetes 26: 1040–1051

    PubMed  CAS  Google Scholar 

  • Lent BA, Lee K-H, Kim R-H (1978) Regulation of rat liver acetyl-CoA carboxylase: stimulation of phosphorylation and subsequent inactivation of liver acetyl-CoA carboxylase by cyclic 3’,5’-monophosphate and effect on the structure of the enzyme. J Biol Chem 253: 8149–8156

    PubMed  CAS  Google Scholar 

  • Masoro EJ (1965) Mechanisms related to the homeostatic regulation of lipogenesis. Ann NY Acad Sci 131: 199–206

    Article  PubMed  CAS  Google Scholar 

  • Mayes PA, Felts JM (1967) Regulation of fat metabolism in the liver. Nature 215: 716–718

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD (1978) New perspectives in the regulation of ketogenesis. Lilly Lecture 1978. Diabetes 28: 517–523

    Google Scholar 

  • McGarry JD, Foster DW (1971) Regulation of ketogenesis from octanoic acid. The role of the tricarboxylic acid cycle and fatty acid synthesis. J Biol Chem 246: 1149–1159

    PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1972) Regulation of ketogenesis and clinical aspects of the ketotic state. Metabolism 21: 471–489

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1976) Ketogenesis and its regulation. Am J Med 61: 9–13

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1977) Hormonal control of ketogenesis - biochemical considerations. Arch Intern Med 137: 495–501

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1979) In support of the roles of malonyl-CoA and carnitine acyl- transferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem 254: 8163–8168

    PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1980) Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 49: 395–420

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Foster DW (1981) Reaffirmation of the extreme sensitivity of mitochondrial fatty acid oxidation to inhibition by malonyl-CoA. Potential pitfalls in demonstrating the effect. Biochem J 200: 217–223

    PubMed  CAS  Google Scholar 

  • McGarry JD, Meier JM, Foster DW (1973) The effects of starvation and refeeding on carbohydrate and lipid metabolism in vivo and in the perfused rat liver. The relationship between fatty acid oxidation and esterification in the regulation of ketogenesis. J Biol Chem 248: 270–278

    PubMed  CAS  Google Scholar 

  • McGarry JD, Robles-Valdes C, Foster DW (1975) The role of carnitine in hepatic ketogenesis. Proc Natl Acad Sci USA 72: 4385–4388

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Wright PH, Foster DW (1975) Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by antiinsulin serum and glucagon. J Clin Invest 55: 1202–1209

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Mannaerts GP, Foster DW (1977) A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 60: 265–270

    Article  PubMed  CAS  Google Scholar 

  • Menahan LA, Wieland O (1969) The role of endogenous lipid in gluconeogenesis and ketogenesis of perfused rat liver. Eur J Biochem 9: 182–188

    Article  PubMed  CAS  Google Scholar 

  • Miller TB Jr, Larner J (1973) Mechanism of control of hepatic glycogenesis by insulin. J Biol Chem 248: 3483–3488

    PubMed  CAS  Google Scholar 

  • Ontko J A, Johns ML (1980) Evaluation of malonyl-CoA in the regulation of long-chain fatty acid oxidation in the liver. Biochem J 192: 959–962

    PubMed  CAS  Google Scholar 

  • Pilkis SJ, El-Maghrabi MR, Pilkis J, Claus TH, Cumming DA (1981) Fructose 2,6-bisphos-phate, a new activator of phosphofructokinase. J Biol Chem 256: 3171–3174

    PubMed  CAS  Google Scholar 

  • Richards CS, Uyeda K (1980) Changes in the concentration of activation factor for phos-phofructokinase in hepatocytes in response to glucose and glucagon. Biochem Biophys Res Commun 97: 1535–1540

    Article  PubMed  CAS  Google Scholar 

  • Robles-Valdes C, McGarry JD, Foster DW (1976) Maternal-fetal carnitine relationships and neonatal ketosis in the rat. J Biol Chem 251: 6007–6012

    PubMed  CAS  Google Scholar 

  • Schade DS, Eaton RP (1975) Glucagon regulation of plasma ketone body concentration in human diabetes. J Clin Invest 56: 1340–1344

    Article  PubMed  CAS  Google Scholar 

  • Seglen PO (1974) Autoregulation of glycolysis, respiration, gluconeogenesis and glycogen synthesis in isolated parenchymal rat liver cells and aerobic and anaerobic conditions. Biochim Biophys Acta 338: 317–336

    Article  CAS  Google Scholar 

  • Tzur R, Tal E, Shapiro B (1964) Alpha-glycerophosphate as regulatory factor in fatty acid esterification. Biochim Biophys Acta 84: 18–23

    PubMed  CAS  Google Scholar 

  • Van Schaftingen E, Hue L, Hers H-G (1980) Fructose 2,6-bisphosphate, the probable structure of the glucose- and glucagon-sensitive stimulator of phosphofructokinase. Biochem J 192: 897–901

    PubMed  Google Scholar 

  • Wieland O, Matschinsky F (1962) Zur Natur der antiketogenen Wirkung von Glycerin und Fructose. Life Sci 2: 49–54

    Article  Google Scholar 

  • Woodside WF (1979) Influence of insulin and glucagon on ketogenesis by isolated rat hepatocytes. Adv Exp Med Biol 111: 97

    PubMed  CAS  Google Scholar 

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Authors
  1. J. D. McGarry
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  2. D. W. Foster
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Editor information

Editors and Affiliations

  1. University of Liège, Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

  2. University of Brussels (V.U.B.), Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

  3. Royal Academy of Medicine of Belgium, Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

  4. Medical Policlinics, University of Liège, Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

  5. Division of Diabetes, University of Liège, Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

  6. Institut de Mèdecine, Hôpital de Bavière, Boulevard de la Constitution, 66, 4020, Liège, Belgium

    Pierre J. Lefèbvre M.D (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head) (Professor of Medicine, Guest Professor, Corresponding Member, Chairman, Head)

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© 1983 Springer-Verlag Berlin Heidelberg

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McGarry, J.D., Foster, D.W. (1983). Glucagon and Ketogenesis. In: Lefèbvre, P.J. (eds) Glucagon I. Handbook of Experimental Pharmacology, vol 66 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68866-9_17

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  • DOI: https://doi.org/10.1007/978-3-642-68866-9_17

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-68868-3

  • Online ISBN: 978-3-642-68866-9

  • eBook Packages: Springer Book Archive

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