, Volume 18, Issue 1, pp 5–15 | Cite as

Glucoreceptor mechanisms and the control of insulin release and biosynthesis

  • S. J. H. Ashcroft
Review Articles


The models proposed for the means whereby the B-cell recognises glucose and related compounds as signals for insulin release and biosynthesis are discussed. The observed correlations between rates of metabolism and insulin release and biosynthesis are consistent with the substrate-site hypothesis. For glucose itself, the enzymes catalysing the phosphorylation of the sugar provide an explanation for the major characteristics of the islet responses, but for N-acetylglucosamine evidence is presented that the sugar transport system fulfils this discriminatory role. Possible mechanisms whereby sugar metabolism may be linked to changes in Ca2+-handling are considered and evidence is given supporting a role for the cytosolic NADPH/NADP+ ratio and the islet content of phosphoenolpyruvate. The nature of the targets for cyclic AMP and Ca2+ is discussed and some properties of islet cAMP-dependent protein kinase are summarised. Evidence is presented for the presence of calmodulin in islets and the possible involvement of calmodulin in stimulussecretion coupling. On the basis of these considerations a speculative hypothesis for the mechanisms involved in the B-cell responses to glucose is out lined.


  1. 1.
    Hellerstrom C (1964) Method for microdissection of intact pancreatic islets of mammals. Acta Endocrinol(Kbh) 45: 122–132Google Scholar
  2. 2.
    Moskalewski S (1965) Isolation and culture of the islets of Langerhans of the guinea pig. Gen Comp Endocrinol 5: 342–353Google Scholar
  3. 3.
    Keen H, Sells R, Jarrett RJ (1965) A method for the study of the metabolism of isolated mammalian islets of Langerhans and some preliminary results. Diabetolgia 1: 28–32Google Scholar
  4. 4.
    Coore HG, Randle PJ (1964) Regulation of insulin secretion studied with pieces of rabbit pancreas incubated in vitro. Biochem J 93: 66–78PubMedGoogle Scholar
  5. 5.
    Grodsky GM, Batts AA, Bennett LL, Vcella C, McWilliams NB, Smith DF (1963) Effects of carbohydrates on secretion of insulin from isolated rat pancreas. Am J Physiol 205: 638–644PubMedGoogle Scholar
  6. 6.
    Randle PJ, Ashcroft SJH, Gill JR (1968) Carbohydrate metabolism and release of hormones. In: Dickens F, Randle PJ, Whelan WJ (eds) Vol 1. Academic Press, London, p 427–447Google Scholar
  7. 7.
    Grodsky GM, Bennett LL (1966) Cation requirements for insulin secretion in the isolated perfused pancreas. Diabetes 15: 910–913PubMedGoogle Scholar
  8. 8.
    Milner RDG, Hales CN (1968) Cations and the secretion of insulin. Biochim Biophys Acta 150: 165–167PubMedGoogle Scholar
  9. 9.
    Malaisse-Lagae F, Malaisse WJ (1971) Stimulus-secretion coupling of glucose-induced insulin release. III Uptake of45calcium by isolated islets of Langerhans. Endocrinology 88: 72–80PubMedGoogle Scholar
  10. 10.
    Malaisse WJ (1977) Calcium fluxes and insulin release in pancreatic islets. Biochem Soc Trans 5: 872–875PubMedGoogle Scholar
  11. 11.
    Hellman B, Sehlin J, Täljedal I-B (1976) Effects of glucose on45Ca2+-uptake by pancreatic islets as studied with the lanthanum method. J Physiol (Lond) 254: 639–656Google Scholar
  12. 12.
    Frankel BJ, Kromhout JA, Imagawa W, Landahl HD, Grodsky GM (1978) Glucose-stimulated Ca-45 uptake in isolated rat islets. Diabetes 27: 365–369PubMedGoogle Scholar
  13. 13.
    R-Candela JL, R-Candela R, Hernandez DM, Castilla-Cortazar T (1963) Insulin secretion in vitro. In: Cori CF, Foglia VG, Leloir LF, Ochoa S (eds) Perspectives in biology. Elsevier Publishing Co., Amsterdam, p 105–107Google Scholar
  14. 14.
    Ashcroft SJH, Weerasinghe LCC, Randle PJ (1973) Interrelationships of islet metabolism, adenosine triphosphate content and insulin release. Biochem J 132: 223–231PubMedGoogle Scholar
  15. 15.
    Ashcroft SJH, Bassett JM, Randle PJ (1972) Insulin secretion mechanisms. Diabetes 21 (Suppl 2): 538–545PubMedGoogle Scholar
  16. 16.
    Ashcroft SJH, Bunce J, Lowry M, Hansen SE, Hedeskov CJ (1978) The effect of sugars on (pro)insulin biosynthesis. Biochem J 174: 517–526PubMedGoogle Scholar
  17. 17.
    Ashcroft SJH, Lowry M (1979)β-Cell recognition of steroisomers of D-glucose. Diabetologia 17: 165–168PubMedGoogle Scholar
  18. 18.
    Zawalich WS, Rognstad R, Pagliara AS, Matschinsky FM (1977) A comparison of the utilization rates and hormonereleasing actions of glucose, mannose and fructose in isolated pancreatic islets. J Biol Chem 252: 8519–8523PubMedGoogle Scholar
  19. 19.
    Capito K, Hedeskov CJ (1976) Inosine-stimulated insulin release and metabolism of inosine in isolated mouse pancratic islets. Biochem J 158: 335–340PubMedGoogle Scholar
  20. 20.
    Hellman B, Idahl L-Å, Lemmark Å, Sehlin J, Täljedal I-B (1974) The pancreaticβ-cell recognition of insulin secretagogues. Comparison of glucose with glyceraldehyde isomers and dihydroxyacetone. Arch Biochem Biophys 162: 448–457PubMedGoogle Scholar
  21. 21.
    Malaisse WJ, Malaisse-Lagae F, Wright PH (1967) A new method for the measurement in vitro of pancreatic insulin secretion. Endocrinology 80: 99–108PubMedGoogle Scholar
  22. 22.
    Ashcroft SJH, Weerasinghe LCC, Bassett JM, Randle PJ (1972) The pentose cycle and insulin release in mouse pancreatic islets. Biochem J 126: 525–532PubMedGoogle Scholar
  23. 23.
    Williams IH, Ashcroft SJH (1978) N-acetylglucosamine and the substrate-site hypothesis for the control of insulin biosyntheses and secretion. FEBS Lett 87: 115–120PubMedGoogle Scholar
  24. 24.
    Ashcroft S J H, Sugden M C, Williams I H (In press) Carbohydrate metabolism and the glucoreceptor mechanism. Horm Metab ResGoogle Scholar
  25. 25.
    Ashcroft SJH, Crossley JR, Crossley PC (1976) The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in rat pancreatic islets. Biochem J 154: 701–707PubMedGoogle Scholar
  26. 26.
    Zawalich WS, Pagliara AS, Matschinsky FM (1977) Effects of iodoacetate, mannoheptulose and 3-0-methylglucose on secretory function and metabolism of isolated pancreatic islets. Endocrinology 100: 1276–1283PubMedGoogle Scholar
  27. 27.
    Matschinsky FM, Ellermann J (1973) Dissociation of the insulin-releasing and the metabolic functions of hexoses in islets of Langerhans. Biochem Biophys Res Commun 50: 193–199PubMedGoogle Scholar
  28. 28.
    Malaisse WJ, Sener A, Koser M, Herchuelz A (1976) Stimulus-secretion coupling of glucose-induced insulin release. Metabolism ofα- andβ-D-glucose in isolated islets. J Biol Chem 251: 5936–5943PubMedGoogle Scholar
  29. 29.
    Malaisse WJ, Sener A, Koser M, Ravazzola M, Malaisse-Lagae F (1977) The stimulus-secretion coupling of glucose-induced insulin release. Insulin release due to glycogenolysis in glucose-deprived islets. Biochem J 164: 447–454PubMedGoogle Scholar
  30. 30.
    Ashcroft SJH (1978) The use of glucose analogues in the elucidation of the mechanisms of insulin release and biosynthesis. FEBS 11th Meeting. In: Esmann V (ed) Regulatory mechanisms of carbohydrate metabolism, Vol 42, Symposium AI, Pergamon Press, Oxford, p 227–236Google Scholar
  31. 31.
    Ashcroft SJH, Nino S (1978) Effects of phloretin and dextranlinked phloretin on pancreatic islet metabolism and insulin release. Biochim Biophys Acta 538: 334–342PubMedGoogle Scholar
  32. 32.
    Davis B, Lazarus N (1976) As in vitro system for studying insulin release caused by secretory granules-plasma membrane interaction: definition of the system. J Physiol (Lond) 256: 709Google Scholar
  33. 33.
    Hellman B, Sehlin J, Täljedal I-B (1971) Evidence for mediated transport of glucose in mammalian pancreaticβ-cells. Biochim Biophys Acta 241: 147–154PubMedGoogle Scholar
  34. 34.
    Ashcroft SJH, Randle PJ (1970) Enzymes of glucose metabolism in normal mouse islets. Biochem J 119: 5–15PubMedGoogle Scholar
  35. 35.
    Matschinsky FM, Ellermann JE (1968) Metabolism of glucose in the islets of Langerhans. J Biol Chem 243: 2730–2736PubMedGoogle Scholar
  36. 36.
    Hellman B, Lernmark Å, Sehlin J, Täljedal I-B (1972) Effects of phloridzin on metabolism and functions of pancreaticβ-cells. Metabolism 21: 60–66PubMedGoogle Scholar
  37. 37.
    Malaisse WJ, Sener A, Levy J (1976) The stimulus-secretion coupling of glucose-induced insulin release. Fasting-induced adaptation in key glycolytic enzymes in isolated islets. J Biol Chem 251: 1731–1737PubMedGoogle Scholar
  38. 38.
    Täljedal I-B (1969) Presence, induction and possible role of glucose 6-phosphatase in mammalian pancreatic islets. Biochem J 114: 387–394PubMedGoogle Scholar
  39. 39.
    Ashcroft SJH, Randle PJ (1970) Glucose phosphorylation and glucose oxidation in mouse pancreatic islets and the release of insulin. In: Falkmer S, Hellman B, Täljedal I-B (eds) The structure and metabolism of the pancreatic islets. Pergamon Press, Oxford, p 225–232Google Scholar
  40. 40.
    Ashcroft SJH, Randle PJ (1969) Metabolism and insulin secretion in isolated islets. Acta Diabetol Lat 6 (Suppl 1): 538–553PubMedGoogle Scholar
  41. 41.
    Williams I H (1978) D. Phil. Thesis, University of OxfordGoogle Scholar
  42. 42.
    Zawalich WS, Dye ES, Matschinsky FM (1979) Metabolism and insulin-releasing capabilities of glucosamine and N-acetyl-glucosamine in isolated rat islets. Biochem J 180: 145–152PubMedGoogle Scholar
  43. 43.
    Ashcroft SJH (1976) The control of insulin release by sugars, In: Porter R, Fitzsimons DW (eds) Ciba Fdn. Symposium 41 (New Series). Elsevier/Excerpta Medica, Amsterdam, p 117–139Google Scholar
  44. 44.
    McDaniel ML, Weaver DC, Roth CE, Fink CJ, Swanson JA, Lacy PE (1977) Characterization of uptake of methylxanthines theophylline and caffeine in isolated pancreatic islets and their effect on D-glucose transport. Endocrinology 101: 1701–1708PubMedGoogle Scholar
  45. 45.
    Hellman B, Sehlin J, Täljedal I-B (1973) Transport of 3-0-methylglucose into mammalian pancreaticβ-cells. Pflügers Arch 340: 51–58Google Scholar
  46. 46.
    Panten U, Christians J, Kriegstein EV, Poser W, Hasselblatt A (1973) Effect of carbohydrates upon fluorescence of reduced pyridine nucleotides from perifused isolated pancreatic islets. Diabetologia 9: 477–482PubMedGoogle Scholar
  47. 47.
    Panten U, Christians J, Kriegstein Ev, Poser W, Hasselblatt A (1974) Studies on the mechanism of L-leudne and α-ketoisocaproic acid-induced insulin release from perifused isolated pancreatic islets. Diabetologia 10: 149–154PubMedGoogle Scholar
  48. 48.
    Malaisse WJ, Hutton JC, Kawazu S, Herchuelz A, Valverde I, Sener A (1979) The stimulus-secretion coupling of glucoseinduced insulin release. The links between metabolic and cationic events. Diabetologia 16: 331–341PubMedGoogle Scholar
  49. 49.
    Malaisse WJ, Sener A, Herchuelz A, Hutton JC (1979) Insulin release: the fuel hypothesis. Metabolism 28: 373–386PubMedGoogle Scholar
  50. 50.
    Sener A, Kawazu S, Hutton JC, Boschero AC, Devis G, Somers G, Herchuelz A, Malaisse WJ (1978) The stimulus-secretion coupling of glucose-induced insulin release. Effect of exogenous pyruvate upon islet function, Biochem J 176: 217–232PubMedGoogle Scholar
  51. 51.
    Ammon HPT, Verspohol E (1976) Pyridine nucleotides in pancreatic islets during inhibition of insulin release by exogenous insulin. Endocrinology 99: 1469–1476PubMedGoogle Scholar
  52. 52.
    Malaisse WJ, Hutton JC, Kawazu S, Sener A (1978) The stimulus-secretion coupling of glucose-induced insulin release. Metabolic effects of menadione in isolated islets. Eur J Biochem 87: 121–130PubMedGoogle Scholar
  53. 53.
    Malaisse WJ, Sener A, Boschero AC, Kawazu S, Devis G, Somers G (1978) The stimulus-secretion coupling of glucose-induced insulin release. Cationic and secretory effects of menadione in the endocrine pancreas. Eur J Biochem 87: 111–120PubMedGoogle Scholar
  54. 54.
    Sener A, Hutton JC, Kawazu S, Boschero AC, Somers G, Devis G, Herchuelz A, Malaisse WJ (1978) The stimulus-secretion coupling of glucose-induced insulin release. The effect of NH4 + upon islet function. J Clin Invest 62: 868–878PubMedGoogle Scholar
  55. 55.
    Ammon HPT, Verspohl EJ (1979) Effect of methylene blue on pyrdine nucleotides and insulin secretion of rat pancreatic islets. Diabetologia 17: 41–44PubMedGoogle Scholar
  56. 56.
    Veech RL, Eggleston LV, Krebs HA (1969) The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver. Biochem. J 115: 609–619PubMedGoogle Scholar
  57. 57.
    Ammon HPT, Akhtar MS, Niklas H, Hegner D (1977) Inhibition of p-chloromercuribenzoate- and glucose-induced insulin release in vitro by methylene blue, diamide and tert-butyl-hydroperoxide. Mol Pharmacol 13: 598–605PubMedGoogle Scholar
  58. 58.
    Hellman B, Lernmark Å, Sehlin J, Söderberg M, Täljedal I-B (1978) On the possible role of thiol groups in the insulin releasing action of mercurials, organic disulfides, alkylating agents and sulfonylureas. Endocrinology 99: 1398–1406Google Scholar
  59. 59.
    Henquin JC (1978) D-glucose inhibits potassium efflux from pancreatic islet cells. Nature 271: 271–273PubMedGoogle Scholar
  60. 60.
    Henquin JC Meissner HP (1978) Valinomycin inhibition of insulin release and alteration of the electrical properties of pancreaticβ-cells. Biochim Biophys Acta 543: 455–464PubMedGoogle Scholar
  61. 61.
    Matthews EK, Sakamoto Y (1975) Pancreatic islet cells: electrogenic and electrodiffusional control of membrane potential. J Physiol (Lond) 246: 439–457Google Scholar
  62. 62.
    Meissner HP (1976) Electrical characterisation of the beta-cells in pancreatic islets. J Physiol (Paris) 72: 757–767Google Scholar
  63. 63.
    Henquin JC (1977) Tetraethylammonium potentiation of insulin release and inhibition of rubidium efflux in pancreatic islets. Biochem Biophys Res Commun 77: 551–556PubMedGoogle Scholar
  64. 64.
    Howell SL, Tyhurst M (1976) Barium accumulation in rat pancreaticβ-cells. J Cell Sci 22: 445–465Google Scholar
  65. 65.
    Sugden MC, Ashcrofts JH (1978) Effects of phosphoenolpyruvate, other glycolytic intermediates and methylxanthines on calcium uptake by a mitochondrial fraction from rat pancreatic islets. Diabetologia 15: 173–180PubMedGoogle Scholar
  66. 66.
    Sugden MC, Ashcroft SJH (1977) Phosphoenolpyruvate in rat pancreatic islets: a possible intracellular trigger of insulin release. Diabetologia 13: 481–486PubMedGoogle Scholar
  67. 67.
    Sugden MC, Ashcroft SJH, Sugden PH (1979) Proteinkinase activities in rat pancreatic islets of Langerhans. Biochem J 180: 219–229PubMedGoogle Scholar
  68. 68.
    Sharp GWG (1979) The adenylate cyclase-cyclic AMP system in islets of Langerhans and its role in the control of insulin release. Diabetologia 16: 287–296PubMedGoogle Scholar
  69. 69.
    Kretsinger RH (1976) Calcium binding proteins. Annu Rev Biochem 45: 239–266PubMedGoogle Scholar
  70. 70.
    Cheung WY(1971) Cyclic 3′5′-nucleotidephosphodiesterase: evidence for and properties of a protein activator. J Biol Chem 246: 2859–2869PubMedGoogle Scholar
  71. 71.
    Cheung WY, Bradham LS, Lynch TJ, Lin YM, Tallant EA (1975) Protein activator of cyclic 3′5′nucleotide phospho-diesterase of bovine or rat brain also activates its adenylate cyclase. Biochem Biophys Res Commun 66: 1055–1062PubMedGoogle Scholar
  72. 72.
    Gopinath RM, Vincenzi FF (1977) Phosphodiesterase protein activator mimics red blood cell cytoplasmic activator of (Ca2+-Mg2+)ATPase. Biochem Biophys Res Commun 77: 1203–1209PubMedGoogle Scholar
  73. 73.
    Cohen P, Burchell A, Foulkes JG, Cohen PTW, Vanaman TC, Nairn AC (1978) Identification of the Ca2+-dependent modulator protein as the fourth sub-unit of rabbit skeletal muscle phosphorylase kinase. FEBS Lett 92: 287–293PubMedGoogle Scholar
  74. 74.
    Wang JM, Teo TS, Ho HC, Stevens FC (1975) Bovine heart protein activator of cyclic nucleotide phosphodiesterase. Adv Cyclic Nucleotide Res 5: 179–194PubMedGoogle Scholar
  75. 75.
    Schulman H, Greengard P (1978) Ca2+-dependent protein phosphorylation system in membranes from various tissues and its activation by “calcium-dependent regulator”. Proc Natl Acad Sci 75: 5432–5436PubMedGoogle Scholar
  76. 76.
    Marcum JM, Dedman JR, Brinkley BR, Means AR (1978) Control of microtubule assembly-disassembly by calcium-dependent regulator protein. Proc Natl Acad Sci 75: 3771–3775PubMedGoogle Scholar
  77. 77.
    Sugden MC, Christie MR, Ashcroft SJH (1979) Presence and possible role of calcium-dependent regulator (calmodulin) in rat islets of Langerhans. FEBS Lett 105: 95–100PubMedGoogle Scholar
  78. 78.
    Levin RM, Weiss B (1977) Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phospho-diesterase. Mol Pharmacol 13: 690–697PubMedGoogle Scholar
  79. 79.
    Sener A, Malaisse WJ (1978) The metabolism of glucose in pancreatic islets. Diabete Metab 4: 127–133PubMedGoogle Scholar
  80. 80.
    Sieghart W, Theoharides T, Alper SL, Douglas WW, Greengard P (1978) Calcium-dependent protein phosphorylation during secretion by exocytosis in the mast cell. Nature 275: 329–331PubMedGoogle Scholar
  81. 81.
    Ernst V, Levin DH, London IM (1978) Evidence that glucose 6-phosphate regulates protein synthesis initiation in reticulocyte lysates. J Biol Chem 253: 167163–7172Google Scholar

Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • S. J. H. Ashcroft
    • 1
  1. 1.Nuffield Department of Clinical BiochemistryJohn Radcliffe HospitalHeadingtonEngland

Personalised recommendations