, Volume 57, Issue 7, pp 1287–1290 | Cite as

Insulin release: the receptor hypothesis

  • Willy J. MalaisseEmail author


It is currently believed that the stimulation of insulin release by nutrient secretagogues reflects their capacity to act as fuel in pancreatic islet beta cells. In this review, it is proposed that such a fuel concept is not incompatible with a receptor hypothesis postulating the participation of cell-surface receptors in the recognition of selected nutrients as insulinotropic agents. Pursuant to this, attention is drawn to such matters as the anomeric specificity of the beta cell secretory response to d-glucose and its perturbation in diabetes mellitus, the insulinotropic action of artificial sweeteners, the possible role of bitter taste receptors in the stimulation of insulin secretion by l-glucose pentaacetate, the recently documented presence of cell-surface sweet taste receptors in insulin-producing cells, the multimodal signalling process resulting from the activation of these latter receptors, and the presence in beta cells of a sweet taste receptor mediating the fructose-induced potentiation of glucose-stimulated insulin secretion.


Bitter taste receptor Insulin release Pancreatic islet beta cells Sweet taste receptor 


Duality of interest

The author declares that there is no duality of interest associated with this manuscript.

Contribution statement

WJM was responsible for the conception and design of the manuscript.


  1. 1.
    Malaisse WJ, Sener A, Herchuelz A, Hutton JC (1979) Insulin release: the fuel hypothesis. Metabolism 28:373–386PubMedCrossRefGoogle Scholar
  2. 2.
    Malaisse WJ (1983) Insulin release: the fuel concept. Diabete Metab 9:313–320PubMedGoogle Scholar
  3. 3.
    Matschinsky FM, Ellerman J, Stillings S, Raybaud F, Pace C, Zawalich W (1975) Hexoses and insulin secretion. In: Hasselblatt A, Bruchhausen FV (eds) Insulin (part 2). Springer, Heidelberg, pp 79–114Google Scholar
  4. 4.
    Meglasson MD, Matschinsky FM (1984) New perspectives on pancreatic islet glucokinase. Am J Physiol 246:E1–E13PubMedGoogle Scholar
  5. 5.
    Garfinkel D, Garfinkel L, Meglasson MD, Matschinsky FM (1984) Computer modelling identifies glucokinase as glucose sensor of pancreatic B cell. Am J Physiol 247:R527–R536PubMedGoogle Scholar
  6. 6.
    Malaisse WJ, Sener A (1985) Glucokinase is not the pancreatic B cell glucoreceptor. Diabetologia 28:520–527PubMedCrossRefGoogle Scholar
  7. 7.
    Malaisse WJ (1987) Insulin release: the glucoreceptor myth. Med Sci Res 15:65–67Google Scholar
  8. 8.
    Hellman B, Sehlin J, Täljedal IB (1971) Evidence for mediated transport of glucose in mammalian pancreatic B cells. Biochim Biophys Acta 241:147–154PubMedCrossRefGoogle Scholar
  9. 9.
    Price S (1973) Pancreatic islet membranes: extraction of a possible glucoreceptor. Biochim Biophys Acta 318:459–463CrossRefGoogle Scholar
  10. 10.
    Bollen M, Malaisse-Lagae F, Malaisse W, Stalmans W (1990) The interaction of phosphorylase a with d-glucose displays α-stereospecificity. Biochim Biophys Acta 1038:141–145PubMedCrossRefGoogle Scholar
  11. 11.
    Malaisse WJ (1991) The anomeric malaise: a manifestation of B cell glucotoxicity. Horm Metab Res 23:307–311PubMedCrossRefGoogle Scholar
  12. 12.
    Marynissen G, Leclercq-Meyer V, Sener A, Malaisse WJ (1990) Perturbation of pancreatic islet function in glucose-infused rats. Metabolism 39:87–95PubMedCrossRefGoogle Scholar
  13. 13.
    Malaisse WJ, Marynissen G, Sener A (1992) Possible role of glycogen accumulation in B cell glucotoxicity. Metabolism 41:814–819PubMedCrossRefGoogle Scholar
  14. 14.
    Malaisse WJ, Maggetto C, Leclercq-Meyer V, Sener A (1993) Interference of glycogenolysis with glycolysis in pancreatic islets from glucose-infused rats. J Clin Invest 91:432–436PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Malaisse WJ, Sener A, Malaisse-Lagae F (1981) Insulin release: reconciliation of the receptor and metabolic hypotheses. Nutrient receptors in islet cells. Mol Cell Biochem 37:157–165PubMedCrossRefGoogle Scholar
  16. 16.
    Rovira A, Garrotte FJ, Valverde I, Malaisse WJ (1987) Anomeric specificity of glucose-induced insulin release in normal and diabetic subjects. Diabetes Res 5:119–124PubMedGoogle Scholar
  17. 17.
    Niki A, Niki H (1975) Is diabetes mellitus a disorder of the glucoreceptor? Lancet 2:658PubMedCrossRefGoogle Scholar
  18. 18.
    Malaisse-Lagae F, Malaisse WJ (1986) Abnormal identification of the sweet taste of d-glucose anomers. Diabetologia 29:344–345 (Letter)PubMedCrossRefGoogle Scholar
  19. 19.
    Malaisse WJ, Vanonderbergen A, Louchami K, Jijakli H, Malaisse-Lagae F (1998) Effects of artificial sweeteners on insulin release and cationic fluxes in rat pancreatic islets. Cell Signal 10:727–733PubMedCrossRefGoogle Scholar
  20. 20.
    Malaisse WJ (1998) The riddle of l-glucose pentaacetate insulinotropic action. Int J Mol Med 2:383–388PubMedGoogle Scholar
  21. 21.
    Malaisse WJ, Malaisse-Lagae F (1997) Bitter taste of monosaccharide pentaacetate esters. Biochem Mol Biol Int 43:1367–1371PubMedGoogle Scholar
  22. 22.
    Pomares R, Ropero AB, Sanchez-Andres JV, Nadal A, Soria B, Malaisse WJ (1999) Effect of hexose pentaacetates on electrical activity and cytosolic Ca2+ in mouse pancreatic islets. Int J Mol Med 3:15–20PubMedGoogle Scholar
  23. 23.
    Malaisse WJ, Best LC, Herchuelz A, et al (1998) Insulinotropic action of β-l-glucose pentaacetate. Am J Physiol 275:E993-El006.Google Scholar
  24. 24.
    Leclercq-Meyer V, Malaisse WJ (1998) Dual mode of action of glucose pentaacetates on hormonal secretion from the isolated perfused rat pancreas. Am J Physiol 275:E610–E617PubMedGoogle Scholar
  25. 25.
    Straub SG, Mulvaney-Musa J, Yajima H, Weiland GA, Sharp GWG (2003) Stimulation of insulin secretion by denatonium, one of the most bitter-tasting substances known. Diabetes 52:356–364PubMedCrossRefGoogle Scholar
  26. 26.
    Nakagawa Y, Nagasawa M, Yamada S et al (2009) Sweet taste receptor expressed in pancreatic beta-cells activate the calcium and cyclic AMP signalling systems and stimulates insulin secretion. PLoS ONE 4:e5106PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Kojima I, Nakagawa Y (2011) The role of the sweet taste receptor in enteroendocrine cells and pancreatic β-cells. Diabetes Metab J 34:451–457CrossRefGoogle Scholar
  28. 28.
    Nakagawa Y, Nagasawa M, Mogami H, Lohse M, Ninomiya Y, Kojima I (2013) Multinodal function of the sweet taste receptor expressed in pancreatic β-cells: generation of diverse patterns of intracellular signals by sweet agonists. Endocr J 60:1191–1206PubMedCrossRefGoogle Scholar
  29. 29.
    Nakagawa Y, Ohtsu Y, Nagasawa M, Shibata H, Kojima I (2013) Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3. Endocr J 10:1507Google Scholar
  30. 30.
    Malaisse WJ (2014) d-fructose metabolism and insulinotropic action in pancreatic islets: metabolic aspects. Curr Top Biochem Res (in press).Google Scholar
  31. 31.
    Malaisse WJ (2014) d-fructose metabolism and insulinotropic action in pancreatic islets: functional aspects. Curr Top Biochem Res (in press).Google Scholar
  32. 32.
    Malaisse WJ (2014) d-fructose metabolism and insulinotropic action in pancreatic islets: pathological aspects. Curr Top Biochem Res (in press).Google Scholar
  33. 33.
    Giroix M-H, Agascioglu E, Oguzhan B et al (2006) Opposite effects of d-fructose on total versus cytosolic ATP/ADP ratio in rat pancreatic islet cells. Biochim Biophys Acta 1757:773–780PubMedCrossRefGoogle Scholar
  34. 34.
    Sener A, Blachier F, Malaisse WJ (1990) Hexose metabolism in pancreatic islets: comparison and interaction between d-glucose and d-fructose. Turk J Med Biol Res 1:5–12Google Scholar
  35. 35.
    Sener A, Malaisse WJ (1996) Hexose metabolism in pancreatic islets: apparent dissociation between the secretory and metabolic effects of d-fructose. Biochem Mol Med 59:182–186PubMedCrossRefGoogle Scholar
  36. 36.
    Viñambres C, Villanueva-Peñacarrillo ML, Valverde I, Malaisse WJ (1997) Failure of d-fructose to stimulate protein biosynthesis in pancreatic islets. Biochem Mol Biol Int 41:571–574PubMedGoogle Scholar
  37. 37.
    Giroix M-H, Scruel O, Ladrière L, Sener A, Portha B, Malaisse WJ (1999) Metabolic and secretory interactions between d-glucose and d-fructose in islets from GK rats. Endocrinology 140:5556–5565PubMedGoogle Scholar
  38. 38.
    Scruel O, Giroix M-H, Sener A, Portha B, Malaisse WJ (1999) Metabolic and secretory response to d-fructose in islets from adult rats injected with streptozotocin during the neonatal period. Mol Genet Metab 68:86–90PubMedCrossRefGoogle Scholar
  39. 39.
    Kyriazis GA, Soundarapandian MM, Tyrberg B (2012) Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc Natl Acad Sci U S A 109:E524–E532PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of BiochemistryUniversité Libre de BruxellesBrusselsBelgium

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