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. 2006 Nov 9;32(3-4):289–306. doi: 10.1007/s10867-006-9017-9

Time-dependent Mechanisms in Beta-cell Glucose Sensing

Thomas Vagn Korsgaard 1, Morten Colding-Jørgensen 1,✉
PMCID: PMC2651527  PMID: 19669468

Abstract

The relation between plasma glucose and insulin release from pancreatic beta-cells is not stationary in the sense that a given glucose concentration leads to a specific rate of insulin secretion. A number of time-dependent mechanisms appear to exist that modify insulin release both on a short and a longer time scale. Typically, two phases are described. The first phase, lasting up to 10 min, is a pulse of insulin release in response to fast changes in glucose concentration. The second phase is a more steady increase of insulin release over minutes to hours, if the elevated glucose concentration is sustained. The paper describes the glucose sensing mechanism via the complex dynamics of the key enzyme glucokinase, which controls the first step in glucose metabolism: phosphorylation of glucose to glucose-6-phosphate. Three time-dependent phenomena (mechanisms) are described. The fastest, corresponding to the first phase, is a delayed negative feedback regulating the glucokinase activity. Due to the delay, a rapid glucose increase will cause a burst of activity in the glucose sensing system, before the glucokinase is down-regulated. The second mechanism corresponds to the translocation of glucokinase from an inactive to an active form. As the translocation is controlled by the product(s) of the glucokinase reaction rather than by the substrate glucose, this mechanism gives a positive, but saturable, feedback. Finally, the release of the insulin granules is assumed to be enhanced by previous glucose exposure, giving a so-called glucose memory to the beta-cells. The effect depends on the insulin release of the cells, and this mechanism constitutes a second positive, saturable feedback system. Taken together, the three phenomena describe most of the glucose sensing behaviour of the beta-cells. The results indicate that the insulin release is not a precise function of the plasma glucose concentration. It rather looks as if the beta-cells just increase the insulin production, until the plasma glucose has returned to normal. This type of integral control has the advantage that the precise glucose sensitivity of the beta-cells is not important for normal glucose homeostasis.

Key words: glucose metabolism, glucose sensing, glucokinase, translocation, time-dependent mechanisms, glucose memory, pancreatic beta-cell, first phase, insulin release, mathematical modelling

References

  • 1.Ashcroft, F.M., Proks, P., Smith, P.A., Ämmälä, C., Bokvist, K., Rorsman, P.: Stimulus-secretion coupling in pancreatic β cells. J. Cell. Biochem. 55, 54–65 (1994) [DOI] [PubMed]
  • 2.Bokvist, K., Eliasson, L., Ämmälä, C., Renström, E., Rorsman, P.: Co-localization of L-type Ca2+ channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic B-cells. EMBO J. 14, 50–57 (1995) [DOI] [PMC free article] [PubMed]
  • 3.Eliasson, L., Proks, P., Ämmälä, C., Ashcroft, F.M., Bokvist, K., Renström, E., Rorsman, P., Smith, P.A.: Endocytosis of secretory granules in mouse pancreatic β-cells evoked by transient elevation of cytosolic calcium. J. Physiol. 493.3, 755–767 (1996) [DOI] [PMC free article] [PubMed]
  • 4.Göpel, S.: Electrophysiology of pancreatic α-, β- and γ-cells studied in intact mouse islets of Langerhans. Universitetstrykeriet, Lund (2001)
  • 5.Polonsky, K.S.: The β-cell in diabetes: from molecular genetics to clinical research. Diabetes 44, 705–717 (1995) [DOI] [PubMed]
  • 6.Rorsman, P.: The pancreatic beta-cell as a fuel sensor: an electrophysiologist's viewpoint. Diabetologia 40, 487–495 (1997) [DOI] [PubMed]
  • 7.Prentki, M., Tornheim, K., Corkey, B.E.: Signal transduction mechanisms in nutrient-induced insulin secretion. Diabetologia 40, S32–S41 (1997) [DOI] [PubMed]
  • 8.Grill, V., Adamson, U., Cerasi, E.: Immediate and time-dependent effects of glucose on insulin release from rat pancreatic tissue, evidence for different mechanisms of action. J. Clin. Invest. 61, 1034–1043 (1978) [DOI] [PMC free article] [PubMed]
  • 9.Nesher, R., Cerasi, E.: Modeling phasic insulin release, immediate and time-dependent effects of glucose. Diabetes 51(Suppl. 1), S53–S59 (2002) [DOI] [PubMed]
  • 10.Agius, L., Matthew, P.: Intracellular binding of glucokinase in hepatocytes and translocation by glucose, fructose and insulin. Biochem. J. 296, 785–796 (1993) [DOI] [PMC free article] [PubMed]
  • 11.Toyoda, Y., Tsuchida, A., Iwami, E., Shironoguchi, H., Miva, I.: Regulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytes. Horm. Metab. Res. 33, 329–336 (2001) [DOI] [PubMed]
  • 12.Agius, L., Aiston, S., Mukhtar, M., de la Iglesia, N.: GKRP/GK: control of metabolic fluxes in hepatocytes. In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 208–221 S. Karger, Basel (2004)
  • 13.Chu, C.A., Fujimoto, Y., Igawa, K., Grimsby, J., Grippo, J.F., Magnuson, M.A., Cherrington, A.D., Shiota, M.: Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats. Am. J. Physiol. Gastrointest. Liver Physiol. 286, 627–634 (2004) [DOI] [PubMed]
  • 14.Noma, Y., Bonner-Weir, S., Latimer, J.B., Davalli, A.M., Weir, G.C.: Translocation of glucokinase in pancreatic β-cells during acute and chronic hyperglycemia. Endocrinol. 137, 1485–1491 (1996) [DOI] [PubMed]
  • 15.Rizzo, M.A., Magnuson, M.A., Drain, P.F., Piston, D.W.: A functional link between glucokinase binding to insulin granules and conformational alterations in response to glucose and insulin. J. Biol. Chem. 37, 34168–34175 (2002) [DOI] [PubMed]
  • 16.Sturis, J., Kurland, I.J., Byrne, M.A., Mosekilde, E., Froguel, P., Pilkis, S.J., Bell, G.I., Polonsky, K.S.: Compensation in pancreatic β-cell function in subjects with glucokinase mutations. Diabetes 43, 718–723 (1994) [DOI] [PubMed]
  • 17.Liang, Y. Najafi, H., Smith, R.M., Zimmerman, E.C., Magnuson, M.A., Tal, M., Matschinsky, F.M.: Concordant glucose induction of glucokinase, glucose usage, and glucose-stimulated insulin release in pancreatic islets maintained in organ culture. Diabetes 41, 792–806 (1992) [DOI] [PubMed]
  • 18.Korsgaard, T.V., Jönsson, R.: Mathematical modelling of beta-cell functionality in health and type II diabetes-a biosimulation approach, Master’s Thesis, Preclinical Development, Novo Nordisk A/S, Department of Physics, Technical University of Denmark (2005)
  • 19.Matschinsky, F., Liang, Y., Kesavan, P., Wang, L., Froguel, P., Velho, G., Cohen, D. Permutt, M.A., Tanizawa, Y., Jetton, T.L., Niswender, K., Magnuson M.A.: Glucokinase as pancreatic β cell glucose sensor and diabetes gene. J. Clin. Invest. 92, 2092–2098 (1993) [DOI] [PMC free article] [PubMed]
  • 20.Matschinsky, F.M.: A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45, 223–241 (1996) [DOI] [PubMed]
  • 21.Giroix, M.-H., Sener, A., Malaisse, W.J.: Hexose metabolism in pancreatic islets, absence of glucose-6-phosphatase in rat islet cells. Mol. Cell. Endorinol. 49, 219–225 (1987) [DOI] [PubMed]
  • 22.Perales, M.-A., Sener, A., Malaisse, W.J.: Hexose metabolism in pancreatic islets: the glucose-6-phosphatase riddle. Mol. Cell. Biochem. 101, 67–71 (1991) [DOI] [PubMed]
  • 23.Malaisse, W.J., Sener, A., Koser, M., Ravazzola, M., Malaisse-Lagae, F.: The stimulus-secretion coupling of glucose-induced insulin release. Biochem. J. 164, 447–454 (1977) [DOI] [PMC free article] [PubMed]
  • 24.Matschinsky, F.M., Magnuson, M.A., Zelent, D., Jetton, T.L., Doliba, N., Han, Y., Taub, R., Grimsby, J.: The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55, 1–12 (2006) [DOI] [PubMed]
  • 25.Sekine, N., Cirulli, V., Regazzi, R., Brown, L.J., Gine, E., Tamarit-Rodriguez, J., Girotti, M., Marie, S., MacDonald, M.J., Wollheim, C.B., Rutter, G.A.: Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic β-cells. J. Biol. Chem. 269, 4895–4902 (1994) [PubMed]
  • 26.Efrat, S., Tal, M., Lodish, H.F.: The pancreatic β-cell glucose sensor. TIBS 19, 535–538 (1994) [DOI] [PubMed]
  • 27.Maiztegui, B., Borelli, M.I., Massa, M.L., Del Zotto, H., Gagliardino, J.J.: Enhanced expression of hexokinase I in pancreatic islets induced by sucrose administration. J. Endocrinol. 189, 311–317 (2006) [DOI] [PubMed]
  • 28.Kennedy, R.T., Kauri, L.M., Dahlgren, G.M., Jung, S.-K.: Metabolic oscillations in β-cells. Diabetes 51(Suppl. 1), S152–S161 (2002) [DOI] [PubMed]
  • 29.Fridlyand, L.E., Tamarina, N. and Philipson, L.H.: Modeling of Ca2+ flux in pancreatic β-cells: role of the plasma membrane and intracellular stores. Am. J. Physiol. Endocrinol. Metab. 285, E138–E154 (2003) [DOI] [PubMed]
  • 30.Cornish-Bowden, A., Cárdenas M.L.: Glucokinase: a monomeric enzyme with positive cooperativity. In: Matschinsky, F.M., Magnuson M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 208–221. S. Karger, Basel (2004)
  • 31.Straub, S.G., Sharp, G.W.G.: Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab. Res. Rev. 18, 451–463 (2002) [DOI] [PubMed]
  • 32.Caumo, A., Luzi, L.: First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am. J. Endocrinol. Metab. 287, E371–E385 (2004) [DOI] [PubMed]
  • 33.Daniel, S., Noda, M., Straub, S.G., Sharp, G.W.G.: Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 48, 1–5 (1999) [DOI] [PubMed]
  • 34.Rorsman, P., Renström, E.: Insulin granule dynamics in pancreatic beta-cells. Diabetologia 46, 1029–1045 (2003) [DOI] [PubMed]
  • 35.Toffolo, G., Breda, E., Cavaghan, M.K., Ehrmann, D.A., Polonsky, K.S., Cobelli, C.: Quantitative indexes of β-cell function during graded up&down glucose infusion from C-peptide minimal models. Am. J. Physiol. Endocrinol. Metab. 280, E2–E10 (2001) [DOI] [PubMed]
  • 36.Breda, E., Cavaghan, M.K., Toffolo, G., Polonsky, K.S., Cobelli, C.: Oral glucose tolerance test minimal model indexes of β-cell function and insulin sensitivity. Diabetes 50, 150–158 (2001) [DOI] [PubMed]
  • 37.Breda, E., Toffolo, G., Polonsky, K.S., Cobelli, C.: Insulin release in impaired glucose tolerance, oral minimal model predicts normal sensitivity to glucose but defective response times. Diabetes 51(Suppl. 1), S227–S233 (2002) [DOI] [PubMed]
  • 38.Baltrusch, S., Wu, C., Okar, D.A., Tiedge, M., Lange, A.J.: Interaction of GK with the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (6PF2K/F26P2ase). In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, From Basics to Novel Therapeutics, pp. 262–274. S. Karger, Basel (2004)
  • 39.Miwa, I., Toyoda, Y., Yoshie, S.: Glucokinase in β-cell insulin-secretory granules. In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 350–359. S. Karger, Basel (2004)
  • 40.Iynedjian, P.B., Pilot, P.-R., Nouspikel, T., Milburn, J.L., Quaade, C., Hughes, S., Ucla, C., Newgard, C.B.: Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. Proc. Natl. Acad. Sci. USA 86, 7838–7842 (1989) [DOI] [PMC free article] [PubMed]
  • 41.Agius, L.: Control of glucokinase translocation in rat hepatocytes by sorbitol and the cytosolic redox state. Biochem. J. 298, 237–243 (1994) [DOI] [PMC free article] [PubMed]
  • 42.Easom, R.A.: β-granule transport and exocytosis. Cell & Develop. Biol. 11, 253–266 (2000) [DOI] [PubMed]
  • 43.Ashcroft, F.M., Harrison, D.E., Ashcroft, S.J.H.: Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells. Nature 312, 446–448 (1984) [DOI] [PubMed]
  • 44.Fujimoto, S., Tsuura, Y., Ishida, H., Tsuji, K., Mukai, E., Kajikawa, M., Hamamoto, Y., Takeda, T., Yamada, Y., Seino, Y.: Augmentation of basal insulin release from rat islets by preexposure to a high concentration of glucose. Am. J. Physiol. Endocrinol. Metab. 279, E927–E940 (2000) [DOI] [PubMed]
  • 45.Aspinwall, C.A., Lakey, J.R.T., Kennedy, R.T.: Insulin-stimulated insulin secretion in single pancreatic beta cells. J. Biol. Chem. 274, 6360–6365 (1999) [DOI] [PubMed]
  • 46.Borge, P.D., Moibi, J., Greene, S.R., Trucco, M., Young, R.A., Gao, Z., Wolf, B.A.: Insulin receptor signaling and sarco/endoplasmic reticulum calcium ATPase in β-cells. Diabetes 51(Suppl. 3), S427–S433 (2002) [DOI] [PubMed]
  • 47.Magnuson, M.A., Matschinsky, F.M.: Glucokinase as a glucose sensor: past, present and future. In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 1–17. S. Karger, Basel (2004)
  • 48.Rocheleau, J.W., Head, W.S., Nicholson, W.E., Powers, A.C., Piston, D.W.: Pancreatic islet β-cells transiently metabolize pyruvate. J. Biol. Chem. 277, 30914–30920 (2002) [DOI] [PubMed]
  • 49.German, M.S.: Glucose sensing in pancreatic islet beta cells: the key role of glucokinase and the glycolytic intermediates. Proc. Natl. Acad. Sci. USA 90, 1781–1785 (1993) [DOI] [PMC free article] [PubMed]
  • 50.Leibiger, B., Berggren, P.-O., Leibiger, I.B.: Regulation of β-cell GK gene transcription by insulin. In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 249–261. S. Karger, Basel (2004)
  • 51.Piston, D.W., Patterson, G.H.: Linear relationship between glucokinase expression, metabolic redox state and insulin secretion. In: Matschinsky, F.M., Magnuson, M.A. (eds.) Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, pp. 339–349. S. Karger, Basel (2004)
  • 52.Persaud, S.J., Asare-Anane, H., Jones, P.M.: Insulin receptor activation inhibits insulin secretion from human islets of Langerhans. FEBS Lett. 510, 225–228 (2002) [DOI] [PubMed]
  • 53.Elahi, D.: In praise of the hyperglycemic clamp. Diabetes Care 19, 278–286 (1996) [DOI] [PubMed]
  • 54.Efendic, S., Portwood, N.: Overview of incretin hormones. Horm. Metab. Res. 36, 742–746 (2004) [DOI] [PubMed]
  • 55.Woods, S.C., Porte D.: Neural control of the endocrine pancreas. Physiol. Rev. 54, 596–619 (1974) [DOI] [PubMed]

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