Summary
The introduction of new techniques and the access to clonal lines of insulin-secreting cells have enabled re-evaluation of glucose effects on Ca2+ movements in pancreatic β cells. It became evident that glucose, in addition to stimulating the entry of Ca2+ also promotes active sequestration of the ion in intracellular stores and its extrusion from the β cells. The balance between these processes will determine the activity of Ca2+ in the cytoplasm and consequently the rate of insulin release. With the demonstration that glucose can not only increase but also lower cytoplasmic Ca2+, it follows that exposure to the sugar under certain conditions results in a paradoxical inhibition of insulin release. In diabetic patients this may be manifest as prompt reduction of circulating concentrations of insulin and C-peptide after an intravenous injection of glucose. The concept of the dual action of glucose might aid in explaining a number of poorly understood phenomena, such as the induction of rhythmic oscillations of the membrane potential of β cells and the fact that their secretory response is improved by prolonged exposure to glucose and after priming with the sugar.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Hellman B (1970) Methodological approaches to studies on the pancreatic islets. Diabetologia 6: 110–120
Hellman B, Idahl L-Å, Lernmark Å, Sehlin J, Täljedal I-B (1974) Membrane sulphydryl groups and the pancreatic beta cell recognition of insulin secretagogues. In: Malaisse WJ, Pirart J (eds) Diabetes. Procedings of the 8th Congress of the International Diabetes Federation, Excerpta Medica, Amsterdam, pp 65–78
Hellman B (1976) Calcium and the control of insulin secretion. In: Lindenlaub E (ed) Meeting of the Minkowski prize winners. FK Schattauer Verlag, Stuttgart, pp 207–222
Malaisse-Lagae F, Malaisse WJ (1971) Stimulus-secretion coupling of glucose-induced insulin release. III. Uptake of 45calcium by isolated islets of Langerhans. Endocrinology 88: 72–80
Hellman B, Sehlin J, Täljedal I-B (1971) Calcium uptake by pancreatic β cells as measured with the aid of 45Ca and mannitol-3H. Am J Physiol 221: 1795–1801
Hellman B, Sehlin J, Täljedal I-B (1976) Effect of glucose on 45Ca2+ uptake by pancreatic islets as studied with the lanthanum method. J Physiol (Lond) 254: 639–656
Wolters GHJ, Wiegman JB, Konijnendijk W (1982) The effect of glucose stimulation on 45calcium uptake of rat pancreatic islets and their total calcium content as measured by a fluorometric micromethod. Diabetologia 22: 122–127
Andersson T, Berggren PO, Gylfe E, Hellman B (1982) Amounts and distribution of intracellular magnesium and calcium in pancreatic β cells. Acta Physiol Scand 114: 235–241
Ribes G, Siegel E, Wollheim CB, Renold AE, Sharp GWG (1981) Rapid changes in calcium content of rat pancreatic islets in response to glucose. Diabetes 30: 52–55
Bergsten P, Hellman B (1984) Differentiation between short and long term effects of glucose on the intracellular calcium content of the pancreatic β cell. Endocrinology 114: 1854–1859
Gylfe E (1982) Glucose-stimulated net uptake of Ca2+ in the pancreatic β cell demonstrated with dual wavelength spectrophotometry. Acta Physiol Scand 114: 149–151
Gylfe E, Andersson T, Rorsman P, Abrahamsson H, Arkhammar P, Hellman P, Hellman B, Oie HK, Gazdar AF (1983) Depolarization-independent net uptake of calcium into clonal insulin-releasing cells. Biosci Rep 3: 927–937
Naber S, McDaniel ML, Lacy PE (1977) The effect of glucose on the acute uptake and efflux of calcium-45 in isolated rat islets. Endocrinology 101: 686–693
Frankel BJ, Kromhout JA, Imagawa W, Landahl HD, Grodsky GM (1978) Glucose-stimulated 45Ca uptake in isolated rat islets. Diabetes 27: 365–369
Wollheim CB, Sharp GWG (1981) Regulation of insulin release by calcium. Physiol Rev 61: 914–973
Hellman B, Andersson T, Berggren P-O, Rorsman P (1980) Calcium and pancreatic β cell function. II. Modification of 45Ca fluxes by Na+ removal. Biochem Med 24: 143–152
Herchuelz A, Malaisse WJ (1980) Regulation of calcium fluxes in rat pancreatic islets: dissimilar effects of glucose and of sodium ion accumulation. J Physiol (Lond) 302: 263–280
Siegel EG, Wollheim CB, Renold AE, Sharp GWG (1980) Evidence for involvement of Na/Ca exchange in glucose-induced insulin release from rat pancreatic islets. J Clin Invest 66: 996–1003
Pershadsingh HA, McDaniel ML, Landt M, Bry CG, Lacy PE, McDonald JM (1980) Ca2+-activated ATPase and ATP-dependent calmodulin-stimulated Ca2+ transport in islet cell plasma membrane. Nature 288: 492–495
Herchuelz A, Malaisse WJ (1981) Calcium movements and insulin release in pancreatic islets. Diabete Metab 7: 283–288
Hellman B, Gylfe E (1985) Calcium and the control of insulin secretion. In: Cheung WY (ed) Calcium and cell function, vol 6. Academic Press, New York, (in press)
Hellman B, Andersson T, Berggren P-O, Flatt P, Gylfe E, Kohnert K-D (1979) The role of calcium in insulin secretion. In: Dumont J, Nunez J (eds) Hormone and cell regulation, vol 3. Elsevier/North Holland Biomedical Press, Amsterdam, pp 69–96
Hellman B, Gylfe E (1985) Glucose regulation of insulin release involves intracellular sequestration of calcium. In: Rubin RP, Weiss GB, Putney Jr JW (eds) Calcium in biological systems. Plenum Publishing Corp, New York, pp 93–99
Gylfe E, Hellman B (1982) Lack of Ca2+ ionophoretic activity of hypoglycemic sulfonylureas in excitable cells and isolated secretory granules. Mol Pharmacol 22: 715–720
Levin SR, Kasson BG, Driessen JF (1978) Adenosine triphosphatases of rat pancreatic islets. Comparison with those of rat kidney. J Clin Invest 62: 692–701
Malaisse WJ, Hutton JC, Kavazu S, Herchuelz A, Valverde I, Sener A (1979) The stimulus-secretion coupling of glucose-induced insulin release. XXXV. Links between metabolic and cationic events. Diabetologia 16: 331–334
Lebrun P, Malaisse WJ, Herchuelz A (1982) Effect of the absence of bicarbonate upon intracellular pH and calcium fluxes in pancreatic islet cells. Biochim Biophys Acta 721: 357–363
Hellman B, Gylfe E (1984) Evidence for glucose stimulation of intracellular buffering of calcium in the pancreatic β cell. Q J Exp Physiol 69: 867–874
Hellman B, Gylfe E (1984) Glucose inhibits 45Ca efflux from pancreatic β cells also in the absence of Na+-Ca2+ countertransport. Biochim Biophys Acta 770: 136–141
Rasmussen H (1981) Calcium and cAMP as synarchic messengers. John Wiley, New York, pp 1–370
Kohnert KD, Hahn HJ, Gylfe E, Borg H, Hellman B (1979) Calcium and pancreatic β cell function. 6. Glucose and intracellular 45Ca distribution. Mol Cell Endocrinol 16: 205–220
Andersson T (1983) Glucose-induced retention of intracellular 45Ca in pancreatic islets. Am J Physiol 245: C343-C347
Hellman B, Honkanen T, Gylfe E (1982) Glucose inhibits insulin release induced by Na+ mobilisation of intracellular calcium. FEBS Lett 148: 289–292
MacDonald MJ (1984) The use of calcium uptake by small amounts of mitochondria from pancreatic islets to study mitochondrial respirations. The effects of diazoxide and sodium. Biochem Int 8: 771–778
Prentki M, Janjic D, Wollheim CB (1983) The regulation of extramitochondrial steady state free Ca2+ concentration by rat insulinoma mitochondria. J Biol Chem 258: 7597–7602
Prentki M, Wollheim CB (1984) Cytosolic free Ca2+ in insulin secreting cells and its regulation by isolated organelles. Experientia 40: 1052–1060
Rorsman P, Berggren P-O, Gylfe E, Hellman B (1983) Reduction of the cytosolic calcium activity in clonal insulin-releasing cells exposed to glucose. Biosci Rep 3: 939–946
Wollheim CB, Pozzan T (1984) Correlation between cytosolic free Ca2+and insulin release in an insulin-secreting cell line. J Biol Chem 259: 2262–2267
Rorsman P, Abrahamsson H, Gylfe E, Hellman B (1984) Dual effects of glucose on the cytosolic Ca2+ activity of mouse pancreatic β cells. FEBS Lett 170: 196–200
Hellman B (1975) The significance of calcium for glucose stimulation of insulin release. Endocrinology 97: 392–398
Bergsten P, Hellman B (1984) Glucose inhibits insulin release when not promoting the entry of calcium into the β cells. Biochem Biophys Res Commun 125: 875–881
Atwater I, Dawson CM, Ribalet B, Rojas E (1979) Potassium permeability activated by intracellular calcium ion concentration in the pancreatic β cell. J Physiol (Lond) 288: 575–588
Ribalet B, Beigelman PM (1979) Cyclic variation of K+ conductance in pancreatic β cells: Ca2+ and voltage dependence. Am J Physiol 237: C137-C146
Cook DL (1984) Electrical pacemaker mechanisms of pancreatic islet cells. Fed Proc 43: 2368–2372
Cook DL, Hales CN (1984) Intracellular ATP directly blocks K+ channels in pancreatic β cells. Nature 311: 271–273
Rorsman P, Trube G (1985) Evidence that D-glucose-induced depolarization in pancreatic β cells involves the closure of an ATP- dependent K+ channel. Acta Physiol Scand (in press)
Henquin JC, Charles S, Nenquin M, Mathot F, Tamagawa T (1982) Diazoxide and D-600 inhibition of insulin release. Distinct mechanisms explain the specificity for different stimuli. Diabetes 31: 776–783
Robertson RP, Brunzell JD, Hazzard WR, Lerner RL, Porte Jr D (1972) Paradoxical hypoinsulinaemia: an alpha-adrenergic-mediated response to glucose. Lancet 2: 787–789
Metz SA, Halter JB, Robertson RP (1979) Paradoxical inhibition of insulin secretion by glucose in human diabetes mellitus. J Clin Endocrinol Metab 48: 827–835
Hellman B, Hällgren R, Abrahamsson H, Bergsten P, Berne C, Gylfe E, Rorsman P, Wide L (1985) The dual action of glucose on the cytosolic Ca2+ activity in pancreatic β cells. Demonstration of an inhibitory effect of glucose on insulin release in the mouse and man. Biomed Biochim Acta 44: 63–70
Efendic S, Enzmann F, Nylén A, Uvnäs Wallensten K, Luft R (1979) Effect of glucose/sulfonylurea interaction on release of insulin, glucagon and somatostatin from isolated perfused rat pancreas. Proc Natl Acad Sci USA 76: 5901–5904
Gylfe E, Hellman B, Sehlin J, Täljedal I-B (1984) Interaction of sulfonylurea with the pancreatic β cell. Experientia 40: 1126–1134
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hellman, B. β-Cell cytoplasmic Ca2+ balance as a determinant for glucose-stimulated insulin release. Diabetologia 28, 494–501 (1985). https://doi.org/10.1007/BF00281983
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF00281983