Summary
Investigation of the subcellular and molecular components of insulin secretion has been made difficult by the small quantities of material available. The recent development of a transplantable rat islet cell tumour of high insulin content and state of differentiation suggested a system more amenable to analysis. To validate the tumour as a model of secretion we have studied its release of insulin. In acute experiments in vitro immunoreactive insulin release was increased by leucine, glucagon, theophylline and dibutyryl cyclic AMP, though not by glucose. Leucine (20mmol/l) plus theophylline (5 mmol/l) caused an abrupt, sustained and rapidly reversible stimulation of two- to fivefold. The response was inhibited by antagonists of cellular oxidative phosphorylation (cyanide, 2,4-dinitrophenol, antimycin A), calcium flux (EGTA, verapamil, Mg2+), calmodulin (trifluoperazine), microtubules (vinblastine, colchicine) and by adrenaline and somatostatin. These findings suggest that the tumour secretes insulin by an exocytotic mechanism similar to that of normal islet tissue.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Chick WL, Warren S, Chute RN, Lauris V (1976) A transplantable rat insulinoma. Diabetes 25: 344
Chick WL, Warren S, Chute RN, Like AA, Lauris V, Kitchen KC (1977) A transplantable insulinoma in the rat. Proc Natl Acad Sci USA 74: 628–632
Hedeskov CJ (1980) Mechanism of glucose-induced insulin secretion. Physiol Rev 60: 442–509
Evans WH (1978) Preparation and characterisation of mammalian plasma membranes. North-Holland Publishing Co, Amsterdam New York Oxford, pp 213–215
Dawson RMC (1968) Physiological media. In: Dawson RMC, Elliott DC, Elliott WH, Jones KM (ed) Data for biochemical research. Oxford University Press, p 507
Wright PH, Makulu DR, Malaisse WJ, Roberts NM, Yu P-L (1968) A method for the immunoassay of insulin. Diabetes 17: 537–546
Fraker PJ, Speck JC Jr (1978) Protein and cell membrane iodinations with a sparingly soluble chloroamide 1,3,4,6-tetrachloro -3a,6a-diphenylglycouril. Biochem Biophys Res Commun 80: 849–857
Lambert AE (1976) The regulation of insulin secretion. Rev Physiol Biochem Pharmacol 75: 97–159
Shapiro S, Eto S, Fleischer N, Baum SG (1975) Regulation of in vitro insulin release from a transplantable Syrian hamster insulinoma. Endocrinology 97: 442–447
Shapiro S, Kaneko Y, Baum SG, Fleischer N (1977) The role of calcium in insulin release from hamster insulinoma cells. Endocrinology 101: 485–493
Sutherland EW, Øye I, Butcher RW (1965). The action of epinephrine and the role of the adenyl cyclase system in hormone actions. In: Pincus G (ed) Recent progress in hormone research XXI. Academic Press, New York, pp 623–646
Malaisse WJ, Malaisse-Lagae F, Wright PH (1967) Effect of fasting upon insulin secretion in the rat. Am J Physiol 213: 843–848
Buchanan KD, Vance JE, Williams RH (1969). Effect of starvation on insulin and glucagon release from isolated islets of Langerhans of the rat. Metab Clin Exp 18: 155–162
Lambert AE, Junod A, Stauffacher W, Jeanrenaud B, Renold AE (Steinbrinck R) (1969) Organ culture of fetal rat pancreas I. Insulin release induced by caffeine and by sugars and some derivatives. Biochim Biophys Acta 184: 529–539
Lambert AE, Jeanrenaud B, Junod A, Renold AE, Steinbrinck R (1969) Organ culture of fetal rat pancreas II. Insulin release induced by amino and organic acids, by hormonal peptides, by cationic alterations of the medium and by other agents. Biochim Biophys Acta 184: 540–553
Grodsky GM (1970). Insulin and the pancreas. Vitam Horm 28: 37–101
Lernmark A, Wenngren BI (1972) Insulin and glucagon release from the isolated pancreas of foetal and newborn mice. J Embryol Exp Morphol 28: 607–614
Coore HG, Randle PJ (1964) Regulation of insulin secretion studied with pieces of rabbit pancreas incubated in vitro. Biochem J 93: 66–78
Milner RDG, Hales CN (1969) The interaction of various inhibitors and stimuli of insulin release studied with rabbit pancreas in vitro, Biochem J 113: 473–479
Hellman B, Anderson 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) Hormones and cell regulation, Vol 3. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 69–96
Naylor WG, Szeto J (1972) Effect of verapamil on contractility, oxygen utilisation, and calcium exchangeability in mammalian heart muscle. Cardiovasc Res 6: 120–128
Malaisse WJ, Herchuelz A, Levy J, Sener A (1977) Calcium antagonists and islet function III. The possible site of action of verapamil. Biochem Pharmacol 26: 735–740
Devis G, Somers G, van Obberghen E, Malaisse WJ (1975) Calcium antagonists and islet function I. Inhibition of insulin release by verapamil. Diabetes 24: 547–551
Hales CN, Milner RDG (1968) Cations and the secretion of insulin from rabbit pancreas in vitro. J Physiol (Lond) 199: 177–187
Malaisse WJ, Devis G, Herchuelz A, Sener A, Somers G (1976) Calcium antagonists and islet function VIII. The effect of magnesium. Diabete Metab 2: 1–4
Henquin J-C, Lambert AE (1975) Cobalt inhibition of insulin secretion and calcium uptake by isolated rat islets. Am J Physiol 228: 1669–1677
Preissler M, Meissner HP (1978) Effects of calcium on the electrical activity of single pancreatic B-cells. Diabetologia 15: 262
Cheung WY (1980) Calmodulin plays a pivotal role in cellular regulation. Science 207: 19–27
Means AR, Dedman JR (1980) Calmodulin — an intracellular calcium receptor. Nature 285: 73–77
Sugden MC, Christie MR, Ashcroft SJH (1979) Presence and possible role of calcium dependent regulator (calmodulin) in rat islets of Langerhans. FEBS Lett 105: 95–100
Valverde I, Vandermeers A, Anjaneyulu R, Malaisse WJ (1979) Calmodulin activation of adenylate cyclase in pancreatic islets. Science 206: 225–227
Levin RM, Weiss B (1977) Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol 13: 690–697
Malaisse WJ, Malisse-Lagae F, Walker MO, Lacy PE (1971) The stimulus-secretion coupling of glucose-induced insulin release V. The participation of a microtubular-microfilamentous system. Diabetes 20: 257–265
Devis G, van Obberghen E, Somers G, Malaisse-Lagae F, Orci L, Malaisse WJ (1974) Dynamics of insulin release and microtubular-microfilamentous system II. Effect of vincristine. Diabetologia 10: 53–59
Somers G, van Obberghen E, Devis G, Ravazzola M, Malaisse-Lagae F, Malaisse WJ (1974) Dynamics of insulin release and microtubular-microfilamentous system III. Effect of colchicine upon glucose-induced insulin secretion. Eur J Clin Invest 4: 299–305
Porte D Jr (1967) A receptor mechanism for the inhibition of insulin release by epinephrine in man. J Clin Invest 46: 86–94
Malaisse W, Malaisse-Lagae F, Wright PH, Ashmore J (1969) Effects of adrenergic and cholinergic agents upon insulin secretion in vitro. Endocrinology 80: 975–978
Alberti KGMM, Christensen NJ, Christensen SE, Hansen AP, Inversen J, Lundbaek K, Seyer-Hansen K, Ørskov H (1973) Inhibition of insulin secretion by somatostatin. Lancet 2: 1299–1301
Koerker DJ, Ruch W, Chideckel E, Palmer J, Goodner CJ, Ensinck J, Gale CC (1974) Somatostatin: hypothalamic inhibitor of endocrine pancreas. Science 184: 482–484
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sopwith, A.M., Hutton, J.C., Naber, S.P. et al. Insulin secretion by a transplantable rat islet cell tumour. Diabetologia 21, 224–229 (1981). https://doi.org/10.1007/BF00252658
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00252658