Summary
The effects ofα-ketoisocaproate (KIC, 10 mmol/l) on glucagon and insulin release were studied in the in vitro perfused rat pancreas. The experiments were performed at low glucose concentration (3.3 mmol/l) in the absence or presence of arginine (10 mmol/l). In all the experiments KIC induced a marked and not rapidly reversible inhibition of glucagon release. This inhibition was more pronounced in the absence (76 percent) than presence of arginine (61 percent). These inhibitory patterns closely duplicated those which were seen in parallel experiments which included a rise in the concentration of glucose (from 3.3 to 11.1 mmol/l). KIC was also a potent stimulator of insulin release. The results are compatible with the view that the intracellular metabolism of KIC and glucose plays an essential role in the regulation of glucagon release by exogenous substrates.
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Assan, R., Attali, J.R., Ballerio, G., Boillot, J., Girard, J.R.: Glucagon secretion induced by natural and artificial amino acids in perfused rat pancreas. Diabetes26, 300–307 (1977)
Edwards, J.C.: A-cell metabolism and glucagon secretion. Postgrad Med. J. (Suppl.)49, 611–615 (1973)
Edwards, J.C., Hellerström, C., Petersson, B., Taylor, K.W.: Oxidation of glucose and fatty acids in normal and in A2-cell rich pancreatic islets isolated from guinea pigs. Diabetologia8, 93–98 (1972)
Edwards, J.C., Taylor, K.W.: Fatty acids and the release of glucagon from isolated guinea-pig islets of Langerhans incubated in vitro. Biochim. Biophys. Acta215, 310–315 (1970)
Fajans, S.S., Quibrera, R., Pek, S., Floyd, J.C., Christensen, H.N., Conn, J.W.: Stimulation of insulin release in the dog by a non metabolizable amino acid. Comparison with leucine and arginine. J. Clin. Endocrinol. Metab.33, 35–41 (1971)
Frankel, B.J., Gerich, J.E., Hagura, R., Fanska, R.E., Gerritsen, G.G., Grodsky, G.M.: Abnormal secretion of insulin and glucagon by the in vitro perfused rat pancreas of the genetically diabetic hamster. J. Clin. Invest.53, 1637–1646 (1974)
Gerich, J.C., Charles, M.A., Grodsky, G.M.: Regulation of pancreatic insulin and glucagon secretion. Annu. Rev. Physiol.38, 353–388 (1976)
Gerich, J.E., Langlois, M., Noacco, C., Karam, J.H., Forsham, J.H.: Lack of glucagon response to hypoglycaemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science182, 171–173 (1973)
Grodsky, G.M., Fanska, R., Lundquist, I.: Interrelationships betweenα andβ anomers of glucose affecting both insulin and glucagon secretion in the perfused rat pancreas. II. Endocrinology97, 573–580 (1975)
Hahn, H.J., Ziegler, M.: Investigations on isolated islets of Langerhans in vitro. 16. Modification of the glucose-dependent inhibition of glucagon secretion. Biochim. Biophys. Acta499, 362–372 (1977)
Hahn, H.J., Ziegler, M., Mohr, E.: Inhibition of glucagon release by glucose and glyceraldehyde on isolated islets of Wistar rats. FEBS Lett.49, 100–102 (1974)
Hutton, J.C., Malaisse, W.J.: Metabolic aspects ofα-ketoisocaproate-induced insulin release in rat pancreatic islets. Diabetologia13, 403 (1977)
Hutton, J.C., Sener, A., Malaisse, W.J.: The redox state of pyridine nucleotides in pancreatic islets and its relevance to 2-ketoisocaproate-induced insulin release. Diabetologia14, 241 (1978)
Kaneto, A., Kosaka, K.: Effects of leucine and isoleucine infused intrapancreatically on glucagon and insulin secretion. Endocrinology91, 691–695 (1972)
Leclercq-Meyer, V., Marchand, J., Leclercq, R., Malaisse, W.J.: Glucagon and insulin release by the in vitro perfused rat pancreas. Influence of the colloid composition of the perfusate. Diabete Metab.2, 57–65 (1976)
Leclercq-Meyer, V., Marchand, J., Malaisse, W.J.: An arginine-like effect of the “fumarate + glutamate + pyruvate” mixture on glucagon relase. Life Sci.20 1193–1198 (1977)
Leclercq-Meyer, V., Marchand, J., Rebolledo, O., Malaisse, W.J., Leclercq, R.: A combined radioimmunoassay for glucagon and insulin. Diabetologia11, 419–425 (1975)
Lundqvist, G.: Enzymatic studies of glucose phosphorylation in the glucagon producing cells of duck pancreas. Horm. Metab. Res.4, 83–96 (1972)
Lundqvist, G.: Enzymatic prerequisites for ATP formation from triose phosphates in the A2 and B cells of the endocrine pancreas of the guinea-pig. Horm. Metab. Res.4, 237–241 (1972)
Malaisse, W.J., Sener, A., Koser, M., Herchuelz, A.: Identification of theα stereospecific glucosensor in the pancreatic B-cell. FEBS Lett.65, 131–134 (1976)
Malaisse, W.J., Sener, A., Koser, M., Herchuelz, A.: Stimulus-secretion coupling of glucose-induced insulin release. Metabolism ofα- andβ-D-glucose in isolated islets. J. Biol. Chem.251, 5936–5943 (1976)
Matschinsky, F.M., Pagliara, A.S., Hover, B.A., Haymond, M.W., Stilings, G.N.: Differential effects of alpha- and beta-D-glucose on insulin and glucagon secretion from the isolated perfused rat pancreas. Diabetes24, 369–372 (1975)
Matschinsky, F.M., Pagliara, A.S., Hover, B.A., Pace, C.S., Ferendelli, J.A., Williams, A.: Hormone secretion and glucose metabolism in islets of Langerhans of the isolated perfused pancreas from normal and streptozotocin diabetic rats. J. Biol. Chem.251, 6053–6061 (1976)
Matschinsky, F.M., Pagliara, A.S., Stillings, S.N., Hover, B.A.: Glucose and ATP levels in pancreatic islet tissue of normal and diabetic rats. J. Clin. Invest.58, 1193–1200 (1976)
Müller, W.A., Faloona, G.R., Unger, R.H.: Abnormal alpha cell function in diabetes. Response to carbohydrate and protein ingestion. N. Engl. J. Med.283, 109–115 (1970)
Müller, W.A., Faloona, G.R., Unger, R.H.: The effect of experimental insulin deficiency on glucagon secretion. J. Clin. Invest.50, 1992–1999 (1971)
Norfleet, W.T., Pagliara, A.S., Haymond, W.M., Matschinsky, F.M.: Comparison of alphaand beta-cell secretory responses in islets with collagenase and in the isolated perfused pancreas of rats. Diabetes24, 961–970 (1975)
Östenson, C.G., Andersson, A., Brolin, S.E., Petersson, B., Hellerström, C.: Effects of insulin on the glucagon release, glucose utilization and ATP content of the pancreatic A2 cells of the guinea pig. In: Glucagon: its role in physiology and clinical medicine. Foa, P.P., Bajaj, J.S., Foa, N.L., (Eds.), pp. 243–254. Berlin, Heidelberg, New York: Springer 1977
Pagliara, A.S., Hover, B.A., Ellerman, J., Matschinsky, F.M.: Iodoacetate and iodoacetamide-induced alterations of pancreaticα- and β-cell responses. Endocrinology97, 698–708 (1975)
Pagliara, A.S., Stillings, S.N., Haymond, M.W., Hover, B.A., Matschinsky, F.M.: Insulin and glucose as modulators of the amino acid-induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats. J. Clin. Invest.55, 244–255 (1975)
Pagliara, A.S., Stillings, S.N., Hover, B., Martin, D.M., Matschinsky, F.M.: Glucose modulation of amino acid-induced glucagon and insulin release in the isolated perfused rat pancreas. J. Clin. Invest.54, 819–832 (1974)
Pagliara, A.S., Stillings, S.N., Zawalich, W.S., Williams, A.D., Matschinsky, F.M.: Glucose and 3-0-methylglucose protection against alloxan poisoning of pancreatic alpha and beta cells. Diabetes26, 973–979 (1977)
Panten, U., Christians, J., Kriegstein, E.W., Poser, W., Hasselblatt, A.: Studies on the mechanism of D-leucine andα-ketoisocaproic acid-induced insulin release from perifused isolated pancreatic islets. Diabetologia10, 149–154 (1974)
Panten, U., Kriegstein, E.W., Poser, W., Schönborn, J., Hasselblatt, A.: Effects of 1-leucine andα-ketoisocaproate acid upon insulin secretion and metabolism of istolated pancreatic islets. FEBS Lett.20, 225–228 (1972)
Pek, S., Fajans, S.S., Floyd, J.C., Jr., Knopf, R.F., Conn, J.W.: Effects upon plasma glucagon of infused and ingested amino acids and of protein meals in man. Diabetes18, 328 (1969)
Pek, S., Santiago, J.C., Tai, T.Y.: L-leucine-induced secretion of glucagon and insulin, and the “off response” to L-leucine in vitro. I. Characterization of the dynamics of secretion. Endocrinology103, 1208–1218 (1978)
Pek, S., Tai, T.Y., Crowther, R., Fajans, S.S.: Glucagon release precedes insulin release in response to common secretagogue. Diabetes25, 764–770 (1976)
Petersson, B., Hellerström, C., Gunnarsson, R.: Structure and metabolism of the pancreatic islets in streptozotocin treated guinea pigs. Horm. Metab. Res.2, 313–317 (1970)
Rocha, D.M., Faloona, G.R., Unger, R.H.: Glucagonstimulating action of 20 amino acids in dogs. J. Clin. Invest.51, 2346–2351 (1972)
Rossini, A.A., Soeldner, J.S., Hiebert, J.M., Weir, G.C., Gleason, R.E.: The effect of glucose anomers upon insulin and glucagon secretion. Diabetologia10, 795–799 (1974)
Samols, E., Tyler, J.M., Marks, V.: Glucagon-insulin relationships. In: Glucagon, molecular physiology, clinical and therapeutic implications. Lefebvre, P.J., Unger, R.H. (Eds.), pp. 151–173. Oxford: Pergamon Press 1972
Schauder, P., Schindler, B., Panten, U., Brown, J.G., Frerichs, H., Creutzfeldt, W.: Insulin release from isolated rat pancreatic islets induced byα-ketoisocaproic acid, L-leucine, D-glucose or D-glyceraldehyde: Effect of gastric inhibitory polypeptide or glucagon. Mol. Cell. Endocrinol.7, 115–123 (1977)
Schönborn, J., Westphal, P., Panten, U.: Insulin release from the isolated perfused rat pancreas induced by L-leucine, 2-aminonorbornane-2-carboxylic acid andα-ketoisocaproic acid. Horm. Metab. Res.7, 127–131 (1975)
Snedecor, G.W.: Statistical methods. Ames: Iowa State University Press 1956
Tai, T.Y., Pek, S., Santiago, J.C.: L-leucine-induced secretion of glucagon and insulin, and the “off response” to L-leucine in vitro. II. The role of D-glucose. Endocrinology103, 1219–1226 (1978)
Unger, R.H., Lefebvre, P.J.: Glucagon physiology. In: Glucagon, molecular physiology, clinical and therapeutic implications. Lefebvre, P.J., Unger, R.H. (Eds.), pp. 213–244. Oxford: Pergamon Press 1972
Unger, R.H., Raskin, P., Srikant, C.B., Orci, L.: Glucagon and the A cells. Recent Prog. Horm. Res.33, 477–517 (1977)
Weir, G.C., Knowlton, S.D., Martin, D.B.: Glucagon secretion from the perfused rat pancreas: studies with glucose and catecholamines. J. Clin. Invest.54, 1403–1412 (1974)
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Leclercq-Meyer, V., Marchand, J., Leclercq, R. et al. Interactions of α-ketoisocaproate, glucose and arginine in the secretion of glucagon and insulin from the perfused rat pancreas. Diabetologia 17, 121–126 (1979). https://doi.org/10.1007/BF01222213
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DOI: https://doi.org/10.1007/BF01222213