Endocrinology, Vol 131, 649-654, Copyright © 1992 by Endocrine Society

ARTICLES

Biochemical mechanisms involved in monomethyl succinate-induced insulin secretion

WS Zawalich and KC Zawalich
Yale University School of Nursing, New Haven, Connecticut 06536-0740.

Esters of succinic acid stimulate insulin secretion from pancreatic beta-cells. Using collagenase-isolated rat islets, the transduction mechanisms involved were investigated. In freshly isolated perifused islets, monomethyl succinate (MMSucc), in the presence of basal (2.75 mM) glucose, stimulated insulin release in a biphasic pattern. This secretory response was dependent on extracellular calcium movement into the beta-cell, since the calcium channel blocker nitrendipine (5 microM) abolished it. The glucokinase inhibitor mannoheptulose (20 mM) had no effect on its secretory action, while the protein kinase-C inhibitor staurosporine (20 nM) reduced secretion to MMSucc. In addition, while ineffective alone, the diacylglycerol kinase inhibitor monooleoylglycerol (25 microM) potentiated MMSucc-induced insulin release. A similarly amplified response occurred in the presence of forskolin (0.25 microM), a compound that elevates islet cAMP levels. The sodium salt of succinic acid (20 mM) had no effect on insulin release in the presence or absence of forskolin. Prior treatment with MMSucc in the presence of 2.75 mM glucose sensitized islets to the usually weak insulin secretory effect of 7.5 mM glucose. Other groups of islets were incubated for 2 h with myo-[2-3H]inositol to label their phosphoinositide pools. These islets were subsequently stimulated, and the kinetics of [3H]inositol efflux and insulin secretion were measured. MMSucc induced a rapid and sustained dose-dependent increase in [3H]inositol efflux rates. In batch-incubated islets, MMSucc increased inositol phosphate levels. Finally, MMSucc (20 mM), in the presence of 8 mM glucose, did not influence the detritiation of [5- 3H]glucose, but reduced the oxidation of [U-14C] glucose. These results support the following conclusions. First, MMSucc is a potent activator of islet phosphoinositide hydrolysis. Second, the activation of protein kinase-C appears to contribute to the acute insulin secretory effect of MMSucc. Third, MMSucc-induced increases in phosphoinositide hydrolysis contribute at least in part to its ability to acutely stimulate insulin release and prime the beta-cell to subsequent stimulation. Finally, mitochondrial events associated with the oxidative metabolism of MMSucc may underlie its insulinotropic action.

This article has been cited by other articles:

				W. S. Zawalich, K. C. Zawalich, G. J. Tesz, J. A. Sterpka, and W. M. Philbrick Insulin secretion and IP levels in two distant lineages of the genus Mus: comparisons with rat islets Am J Physiol Endocrinol Metab, May 1, 2001; 280(5): E720 - E728. [Abstract] [Full Text] [PDF]

				W. S. Zawalich and K. C. Zawalich A Link between Insulin Resistance and Hyperinsulinemia: Inhibitors of Phosphatidylinositol 3-Kinase Augment Glucose-Induced Insulin Secretion from Islets of Lean, But Not Obese, Rats Endocrinology, September 1, 2000; 141(9): 3287 - 3295. [Abstract] [Full Text] [PDF]

				W. S. Zawalich, M. Bonnet-Eymard, and K. C. Zawalich Glucose-induced desensitization of the pancreatic beta -cell is species dependent Am J Physiol Endocrinol Metab, December 1, 1998; 275(6): E917 - E924. [Abstract] [Full Text] [PDF]

				W. S. Zawalich and K. C. Zawalich Influence of Pyruvic Acid Methyl Ester on Rat Pancreatic Islets. EFFECTS ON INSULIN SECRETION, PHOSPHOINOSITIDE HYDROLYSIS, AND SENSITIZATION OF THE BETA CELL J. Biol. Chem., February 7, 1997; 272(6): 3527 - 3531. [Abstract] [Full Text] [PDF]

				R. J. Mertz, J. F. Worley III, B. Spencer, J. H. Johnson, and I. D. Dukes Activation of Stimulus-Secretion Coupling in Pancreatic beta-Cells by Specific Products of Glucose Metabolism J. Biol. Chem., March 1, 1996; 271(9): 4838 - 4845. [Abstract] [Full Text] [PDF]