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Am J Physiol Endocrinol Metab (April 9, 2002). doi:10.1152/ajpendo.00041.2002
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Articles in PresS, published online ahead of print April 9, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00041.2002
Submitted on February 1, 2002
Accepted on March 18, 2002

Differences between mouse and rat pancreatic islets in succinate responsiveness and malic enzyme relevant to anaplerosis

Michael J. MacDonald1*

1 Medical School, University of Wisconsin, Madison, WI, USA

* To whom correspondence should be addressed. E-mail: mjmacdon{at}facstaff.wisc.edu.

Succinic acid methyl esters are potent insulin secretagogues in rat pancreatic islets, but they do not stimulate insulin release in mouse islets. Unlike rat and human islets, mouse islets lack malic enzyme and, therefore, are unable to form pyruvate from succinate-derived malate for net synthesis of acetyl-CoA. Dimethyl[2,3-14C]succinate is metabolized in the citric acid cycle in mouse islets to the same extent as in rat islets indicating that endogenous acetyl-CoA condenses with oxaloacetate derived from succinate. However, without malic enzyme the net synthesis from succinate of the citric acid cycle intermediates citrate, isocitrate and {alpha}-ketoglutarate cannot occur. Glucose and other nutrients that augment {alpha}-ketoglutarate formation are secretagogues in mouse islets with potencies similar to those in rat islets. All cycle intermediates can be net-synthesized from {alpha}-ketoglutarate. Rotenone, an inhibitor of site I of the electron transport chain, inhibits methyl succinate-induced insulin release in rat islets even though succinate oxidation forms ATP at sites II and III of the respiratory chain. Thus generating ATP, NADH and anaplerosis of succinyl-CoA plus the four-carbon dicarboxylic acids of the cycle and its metabolism in the citric acid cycle is insufficient for a fuel to be insulinotropic; it must additionally promote anaplerosis of {alpha}-ketoglutarate or two intermediates interconvertible with {alpha}-ketoglutarate, citrate and isocitrate.




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