Differences between mouse and rat pancreatic islets: succinate responsiveness, malic enzyme, and anaplerosis.
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-(14)C]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.
University of Wisconsin Childrens Diabetes Center, Madison, Wisconsin 53706, USA> mjmacdon@facstaff.wisc.edu
Michael J
MJ
MacDonald
D000818:Animals; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008291:Malate Dehydrogenase / Q000172:deficiency / Q000378:metabolism*; D051379:Mice / Q000502:physiology*; D008815:Mice, Inbred Strains; D051381:Rats / Q000502:physiology*; D011919:Rats, Inbred Strains; D012038:Regeneration; D012402:Rotenone / Q000494:pharmacology; D013386:Succinates / Q000378:metabolism / Q000494:pharmacology*
D007328:Insulin; D007329:Insulin Antagonists; D013386:Succinates; D012402:Rotenone; C056451:dimethyl succinate; D008291:Malate Dehydrogenase; C041105:monomethyl succinate