title: Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice.
abstract: Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350-750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-α in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes.
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Weiran
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
authors.forename: Muchao
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D001786:Blood Glucose; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D004435:Eating; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010072:Oxamic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D007770:L-Lactate Dehydrogenase; D019344:Lactic Acid; D008055:Lipids; D010072:Oxamic Acid