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.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

“…In this study, we showed that treatment with OXA decreased lactate production in the skeletal muscle and adipose tissue, lowered serum lactate and proinflammatory cytokine levels, and improved insulin sensitivity, islet morphology, beta-cell mass, and glycemic control in db/db mice, which was consistent with the findings of our previous study [24]. Furthermore, we demonstrated for the first time that OXA significantly improved inflammation and insulin sensitivity of the skeletal muscle and adipose tissue in db/db mice.…”

“…Group 1 comprised db/ + mice treated with normal saline (ns, 0.9% NaCl) by intraperitoneal injection ( db/ + Control [CON] group), whereas groups 2-5 comprised db/db mice administrated with NS ( db/db CON group), 550 mg/kg of body weight of OXA (Sigma-Aldrich, St. Louis, MO, USA; db/db OXA group), 250 mg/kg of body weight of MET (Bristol-Myers Squibb, Shanghai, China; db/db MET group), or both compounds (550/250 mg/kg of body weight; db/db OXA + MET group) by intraperitoneal injection daily for 8 weeks. The OXA dose was selected based on the results of our previous study, which showed that administration of OXA at the doses of 350, 550, and 750 mg/kg body weight could improve the glycemic control in db/db mice [24]. Food intake (determined by collecting and weighing uneaten food) was evaluated 3 times per week.…”

“…Lactate production in the skeletal muscle and adipose tissues was measured as previously described [24]. Briefly, the samples were rapidly thawed, blotted dry, and weighed.…”

“…Numerous studies, including cross-sectional and prospective studies, have found that blood lactate is elevated among patients with obesity, a condition associated with IR, and that blood lactate may represent an independent risk factor for the development of T2DM [20,21,22,23]. In our previous study, we showed that the production of lactate was increased in the adipose tissue and skeletal muscle, and that serum levels of lactate and pro-inflammatory cytokines were elevated in diabetic db/db mice, whereas treatment with the LDH competitive inhibitor oxamate (OXA) reduced serum lactate and pro-inflammatory cytokines levels and improved insulin sensitivity and blood glucose control [24]. These results indicated that increased tissue lactate production, likely mediated via a pro-inflammatory response, may be at least partially accountable for IR and diabetes in db/db mice, and that oxamic acid derivatives might be a potential drug to treat T2DM.…”

Retrospective evaluation of the association between admission blood glucose and l‐lactate concentrations in ponies and horses with gastrointestinal disease (2008‐2016): 545 cases

“…In people, increases in l ‐lactate concentrations are closely associated with fasting glucose and insulin concentrations, insulin resistance, and type 2 diabetes . Increases in l ‐lactate concentration are predictive of development of insulin resistance and might be an independent risk factor for the development of type 2 diabetes . In a mouse model, increased l ‐lactate production by adipose and muscle tissue was thought to be at least partially responsible for insulin resistance and diabetes .…”