Novel Safe And Effective Strategy For Hyperglycemia By Targeting To Uncoupling Of Mitochondria And Pyruvate Dehydrogenase

Diabetes,which is characterized by hyperglycemia,is developing into a growing public health problem worldwide and becoming a serious threat to human lives.Unrestrained hyperglycemia leads to severe complications including cardiovascular disorders,nephropathy and retinopathy.Most diabetic patients rely on pharmacotherapy for hyperglycemic control and preventing complications.2,4-dinitrophenol(DNP),is a classical mitochondrial uncoupler,which increases heat production instead of ATP production by uncoupling mitochondrial electronic transport chain and ATP synthesis and had been approved for weight loss in the 1930 s.However,DNP was taken off the market because the emergence of severe adverse effects including hyperthermia,hyperthermia,hyperlactacidemia and even death.The side effects of DNP were clarified to closely associated with excessive promotion of fatty acid oxidation leading to hyperthemia,and the compensatory ATP generation by glycolysis contribution to lactate production.Then,we hypothesized that increasing of glucose oxidation by oxidative substrate preference from fatty acid to glucose through the reduction of anaerobic glycolysis would be a safe and effective mean to improve hyperglycemia.Based on the hypothesis,DCA as a pyruvate dehydrogenase(PDH)activator was identified following testing the effects of DNP combined with cell metabolic modulators.In myotubes,hepatocytes and 3T3-L1 cells,DCA combined with DNP inhibited anaerobic glycolysis without affecting uncoupling actions of DNP.Consistently,fatty acid oxidation and lactate production stimulated by DNP was declined by DCA in myotubes,hepatocytes and 3T3-L1 cells.Also,DCA further promoted glucose oxidation induced by DNP in myotubes.Furthermore,DCA combined with DNP increased energy expenditure in vivo,which might result from selective promotion of glucose utilization.Subsequently,DCA combined with DNP exhibited a further promotion on glucose clearance in streptozotocin-inducedhyperglycemic mice than DNP alone.Meanwhile,insulin resistance derived from continuous activation of PDH by DCA was improved by combinational treated with DNP.In terms of security,hyperthermia and fatality rate caused by high dosage of DNP was blocked by pre-treated with DCA in mice.These results indicated that targeting to mitochondrial uncoupling combined with PDH activation would be a safe and effective strategy to hyperglycemia therapy.Based on the concept,a novel compound possessing the actions of uncoupling and PDH activation,6j,was identified.And 6j selectively uncoupled myotubes and hepatocytes,and preferentially promoted glucose oxidation in vitro.And the reduction of fasting blood glucose and improvement of glucose intolerance was observed in diabetic ob/ob mice chronically treated with 6j.Meanwhile,hyperthermia and lactate overproduction derived from uncoupling actions in vivo was not happened during chronic treated with 6j.In conclusion,we demonstrated that targeting to mitochondrial uncoupling combined with PDH activation is a safe and effective strategy to improve hyperglycemia through examination of the safe and effective of DNP combined with DCA and dual-functional compound in hyperglycemia therapy.Our study demonstrated that targeting to mitochondrial uncoupling combined with PDH activation would be a safe and effective strategy to hyperglycemia therapy and provides a new and practical pharmacological target for treating hyperglycemia.