Mibefradil Improves Glucose Metabolism And Mechanism Through The CaMKⅡ-foxo1 Pathway

Background:Diabetes mellitus(DM),a chronic disease mainly caused by metabolic disorders,has now gone from a rare disease to a serious disease that has become a global epidemic,with the prevalence of type 2 diabetes mellitus(T2DM)in particular rising sharply in all populations.Due to the complex pathogenesis of T2 DM,the limited treatment is the biggest obstacle to the new bottleneck of the clinical treatment of T2 DM.Therefore,further exploration of the specific molecular mechanism of T2 DM progression can help to find new therapeutic ideas and targets for clinical treatment.Insulin resistance(IR)is the core of the development of T2 DM.Studies have confirmed that patients with T2 DM develop persistent calcium disturbance during the course of the disease.However,the treatment of diabetic animal models with calcium channel antagonists can improve its intracellular regulatory disorder,and regulate its abnormal calcium ions to improve glucose metabolism.Therefore,the in-depth calcium ion disorder under the condition of insulin resistance can bring new ideas and new targets for the clinical treatment of DM.Mibefradil is a specific type T calcium channel blocker and has been shown to improve blood glucose in diabetic mice,possibly by blocking the type T calcium channel.At the same time,it has been found that intracellular calcium ion concentration can activate calmodulin 2(CaMKⅡ)and increase glycogen output.Activation of CaMKⅡ enhances nuclear translocation of the transcription factor FoxO1,which is closely related to the pathogenesis of diabetes.Under physiological conditions,insulin can activate the phosphorylation of FoxO1 and make the FoxO1 nucleus excrete,and regulate the key speed limiting enzymes of gluconeogenesis: Phosphoenolpyruvate Carboxykinas(PEPCK)and glucose-6-phosphokinase(G6Pase)expression down-regulated,the gluconeogenesis process is weakened,and the blood glucose drops.Therefore,this study set out to study the role and mechanism of Mibefradil regulating camkii-foxo1-related pathway in diabetic glucose metabolism and preliminarily explore the relationship between improving calcium ion disorder and regulating glucose metabolism,further elaborate the pathogenesis of diabetes,and find possible new directions for clinical treatment and prevention of diabetesMethods:1.To explore that Mibefradil can improve glucose metabolism and protect cardiac muscle cells in streptozotocin and high-fat feed(STZ/HFD)mice.STZ and high-fat feed were used to construct the STZ/HFD model of C57BL/6 mice,and Mibefradil was injected into the abdomen for treatment.Changes in basic indicators,liver,heart and symptoms of the mice were observed and changes in related indicators were detected.2.Mibefradil was studied to improve glucose metabolism through the CaMKⅡ-FoxO1 pathway.Palmitate(PA)induced IR model was used to detect glycogen synthesis,glucose consumption,CaMKⅡ-FoxO1 signaling pathway related gene and protein expression levels,and its phosphorylation levels.Results:1.To explore whether Mibefradil treatment can improve glucose metabolism and protect diabetic target organs in STZ/HFD mice.STZ and high-fat diet were used to construct the STZ/HFD model of C57BL/6 mice.After one week of intrabdominal injection of Mibefradil,the pathological changes of basic glucose metabolism indexes and diabetic target organs such as heart and liver in each group were detected.2.Elucidated that Mibefradil improves glucose metabolism through the CaMKⅡ-FoxO1 pathway.PA induced IR model was used to detect glycogen synthesis,glucose consumption,CaMKⅡ-FoxO1 signaling pathway related gene and protein expression levels,and its phosphorylation levelsConclusion:Mibefradil has the effect of reducing hyperglycemia in type 2 diabetes mellitus and protecting liver and heart tissues under the condition of diabetes mellitus.It is realized by improving intracellular calcium disorder and regulating the CaMKⅡ/AKT/FoxO1 pathway.