Arecoline Improved Glucose Metabolism In Type 2 Diabetes Rats By Car And Pxr

[BACKGROUD AND OBJECTIVE]Type 2 diabetes mellitus is a serious disease to human health. Although several theories or hypotheses about it have been proposed during the past decades, none can completely explain the whole process of the pathogenesis of T2DM because this dis-ease is associated with multiple risk factors. Liver insulin resistance is the key point in the occurrence and development of T2DM, which is described as a phenomenon that excess hepatic glucose were producted.Arecoline is extracted from natural plant alkaloid. The study found that tumor ne-crosis factor and IL expression was inhibited in oral keratinocyte cells by Arecoline. Al-so arecoline reduced inflammatory factor expression induced by oxidized low density lipoprotein or high glucose in vascular endothelial cells or macrophage of rat. Arecoline is metabolized by CAR or PXR in liver. Recently some study reported that excitomotor of CAR or PXR have ablilty to down-regulate the lever of blood glucose and improve insulin sensitivity in liver. So, we speculated that arecoline may be inhibited inflamma-tory factor expression and improve liver insulin sensitivity in type 2 diabetes rats by CAR or PXR.With regards to this, we will investigate the effect of different concentrations of arecoline on the levels of fasting blood glucose and the expression of carbohydrate me-tabolic enzymes, transcription factors, CAR, PXR, inflammatory cytokines and key fac-tors of insulin signal pathway in type 2 diabetes rats induced by high-glucose diet, and explore the underlying mechanisms. [METHODS]1) A type 2 diabetic rat model was established by fed with high fructose diet;2) The blood glucose, lipid level, hepatic function, liver histology fasting plasma glucagon and fasting insulin were measured;3) Pathogenic changes of rats liver tissue by Hematoxylin-eosin staining;4) Apoptosis of rats liver tissue by tunel staining;5) The mRNA expression of liver PEPCK, G6Pase, FoxO1, PGC-1α,CAR, PXR, NF-κB, TNF-α,IRS-2 were detected by Reverse transcription polymerase chain reaction (RT-PCR);6) The protein expression of p-AKT and FoxO1 was detected by western blotting.[RESULTS]1. Lqw dose arecoline can safely decrease the level of fasting blood glucose and TG in type 2 diabetes rats.1) Type 2 diabetes rats were treated with 0.5,1,5,10,20,50 mg/kg are-coline with abdominal injection for 4 weeks. The level of body weight, fasting blood glucose, lipid level, fasting plasma glucagon and fasting insulin were de-creased, but not 0.5 mg/kg arecoline (p<0.01).2) HE staining of liver shows that 1,5 mg/kg arecoline can improve liver in-jury in type 2 diabetes rats induced by high-glucose diet, such as decreased the number of inflammation cells and intracellular lipid droplets. But 10,20,50 mg/kg arecoline have toxicants in liver.3) The apoptotic index measured by TUNEL increased gradually with adding the concentrations of 10,20,50 mg/kg arecoline (P<0.05).4) Serum ALT and LDH levels were elevated in 0.5,10,20,50 mg/kg arecoline groups and decreased significantly in 1,5 mg/kg arecoline groups. So low dose arecoline can safely decrease the level of fasting blood glucose and TG in type 2 diabetes rat in our test.2. Low dose arecoline can decrease the mRNA level of PEPCK,G6Pase,FoxO1and PGC-1 a in type 2 diabetes rats.1) The results showed that the mRNA levels of PEPCK,G6Pase,FoxO1 and PGC-1 a were elevated in type 2 diabetes rat.2) 1,5 mg/kg arecoline can decreased the mRNA levels of PEPCK,G6Pase,FoxO1 and PGC-1 a in type 2 diabetes rat liver3) Control+arecoline groups was not significantly different compared to control group.3. Low dose arecoline can decrease the mRNA level of inflammation factors in type 2 diabetes rats.1) The results showed that the mRNA levels of TNF-αand IL-6 were higher in type 2 diabetes rat.2)Arecoline of dose on 1,5 mg/kg can decreased the mRNA levels of TNF-αand IL-6 in type 2 diabetes rat liver.3) Control+arecoline groups was not significantly different compared to control group.4. Low dose arecoline can improve the insulin sensitivity of liver in type 2 diabetes rats1) IRS-2 mRNA and the p-AKT protein were down-regulated in type 2 diabetes rats liver.2) 1,5 mg/kg arecoline can up-regulated IRS-2 mRNA and the p-AKT protein in type 2 diabetes rats liver.3) Control+arecoline groups was not significantly different compared to control group. 5. Low dose arecoline can elevate the mRNA level of CAR,PXR and de-crease the mRNA level of NF-κB in type 2 diabetes rats.1) The results showed that the mRNA levels of CAR and PXR were decreased and NF-κB mRNA levels were elevated in type 2 diabetes rat.2) Dose of arecoline on 1,5 mg/kg can improve the mRNA levels of CAR, PXR and decrease NF-κB mRNA in type 2 diabetes rat liver.3) Control+arecoline groups was not significantly different compared to control group.[CONCLUSION]1. Glucose metabolism can be improved with adding the concentrations low dose arecoline (1,5 mg/kg) in type 2 diabetes rats.2. PXR and CAR with up-regulated in 1,5 mg/kg arecoline can cross-talk with FoxO1 and PGC-1α; in other hand, it can down-regulated NF-κB and inflammation factors mRNA, indirectly improve liver insulin sensitiv-ity in type 2 diabetes rats.