Experimental Study On The Effect Of Compound CXW On Enhancing Insulin Reactivity And Its Mechanism

Type2diabetes, characterized by chronic hyperglycaemia, is resulted from insulin resistance with or without impaired insulin secretion. Although the molecular mechanism of insulin resistance has been unclearly, it may be attributed to the aberrant insulin signaling pathway. PTP1B, the first identified member of the protein tyrosine phosphatase family, has been well documented as a negative regulator of insulin signaling pathway. Thus, PTP1B inhibitor, a potential insulin sensitizer, may be a novel therapeutic strategy for the type2diabetes treatment. The serum insulin level shows varied during the insulin resistant progress. It has been demonstrated that the transcription factor ChREBP is regulated by the high blood glucose level, and plays a key role in hepatic lipogenesis.The investigation previously showed that CXW, a chemical compound, ameliorates insulin resistance significantly by reversing hyperinsulinemia and glycolipid metabolic disorders in both high-fat-die-induced DIO mice and type2diabeties KKAy mice. Here, the effects of CXW on the improvement of insulin sensitivity in cell models and the association between CXW and PTP1B were explored. The results showed that compound CXW enhanced the responses to insulin significantly by increasing the insulin-stimulated phosphorylation of IRβ and its downstream Akt in HepG2hepatocyte, and by increasing the abilities of insulin-induced glucose uptake significantly in both C2C12myotubes and3T3-L1adipocytes, respectively. The PTP1B activity were remarkably inhibited by CXW in vitro with the IC50of5.98×10-7M and1.257×10-6M against GST-PTP1B, a full-length human PTP1B protein(75kD), and His-PTPIB, containing the human PTP1B active domain(39kD), respectively. Notably, the PTP1B expression was not affected by CXW in HepG2hepatocyte. The results from the CD spectra analysis indicated that CXW could bind directly with PTP1B, and induce the minor conformational changes of PTP1B protein. Taken together, CXW could increase insulin sensitivity by inhibiting PTP1B activities in cell models.High blood glucose levels can upregulate the expression of hepatic ChREBP, FAS and ACC, resulting in the regulation of hepatic lipid metabolism. Hyperinsulinemia is considered as one of the main features of insulin resistance. To explore the effects of high serum insulin levels on the expression of ChREBP, ACC, and FAS, the KKAy mice with high levels of both serum insulin and glucose and the DIO mice with high serum insulin levels alone were utilized, respectively. The results showed that hyperinsulinemia may cause glycolipid metabolic disorders by up-regulating the expression of ChREBP in vivo. Whether or not the improvement of hyperinsulinemia by CXW via the factor ChREBP, it needs to be further investigated.In summary, compound CXW could increase insulin sensitivity in HepG2hepatocyte, C2C12myotubes and3T3-L1adipocytes, respectively, by inhibiting PTP1B activity.