Serpentine Enhances Insulin Regulation of Blood Glucose through Insulin Receptor Signaling Pathway

Insulin sensitizers targeting insulin receptors (IR) are a potential drug for the treatment of diabetes. Serpentine is an alkaloid component in the root of Catharanthus roseus (L.) G. Don. Serpentine screened by surface plasmon resonance (SPR) technology has the ability to target IR. The objective of this study was to investigate whether serpentine could modulate the role of insulin in regulating blood glucose through insulin receptors in cells and in animal models of diabetes. SPR technology was used to detect the affinity of different concentrations of serpentine with insulin receptors. The Western blotting method was used to detect the expression levels of key proteins of the insulin signaling pathway in C2C12 cells and 3T3-L1 cells as well as in muscle and subcutaneous adipose tissue of diabetic mice after serpentine and insulin treatment. Diabetic mice were divided into four groups and simultaneously injected with insulin or serpentine, and the blood glucose concentration and serum levels of insulin, glucagon, and C-peptide were measured 150 min later. mRNA levels of genes related to lipid metabolism and glucose metabolism in liver, muscle, and subcutaneous adipose tissue were detected by RT-PCR. Serpentine was able to bind to the extracellular domain of IR with an affinity of 2.883 × 10−6 M. Serpentine combined with insulin significantly enhanced the ability of insulin to activate the insulin signaling pathway and significantly enhanced the glucose uptake capacity of C2C12 cells. Serpentine enhanced the ability of low-dose insulin (1 nM) and normal-dose insulin (100 nM) to activate the insulin signaling pathway. Serpentine also independently activated AMPK phosphorylation, thus stimulating glucose uptake by C2C12 cells. In high-fat-diet/streptozotocin (HFD/STZ)-induced diabetic mice, serpentine significantly prolonged the hypoglycemic time of insulin, significantly reduced the use of exogenous insulin, and inhibited endogenous insulin secretion. In addition, serpentine alone significantly increased the expression of GSK-3β mRNA in muscle tissue, thus enhancing glucose uptake, and at the same time, serpentine significantly increased glucagon secretion and liver gluconeogenesis. Serpentine enhances the ability of insulin to regulate blood glucose through the insulin receptor, and can also regulate blood glucose alone, but it has a negative regulation mechanism and cannot produce a hypoglycemic effect. Therefore, serpentine may be useful as an insulin sensitizer to assist insulin to lower blood glucose.