Upregulation of GLUT4 Expression and Glucose Homeostasis by Synthetic Peptides HL-7 and HL-10 in in-vitro and in-vivo Diabetic Models

This study aimed to investigate the effect of two synthetic peptides, HL-7 and HL-10, extracted from the venom of H. lepturus, on insulin secretion and glucose absorption. The INS-1 cell line was used to measure the amount of insulin secretion in the culture medium, while the HSkMC cell line was applied to analyze the amount of glucose uptake and GLUT4, AMP and Akt gene expression. Also, streptozotocin-induced diabetic rats were used to assess plasma glucose, insulin concentrations, and GLUT4 gene expression levels in soleus muscle isolated from rats. Finally, the in-silico analysis evaluated the interaction of the two peptides with the transcription factor NF-kappa B. The results showed that the amount of insulin released and glucose uptake by INS-1 and HSkMC cells treated with HL-7 and HL-10 peptides significantly increased (p < 0.0001). Accordingly, both peptides decreased plasma glucose and elevated insulin levels in diabetic rats compared to untreated diabetic rats (p < 0.0001). Also, an increase was found in GLUT4 gene expression at both mRNA and protein levels in peptide-treated cells compared to untreated cells. Also, an increase in GLUT4, AMPK and Akt gene expression was observed at both mRNA and protein levels in peptide-treated cells compared to untreated cells. The in-silico results demonstrated strong hydrogen bonds between the two peptides with the NF-kappa B protein, indicating the possible inhibitory role of these peptides against NF-kappa B. The results of the present study showed that the two peptides can control diabetes and glucose homeostasis in a glucose-dependent and -independent manner. Also, one of the reasons for increased glucose uptake can be due to the regulation of key upstream signaling kinases such as AMPK and Akt, which ultimately leads to the regulation of GLUT4 expression and facilitating glucose uptake by peptide-treated HSkMC cells. Since the analyzed synthetic peptides had no significant toxicity against INS-1 and HSkMC cells, they could be suitable candidates for humans with diabetes in clinical trials.