In vitro effects of endogenous and exogenous cannabinoids on insulin resistance and secretion

Type 2 diabetes mellitus results from a combination of insulin resistance and impaired insulin secretion. The aim of this study is to investigate the effect of endogenous and exogenous cannabinoids on insulin resistant cell lines, viz skeletal muscle (C2C12) and fat (3T3-L1), and to investigate the effects of these cannabinoids on insulin secretion in pancreatic β-cells (INS 1). Insulin resistance was induced in the cells using 20 ng/mL TNF-α (3T3-L1) and 100 nM insulin (C2C12). Insulin resistant cells were exposed to cannabinoids for 48 hours after which glucose uptake, RT-PCR and Western blot analysis was performed. Additionally, adipokine assays were performed on the 3T3-L1 cells. The insulin resistant 3T3-L1 and C2C12 cells had reduced glucose uptake, decreased IRS-1 and Glut-4 expression indicative of an insulin resistant state. The extract and THC significantly enhanced glucose uptake, IRS-1 and Glut-4 in 3T3-L1 and C2C12 cells. The extract and THC thus have the potential to be an insulin sensitizing agent. Interleukin-6 was significantly decreased by THC. INS 1 cells, cultured under normoglycemic conditions, were exposed to cannabinoids for 48 hours after which glucose-stimulated insulin secretion, radioimmunoassay, oxygen consumption, RT-PCR and Western blot analysis was performed. Insulin stimulatory index was not significantly affected after cannabinoid exposure, except by THC. The cannabinoids decreased insulin content, in a concentration dependent manner, but the inhibition mechanism remains elusive. The cannabinoid Treated cells showed insulin gene expression levels similar to the control, while only THC proved effective in significantly stimulating Glut-2 gene expression. Oxygen consumption studies showed levels lower than the control cells. Most of the cannabinoids inhibited insulin secretion under normoglycemia except THC, while the cannabinoids exhibited the potential to improve insulin resistant adipocyte and myocytes response to glucose and gene regulatio