A novel insulin mimetic without a proliferative effect on vascular smooth muscle cells

Background: Insulin induces vascular smooth muscle cell. (VSMC) proliferati on, which is an important step in the atherosclerotic process. Recently, a nonpeptidyl fungal metabolite originally referred to as L-783,281, but also known as demethylasterriquinone B-1 (DMAQB-1), was found to have hypoglyce mic activity in diabetic mice through interaction with the intracellular be ta subunit of the insulin receptor. This study was designed to determine wh ether DMAQB-1 has an insulin-like proliferative effect on human infragenicu lar VSMCs. Methods: Human infragenicular VSMCs were isolated from diabetic patients un dergoing amputations. DMAQB-1 cell culture dose response was measured in bo th serum-free media and media with 1% fetal bovine serum (PBS). A working, concentration of DMAQB-1 that ranged from 0.5 to 500 nmol/L was studied in the presence of varying concentrations of glucose and insulin. The ability of DMAQB-1 to stimulate glucose transport at less than or equal to 100 nmol /L was determined by [C-14]-2-deoxyglucose uptake. DNA synthesis was used a s the marker for proliferative stimulus and detected by [H-3]-thymidine upt ake measured at 24 hours. Analysis of variance was used to compare the resu lts among the groups; a P value less than .05 was considered significant. P olynomial regression was used to calculate the median lethal dose. Results: In normal glucose media (100 mg/dL), various concentrations of DMA QB-1 demonstrated a small but statistically significant decrease in DNA syn thesis at 0.5 nmol/L in serum-free media and at 0.5 nmol/L in media supplem ented with 1% FBS. The corresponding median lethal dose mas 107 nmol/L in s erum-free media and 650 nmol/L in media supplemented with 1% FBS. A DMAQB-1 concentration of 5 nmol/L induced glucose transport that was equivalent to an insulin concentration of 100 muU/mL. In serum-free, high glucose media (200 mg/dL), DMAQB-1 concentrations up to 500 nmol/L did not cause a statis tically significant change in DNA synthesis. When serum-free, high glucose media was combined with mild (100 muU/mL) or moderate (250 muU/mL) concentr ations of insulin, DMAQB-1 caused no statistically significant increase in DNA synthesis. Conclusion: Nontoxic doses of DMAQB-1 can induce glucose transport equivale nt to insulin in the physiologic range. However, DMAQB-1 does not have an i nsulin-like proliferative effect on human VSMCs in normal-glucose, high-glu cose, or high-insulin environments.