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

Michael A. Weber, Anne Lidor, Subodh Arora, Gino M. Salituro, Bei B. Zhang, Anton N. Sidawy

Research output: Contribution to journalArticle

Abstract

Background: Insulin induces vascular smooth muscle cell (VSMC) proliferation, 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 hypoglycemic activity in diabetic mice through interaction with the intracellular β subunit of the insulin receptor. This study was designed to determine whether DMAQB-1 has an insulin-like proliferative effect on human infragenicular VSMCs. Methods: Human infragenicular VSMCs were isolated from diabetic patients undergoing amputations. DMAQB-1 cell culture dose response was measured in both serum-free media and media with 1% fetal bovine serum (FBS). 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 [14C]-2-deoxyglucose uptake. DNA synthesis was used as the marker for proliferative stimulus and detected by [3H]-thymidine uptake measured at 24 hours. Analysis of variance was used to compare the results among the groups; a P value less than .05 was considered significant. Polynomial regression was used to calculate the median lethal dose. Results: In normal glucose media (100 mg/dL), various concentrations of DMAQB-1 demonstrated a small but statistically significant decrease in DNA synthesis at 0.5 nmol/L in serum-free media and at 5 nmol/L in media supplemented with 1% FBS. The corresponding median lethal dose was 107 nmol/L in serum-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 μU/mL. In serum-free, high glucose media (200 mg/dL), DMAQB-1 concentrations up to 500 nmol/L did not cause a statistically significant change in DNA synthesis. When serum-free, high glucose media was combined with mild (100 μU/mL) or moderate (250 μU/mL) concentrations of insulin, DMAQB-1 caused no statistically significant increase in DNA synthesis. Conclusion: Nontoxic doses of DMAQB-1 can induce glucose transport equivalent to insulin in the physiologic range. However, DMAQB-1 does not have an insulin-like proliferative effect on human VSMCs in normal-glucose, high-glucose, or high-insulin environments.

Original languageEnglish (US)
Pages (from-to)1118-1126
Number of pages9
JournalJournal of vascular surgery
Volume32
Issue number6
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'A novel insulin mimetic without a proliferative effect on vascular smooth muscle cells'. Together they form a unique fingerprint.

  • Cite this

    Weber, M. A., Lidor, A., Arora, S., Salituro, G. M., Zhang, B. B., & Sidawy, A. N. (2000). A novel insulin mimetic without a proliferative effect on vascular smooth muscle cells. Journal of vascular surgery, 32(6), 1118-1126. https://doi.org/10.1067/mva.2000.111280