Acute insulin resistance stimulates and insulin sensitization attenuates vascular smooth muscle cell migration and proliferation

Differential activation/deactivation of insulin signaling, PI ‐3K and MAP ‐K pathways by high glucose and palmitate, with/out the insulin sensitizer pioglitazone ( PIO ), have been previously shown in vascular smooth muscle cells ( VSMC s). To determine the biological impact of these molecular changes, we examined VSMC migration and proliferation (“M”&”P”) patterns in similar conditions. VSMC s from healthy human coronary arteries were incubated in growth medium and “M”&”P” were analyzed after exposure to high glucose (25 mmol/L) ± palmitate (200  μ mol/L) and ±  PIO (8  μ mol/L) for 5 h. “M”&”P” were assessed by: (1) polycarbonate membrane barrier with chemo‐attractants and extended cell protrusions quantified by optical density ( OD 595  nm); (2) % change in radius area (2D Assay) using inverted microscopy images; and (3) cell viability assay expressed as cell absorbance ( ABS ) in media. “M” in 25 mmol/L glucose media increased by ~25% from baseline and % change in radius area rose from ~20% to ~30%. The addition of PIO was accompanied by a significant decrease in “M” from 0.25 ± 0.02 to 0.19 ± 0.02; a comparable decline from 0.25 ± 0.02 to 0.18 ± 0.02 was also seen with 25 mmol/L of glucose +200  μ mol/L of palmitate. When PIO was coincubated with high glucose plus palmitate there was a 50% reduction in % change in radius. A ~10% increase in ABS , reflecting augmented “P” in media with 25 mmol/L glucose versus control was documented. The addition of PIO reduced ABS from 0.208 ± 0.03 to 0.183 ± 0.06. Both high glucose and palmitate showed ABS of ~0.140 ± 0.02, which decreased with PIO to ~0.120 ± 0.02, indicating “P” was reduced. Conclusion: These results confirm that high glucose and palmitate stimulate VSMC s migration and proliferation in vitro, which is attenuated by coincubation with the insulin sensitizer PIO . Although, we cannot ascertain whether these functional changes are coincident with the activation/deactivation of signal molecules, our findings are consistent with the theory that differential regulation of insulin signaling pathways in VSMC s in insulin‐resistant states plays an important role in inflammation, arterial wall thickening, and plaque formation during development of atherosclerosis.