Abrogation of Insulin-like Growth Factor-I (IGF-I) and Insulin Action by Mevalonic Acid Depletion

Abstract

High concentrations of statin were necessary to impair insulin-mediated glucose uptake (300 nM ‫؍‬ 33% ؎ 12% p < 0.05), and this process was not effected by farnesyl transferase inhibition. Gycosylation inhibitors mimicked the effect of statin treatment (tunicamycin p < 0.001, castanospermine p < 0.05, deoxymannojirimycin p < 0.05), and there was insulin proreceptor accumulation. These data imply that HMG-CoA reductase inhibitors disrupt IGF-I signaling by combined effects on Ras prenylation and IGF receptor glycosylation, whereas insulin signaling is only affected by disrupted receptor glycosylation.

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

“…We have previously shown that HMG-CoA reductase inhibitors are potent inhibitors of IGF signaling in 3T3-L1 preadi- pocytes (17), and so we next investigated whether cerivastatin would modulate inhibition of the osteogenic differentiation and mineralization of VSMCs by IGF. Fig.…”

“…IGFR Localization-To determine the effect of HMG-CoA reductase inhibitors on the cell-surface expression of the IGFR, confluent VSMCs (in T75 flasks) were treated with and without cerivastatin for 4 days, and membranes were prepared as described previously (17). Briefly, cells were washed three times with ice-cold PBS, scraped into 50 mM HEPES and protease inhibitor mixture (Calbiochem), and sonicated (3 ϫ 5 s, MSE sonicator, amplitude of 16 m).…”

“…The role of IGF-I in the terminal differentiation of multiple cell types is well known (14 -16), but its role in phenotype maintenance is less well understood. We have previously shown that IGF signaling can be attenuated in 3T3-L1 cells using HMG-CoA reductase inhibitors through their effects on IGF receptor (IGFR) glycosylation and Ras prenylation (17). Therefore, by removing this protective pathway, we hypothesized that HMG-CoA reductase inhibitors would also render vascular cells more vulnerable to osteogenic differentiation and subsequent mineralization.…”

Statins in the Treatment of Polycystic Ovary Syndrome

“…In addition, by decreasing FPP and subsequently dolichol synthesis, statins have an inhibitory effect on N-linked glycosylation 130 and therefore, insulin and Type 1 IGF-1 proreceptor cleavage may be impaired. In addition, statins possess both indirect and direct antioxidant activity 136 .…”

“…Dolichol, a product of the mevalonate pathway, is required for the maturation of insulin and Type 1 IGF-I receptors 120 . Specifically, dolichol acts as a carbohydrate donor during N-linked glycosylation of membrane-targeted proteins 130 . While this post-translational modification is not critical for most cell surface receptors, the Type 1 IGF and insulin receptors require glycosylation for proper proreceptor cleavage, without which the proreceptor is retained within the endoplasmic reticulum 131,132 ; thus dolichol is essential for insulin and IGF-I signaling.…”