Abstract
Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.
Highlights
Clinical trials have revealed beneficial actions of trivalent chromium (Cr3+) on glycemic control [1,2,3], yet a mechanism of action remains unknown
In cells treated with hyperinsulinemia in the presence of a low, pharmacologically relevant dose (10 nM) of CrPic for 16 h [4,6], the acute ability of insulin to stimulate glucose transport was corrected
Studies have suggested that a beneficial aspect of CrPic on glucose transport may entail countering defects in insulin signaling, thereby improving GLUT4 translocation to the plasma membrane (PM) [21,22,23,24]
Summary
Clinical trials have revealed beneficial actions of trivalent chromium (Cr3+) on glycemic control [1,2,3], yet a mechanism of action remains unknown In this regard, data collected in our lab as well as others revealed that Cr3+ exerts its influence on PM parameters [4,5,6]. Parallel experiments have since established that nutriaent overabundance promotes elevations in membrane cholesterol content in 3T3-L1 adipocytes and L6 myotubes, as well as in skeletal muscle of C57Bl/6J mice and Zucker rats [8,9,10,11,12] These membrane perturbations were observed concomitant with a loss of cortical filamentousactin (F-actin) necessary for proper incorporation of the insulin sensitive glucose transporter GLUT4 into the PM. Data revealed increased glucose flux through the hexosamine biosynthesis pathway (HBP) promoted elevated O-linked N-acetylglucosamine (O-GlcNAc) modification of specificity protein 1 (Sp1), leading to transcriptional activation of HMG-CoA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
