Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions

Abstract

Since trivalent chromium (Cr 3+ ) enhances glucose metabolism, interest in the use of Cr 3+ as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr 3+ may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake. A recent study in our laboratory shows that exposure of 3T3-L1 adipocytes to chromium picolinate (CrPic, 10 nM) induces a loss of plasma membrane cholesterol. Concomitantly, accumulation of intracellularly sequestered glucose transporter GLUT4 at the plasma membrane was dependent on the CrPic-induced cholesterol loss. Since CrPic supplementation has the greatest benefit on glucose metabolism in hyperglycemic insulin-resistant individuals, we asked here if the CrPic effect on cells was glucose-dependent. We found that GLUT4 redistribution in cells treated with CrPic occurs only in cells cultured under high glucose (25 mM) conditions that resemble the diabetic-state, and not in cells cultured under non-diabetic (5.5 mM glucose) conditions. Examination of the effect of CrPic on proteins involved in cholesterol homeostasis revealed that the activity of sterol regulatory element-binding protein (SREBP), a membrane-bound transcription factor ultimately responsible for controlling cellular cholesterol balance, was upregulated by CrPic. In addition, ABCA1, a major player in mediating cholesterol efflux was decreased, consistent with SREBP transcriptional repression of the ABCA1 gene. Although the exact mechanism of Cr 3+ -induced cholesterol loss remains to be determined, these cellular responses highlight a novel and significant effect of chromium on cholesterol homeostasis. Furthermore, these findings provide an important clue to our understanding of how chromium supplementation might benefit hypercholesterolemia-associated disorders.

Evaluation of insulin binding and signaling activity of newly synthesized chromium(III) complexes in vitro

“…Similar results were presented by Pattar et al (47), who found that chromium picolinate decreased the content of membrane cholesterol in 3T3-L1 cells. This mechanism was connected with enhanced glucose transport stimulated by insulin and increased the translocation of gLuT4 into the plasma membrane.…”

Chromium chloride increases insulin‐stimulated glucose uptake in the perfused rat hindlimb

“…Pattar et al (50) found that chromium increased membrane fluidity in mouse 3T3-L1 adipocytes. Evans and Bowman (29) found that the addition of chromium led to an increase in plasma membrane fluidity in rat myoblasts.…”

“…It has been reported that chromium supplementation affects glucose uptake through augmentation of the fluidity of the plasma membrane (22,29,50). It is postulated that GLUT4 has an increased affinity for areas of the plasma membrane that exhibit greater fluidity, leading to an increased incorporation of GLUT4 into the plasma membrane (53).…”

“…However, when non-insulin resistant muscles or adipose cultures were examined, there was no alteration in insulin signaling, but an increase in plasma membrane fluidity (22,29,50). There is a possibility that both of these are viable mechanisms of chromium action.…”

“…The majority of studies have shown that chromium increases insulin signaling by increasing phosphorylation of the insulin receptor, leading to an increase in Akt activation (27,67,68). However, other studies have determined that augmentation of the plasma membrane is responsible for the increase in glucose uptake (22,50).…”