Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice

Objective: Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of d ‐phenylalanine (Cr(d ‐phe)₃) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(d ‐phe)₃ suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals. Methods and Procedures: C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(d ‐phe)₃ (3.8 μg of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), α subunit of translation initiation factor 2 (eIF2α) and inositol‐requiring enzyme‐1 (IRE‐1), p‐c‐Jun, and insulin receptor substrate‐1 (IRS‐1) phosphoserine‐307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(d ‐phe)₃. Results: ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(d ‐phe)₃. Markers of insulin resistance (phospho‐c‐Jun and IRS‐1 phosphoserine) and ER stress (p‐PERK, p‐IRE‐1, p‐eIF2α), which were elevated in ob/ob mice, were attenuated following Cr(d ‐phe)₃ treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(d ‐phe)₃ attenuated ER stress induced by thapsigargin. Discussion: Oral Cr(d ‐phe)₃ treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin‐resistant mice.