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 mu g 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), a subunit of translation initiation factor 2 (eIF2 alpha) 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-eIF2 alpha), 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.