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
C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(D-phe)(3) (3.8 mug 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), alpha subunit of translation initiation factor 2 (eIF2alpha) 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-eIF2alpha), 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.


CONCLUSIONS
Oral Cr(D-phe)(3) treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin-resistant mice.
Sreejayan
Nair
N
Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming, Laramie, Wyoming, USA. sreejay@uwyo.edu
Dong
Feng
F
Kandadi
Machender R
MR
Yang
Xiaoping
X
Ren
Jun
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002857:Chromium / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D018149:Glucose Intolerance / Q000188:drug therapy / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014131:Trace Elements / Q000494:pharmacology* / Q000627:therapeutic use; D019892:eIF-2 Kinase / Q000378:metabolism
D001786:Blood Glucose; D002857:Chromium; D007328:Insulin; D020738:Leptin; D008055:Lipids; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019284:Thapsigargin; D014131:Trace Elements; D019892:eIF-2 Kinase; C486556:Ern2 protein, mouse