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

N. Sreejayan, F. Dong, M.R. Kandadi, X. Yang, J. Ren

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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. © 2008 The Obesity Society.
Original languageEnglish
Pages (from-to)1331-1337
Number of pages7
JournalObesity
Volume16
Issue number6
DOIs
Publication statusPublished - 2008

Fingerprint

Obese Mice
Endoplasmic Reticulum Stress
Glucose Intolerance
Chromium
Insulin Resistance
Liver
Insulin
Phosphoserine
Insulin Receptor Substrate Proteins
Thapsigargin
Inositol
Phosphotransferases
Prokaryotic Initiation Factor-2
Glucose
Skeletal Muscle Fibers
Enzymes
Glucose Tolerance Test
Phenylalanine
Endoplasmic Reticulum
Muscle Cells

Cite this

Sreejayan, N. ; Dong, F. ; Kandadi, M.R. ; Yang, X. ; Ren, J. / Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice. In: Obesity. 2008 ; Vol. 16, No. 6. pp. 1331-1337.
@article{249daff6efcb4dae85c1ecb4752062c4,
title = "Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice",
abstract = "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. {\circledC} 2008 The Obesity Society.",
author = "N. Sreejayan and F. Dong and M.R. Kandadi and X. Yang and J. Ren",
note = "Cited By :55 Export Date: 10 November 2017 Correspondence Address: Sreejayan, N.; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wyoming, Laramie, WY, United States; email: sreejay@uwyo.edu Chemicals/CAS: chromium, 16065-83-1, 7440-47-3; insulin, 9004-10-8; lactone, 1338-03-0; lipid, 66455-18-3; Blood Glucose; Chromium, 7440-47-3; eIF-2 Kinase, EC 2.7.1.37; Ern2 protein, mouse, EC 2.7.1.-; Insulin, 11061-68-0; Lactones; Leptin; Lipids; Membrane Proteins; PERK kinase, EC 2.7.10.-; Protein-Serine-Threonine Kinases, EC 2.7.11.1; Sesquiterpenes; thapsigargicin, 67526-94-7; Trace Elements References: Sowers, J.R., Frohlich, E.D., Insulin and insulin resistance: Impact on blood pressure and cardiovascular disease (2004) Med Clin North Am, 88, pp. 63-82; Anderson, R.A., Chromium in the prevention and control of diabetes (2000) Diabetes Metab, 26, pp. 22-27; Jeejeebhoy, K.N., Chu, R.C., Marliss, E.B., Greenberg, G.R., Bruce-Robertson, A., Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition (1977) Am J Clin Nutr, 30, pp. 531-538; Cefalu, W.T., Hu, F.B., Role of chromium in human health and in diabetes (2004) Diabetes Care, 27, pp. 2741-2751; Vincent, J.B., Recent advances in the nutritional biochemistry of trivalent chromium (2004) Proc Nutr Soc, 63, pp. 41-47; Anderson, R.A., Cheng, N., Bryden, N.A., Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes (1997) Diabetes, 46, pp. 1786-1791; Martin, J., Wang, Z.Q., Zhang, X.H., Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes (2006) Diabetes Care, 29, pp. 1826-1832; Kleefstra, N., Houweling, S.T., Jansman, F.G., Chromium treatment has no effect in patients with poorly controlled, insulin-treated type 2 diabetes in an obese Western population: A randomized, double-blind, placebo-controlled trial (2006) Diabetes Care, 29, pp. 521-525; Gunton, J.E., Cheung, N.W., Hitchman, R., Chromium supplementation does not improve glucose tolerance, insulin sensitivity, or lipid profile: A randomized, placebo-controlled, double-blind trial of supplementation in subjects with impaired glucose tolerance (2005) Diabetes Care, 28, pp. 712-713; Nakatani, Y., Kaneto, H., Kawamori, D., Involvement of endoplasmic reticulum stress in insulin resistance and diabetes (2005) J Biol Chem, 280, pp. 847-851; Hotamisligil, G.S., Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes (2005) Diabetes, 54 (SUPPL. 2), pp. S73-S78; Ozcan, U., Cao, Q., Yilmaz, E., Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes (2004) Science, 306, pp. 457-461; Yusta, B., Baggio, L.L., Estall, J.L., GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress (2006) Cell Metab, 4, pp. 391-406; Ozcan, U., Yilmaz, E., Ozcan, L., Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes (2006) Science, 313, pp. 1137-1140; Yang, X., Palanichamy, K., Ontko, A.C., A newly synthetic chromium complex-chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance (2005) FEBS Lett, 579, pp. 1458-1464; Li, S.Y., Yang, X., Ceylan-Isik, A.F., Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch (2006) Diabetologia, 49, pp. 1434-1446; Yang, X., Li, S.Y., Dong, F., Ren, J., Sreejayan, N., Insulin-sensitizing and cholesterol-lowering effects of chromium (D-Phenylalanine)3 (2006) J Inorg Biochem, 100, pp. 1187-1193; Ran, J., Hirano, T., Adachi, M., Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats (2004) Am J Physiol Endocrinol Metab, 287, pp. E227-E232; Sreejayan, N., Lin, Y., Hassid, A., NO attenuates insulin signaling and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B-mediated mechanism (2002) Arterioscler Thromb Vasc Biol, 22, pp. 1086-1092; Sykiotis, G.P., Papavassiliou, A.G., Serine phosphorylation of insulin receptor substrate-1: A novel target for the reversal of insulin resistance (2001) Mol Endocrinol, 15, pp. 1864-1869; Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med 2005;37:347-356; Cefalu, W.T., Wang, Z.Q., Zhang, X.H., Baldor, L.C., Russell, J.C., Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats (2002) J Nutr, 132, pp. 1107-1114; Clodfelder, B.J., Gullick, B.M., Lukaski, H.C., Neggers, Y., Vincent, J.B., Oral administration of the biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ increases insulin sensitivity and improves blood plasma variables in healthy and type 2 diabetic rats (2005) J Biol Inorg Chem, 10, pp. 119-130; Kim, D.S., Kim, T.W., Park, I.K., Kang, J.S., Om, A.S., Effects of chromium picolinate supplementation on insulin sensitivity, serum lipids, and body weight in dexamethasone-treated rats (2002) Metabolism, 51, pp. 589-594; Pattar, G.R., Tackett, L., Liu, P., Elmendorf, J.S., Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions (2006) Mutat Res, 610, pp. 93-100; Urano, F., Wang, X., Bertolotti, A., Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 (2000) Science, 287, pp. 664-666; Aguirre, V., Uchida, T., Yenush, L., Davis, R., White, M.F., The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) (2000) J Biol Chem, 275, pp. 9047-9054; Rui, L., Fisher, T.L., Thomas, J., White, M.F., Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2 (2001) J Biol Chem, 276, pp. 40362-40367",
year = "2008",
doi = "10.1038/oby.2008.217",
language = "English",
volume = "16",
pages = "1331--1337",
journal = "Obesity",
issn = "1930-7381",
publisher = "Wiley-Blackwell",
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}

Sreejayan, N, Dong, F, Kandadi, MR, Yang, X & Ren, J 2008, 'Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice', Obesity, vol. 16, no. 6, pp. 1331-1337. https://doi.org/10.1038/oby.2008.217

Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice. / Sreejayan, N.; Dong, F.; Kandadi, M.R.; Yang, X.; Ren, J.

In: Obesity, Vol. 16, No. 6, 2008, p. 1331-1337.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice

AU - Sreejayan, N.

AU - Dong, F.

AU - Kandadi, M.R.

AU - Yang, X.

AU - Ren, J.

N1 - Cited By :55 Export Date: 10 November 2017 Correspondence Address: Sreejayan, N.; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wyoming, Laramie, WY, United States; email: sreejay@uwyo.edu Chemicals/CAS: chromium, 16065-83-1, 7440-47-3; insulin, 9004-10-8; lactone, 1338-03-0; lipid, 66455-18-3; Blood Glucose; Chromium, 7440-47-3; eIF-2 Kinase, EC 2.7.1.37; Ern2 protein, mouse, EC 2.7.1.-; Insulin, 11061-68-0; Lactones; Leptin; Lipids; Membrane Proteins; PERK kinase, EC 2.7.10.-; Protein-Serine-Threonine Kinases, EC 2.7.11.1; Sesquiterpenes; thapsigargicin, 67526-94-7; Trace Elements References: Sowers, J.R., Frohlich, E.D., Insulin and insulin resistance: Impact on blood pressure and cardiovascular disease (2004) Med Clin North Am, 88, pp. 63-82; Anderson, R.A., Chromium in the prevention and control of diabetes (2000) Diabetes Metab, 26, pp. 22-27; Jeejeebhoy, K.N., Chu, R.C., Marliss, E.B., Greenberg, G.R., Bruce-Robertson, A., Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition (1977) Am J Clin Nutr, 30, pp. 531-538; Cefalu, W.T., Hu, F.B., Role of chromium in human health and in diabetes (2004) Diabetes Care, 27, pp. 2741-2751; Vincent, J.B., Recent advances in the nutritional biochemistry of trivalent chromium (2004) Proc Nutr Soc, 63, pp. 41-47; Anderson, R.A., Cheng, N., Bryden, N.A., Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes (1997) Diabetes, 46, pp. 1786-1791; Martin, J., Wang, Z.Q., Zhang, X.H., Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes (2006) Diabetes Care, 29, pp. 1826-1832; Kleefstra, N., Houweling, S.T., Jansman, F.G., Chromium treatment has no effect in patients with poorly controlled, insulin-treated type 2 diabetes in an obese Western population: A randomized, double-blind, placebo-controlled trial (2006) Diabetes Care, 29, pp. 521-525; Gunton, J.E., Cheung, N.W., Hitchman, R., Chromium supplementation does not improve glucose tolerance, insulin sensitivity, or lipid profile: A randomized, placebo-controlled, double-blind trial of supplementation in subjects with impaired glucose tolerance (2005) Diabetes Care, 28, pp. 712-713; Nakatani, Y., Kaneto, H., Kawamori, D., Involvement of endoplasmic reticulum stress in insulin resistance and diabetes (2005) J Biol Chem, 280, pp. 847-851; Hotamisligil, G.S., Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes (2005) Diabetes, 54 (SUPPL. 2), pp. S73-S78; Ozcan, U., Cao, Q., Yilmaz, E., Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes (2004) Science, 306, pp. 457-461; Yusta, B., Baggio, L.L., Estall, J.L., GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress (2006) Cell Metab, 4, pp. 391-406; Ozcan, U., Yilmaz, E., Ozcan, L., Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes (2006) Science, 313, pp. 1137-1140; Yang, X., Palanichamy, K., Ontko, A.C., A newly synthetic chromium complex-chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance (2005) FEBS Lett, 579, pp. 1458-1464; Li, S.Y., Yang, X., Ceylan-Isik, A.F., Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch (2006) Diabetologia, 49, pp. 1434-1446; Yang, X., Li, S.Y., Dong, F., Ren, J., Sreejayan, N., Insulin-sensitizing and cholesterol-lowering effects of chromium (D-Phenylalanine)3 (2006) J Inorg Biochem, 100, pp. 1187-1193; Ran, J., Hirano, T., Adachi, M., Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats (2004) Am J Physiol Endocrinol Metab, 287, pp. E227-E232; Sreejayan, N., Lin, Y., Hassid, A., NO attenuates insulin signaling and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B-mediated mechanism (2002) Arterioscler Thromb Vasc Biol, 22, pp. 1086-1092; Sykiotis, G.P., Papavassiliou, A.G., Serine phosphorylation of insulin receptor substrate-1: A novel target for the reversal of insulin resistance (2001) Mol Endocrinol, 15, pp. 1864-1869; Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med 2005;37:347-356; Cefalu, W.T., Wang, Z.Q., Zhang, X.H., Baldor, L.C., Russell, J.C., Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats (2002) J Nutr, 132, pp. 1107-1114; Clodfelder, B.J., Gullick, B.M., Lukaski, H.C., Neggers, Y., Vincent, J.B., Oral administration of the biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ increases insulin sensitivity and improves blood plasma variables in healthy and type 2 diabetic rats (2005) J Biol Inorg Chem, 10, pp. 119-130; Kim, D.S., Kim, T.W., Park, I.K., Kang, J.S., Om, A.S., Effects of chromium picolinate supplementation on insulin sensitivity, serum lipids, and body weight in dexamethasone-treated rats (2002) Metabolism, 51, pp. 589-594; Pattar, G.R., Tackett, L., Liu, P., Elmendorf, J.S., Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions (2006) Mutat Res, 610, pp. 93-100; Urano, F., Wang, X., Bertolotti, A., Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 (2000) Science, 287, pp. 664-666; Aguirre, V., Uchida, T., Yenush, L., Davis, R., White, M.F., The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) (2000) J Biol Chem, 275, pp. 9047-9054; Rui, L., Fisher, T.L., Thomas, J., White, M.F., Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2 (2001) J Biol Chem, 276, pp. 40362-40367

PY - 2008

Y1 - 2008

N2 - 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. © 2008 The Obesity Society.

AB - 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. © 2008 The Obesity Society.

U2 - 10.1038/oby.2008.217

DO - 10.1038/oby.2008.217

M3 - Article

VL - 16

SP - 1331

EP - 1337

JO - Obesity

JF - Obesity

SN - 1930-7381

IS - 6

ER -