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Hyperketonemia decreases mitochondrial membrane potential and its normalization with chromium (III) supplementation in monocytes

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Abstract

Altered cellular mitochondrial membrane potential (MMP) has been implicated in the increased insulin resistance and the risk for diabetes. Hyperketonemia is increasingly being identified in type 2 diabetic patients in addition to those with type 1 diabetes. No previous study has examined the effect of hyperketonemia and trivalent chromium on cellular mitochondrial membrane potential (MMP) in any cell type. Using a U937 monocyte cell culture model, this study examined the hypothesis that hyperketonemia decreases and trivalent chromium normalizes the cellular MMP level. Cells were cultured with control and ketone bodies [acetoacetate (AA), β-hydroxybutyrate (BHB)] in the absence or the presence (0.5–100 μM) of Cr3+ at 37°C for 24 h. The MMP was determined using DiOC6 and flow cytometry. The results show a significant decrease in MMP in cells treated with AA, but not in the cells treated with BHB. The effect of AA on cellular MMP was prevented in chromium (III)-pretreated cells. Thus, hyperketonemia decreases the MMP, and supplementation with chromium (III) normalizes altered MMP, which may play a role in the improvement in glucose metabolism seen after chromium (III) supplementation in some studies with diabetic animals and patients.

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References

  1. Kim J-a, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102(4):401–414

    Article  CAS  PubMed  Google Scholar 

  2. Turner N, Heilbronn LK (2008) Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol Metab 19(9):324–330

    Article  CAS  PubMed  Google Scholar 

  3. Morino K, Petersen Kitt Falk, Dufour Sylvie, Befroy Douglas, Frattini Jared, Shatzkes Nadine, Neschen Susanne, White Morris F, Bilz Stefan, Sono Saki, Pypaert Marc, Shulman Gerald I (2005) Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115(12):3587–3593

    Article  CAS  PubMed  Google Scholar 

  4. Szendroedi J, Schmid AI, Meyerspeer M, Cervin C, Kacerovsky M, Smekal G, Graser-Lang S, Groop L, Roden M (2009) Impaired mitochondrial function and insulin resistance of skeletal muscle in mitochondrial diabetes. Diabetes Care 32(4):677–679

    Article  CAS  PubMed  Google Scholar 

  5. Mogensen M, Sahlin K, Fernstrom M, Glintborg D, Vind BF, Beck-Nielsen H, Hojlund K (2007) Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56(6):1592–1599

    Article  CAS  PubMed  Google Scholar 

  6. Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53(90001):S96–102

    Article  CAS  PubMed  Google Scholar 

  7. Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307(5708):384–387

    Article  CAS  PubMed  Google Scholar 

  8. Lim J, Lee J, Suh Y, Kim W, Song J, Jung M (2006) Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells. Diabetologia 49(8):1924–1936

    Article  CAS  PubMed  Google Scholar 

  9. Pieczenik SR, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83(1):84–92

    Article  CAS  PubMed  Google Scholar 

  10. Sirikul B, Gower BA, Hunter GR, Larson-Meyer DE, Newcomer BR (2006) Relationship between insulin sensitivity and in vivo mitochondrial function in skeletal muscle. Am J Physiol Endocrinol Metab 291(4):E724–E728

    Article  CAS  PubMed  Google Scholar 

  11. Anderson RACN, Bryden NA, Polansky MM, Cheng N, Chi J, Feng J (1997) Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46:1786–1791

    Article  CAS  PubMed  Google Scholar 

  12. Ding W, Chai Z, Duan P, Feng W, Qian Q (1998) Serum and urine chromium concentrations in elderly diabetics. Biol Trace Elem Res 63(3):231–237

    Article  CAS  PubMed  Google Scholar 

  13. Ekmekcioglu C, Prohaska C, Pomazal K, Steffan I, Schernthaner G, Marktl W (2001) Concentrations of seven trace elements in different hematological matrices in patients with type 2 diabetes as compared to healthy controls. Biol Trace Elem Res 79(3):205–219

    Article  CAS  PubMed  Google Scholar 

  14. Pineau A, Guillard O, Risse J (1992) A study of chromium in human cataractous lenses and whole blood of diabetics, senile, and normal population. Biol Trace Elem Res 32(1):133–138

    Article  CAS  PubMed  Google Scholar 

  15. Cefalu WT, Wang ZQ, Zhang XH, Baldor LC, Russell JC (2002) Oral Chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA Corpulent) Rats. J Nutr 132(6):1107–1114

    CAS  PubMed  Google Scholar 

  16. Lamson D, Plaza S (2002) The safety and efficacy of high-dose chromium. Alternative Medicine Review J Clin Ther 7(3):218–235

    Google Scholar 

  17. Lee NA, Reasner CA (1994) Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM. Diabetes Care 17(12):1449–1452

    Article  CAS  PubMed  Google Scholar 

  18. Offenbacher EG, Pi-Sunyer FX (1980) Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes 28:919–925

    Article  Google Scholar 

  19. Vincent JB (1999) Mechanisms of chromium action: low-molecular-weight chromium-binding substance. J Am Coll Nutr 18(1):6–12

    CAS  PubMed  Google Scholar 

  20. Jeejeebhoy KN (1999) Chromium and parenteral nutrition. J Trace Elem Exp Med 12(2):85–89

    Article  CAS  Google Scholar 

  21. Jain SK, Rains JL, Croad JL (2007) Effect of chromium niacinate and chromium picolinate supplementation on lipid peroxidation, TNF-[alpha], IL-6, CRP, glycated hemoglobin, triglycerides, and cholesterol levels in blood of streptozotocin-treated diabetic rats. Free Radic Biol Med 43(8):1124–1131

    Article  CAS  PubMed  Google Scholar 

  22. Candiloros H MS, Zeghari N, Donner M, Drouin P, Ziegler O (1995) Decreased erythrocyte membrane fluidity in poorly controlled IDDM. Influence of ketone bodies. Diabetes Care 18(4):549–551

    Article  PubMed  Google Scholar 

  23. Newton CA, Raskin P (2004) Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 164(17):1925–1931

    Article  CAS  PubMed  Google Scholar 

  24. Umpierrez G, Kitabchi A (2003) Diabetic ketoacidosis: risk factors and management strategies. Treat Endocrinol 2(2):95–108

    Article  PubMed  Google Scholar 

  25. Yared Z, Chiasson J (2003) Ketoacidosis and the hyperosmolar hyperglycemic state in adult diabetic patients. Diagnosis and treatment. Minervia Med 94(6):409–418

    CAS  Google Scholar 

  26. Jain SK, Kannan K (2001) Chromium chloride inhibits oxidative stress and tnf-[alpha] secretion caused by exposure to high glucose in cultured U937 monocytes. Biochem Biophys Res Commun 289(3):687–691

    Article  CAS  PubMed  Google Scholar 

  27. Kannan K, Jain SK (2004) Effect of vitamin B6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H2O2-treated U937 monocytes. Free Radic Biol Med 36(4):423–428

    Article  CAS  PubMed  Google Scholar 

  28. Jain SK, Rains JL, Croad JL (2007) High glucose and ketosis (acetoacetate) increases, and chromium niacinate decreases, IL-6, IL-8, and MCP-1 secretion and oxidative stress in U937 monocytes. Antioxid Redox Signal 9(10):1581–1590

    Article  CAS  PubMed  Google Scholar 

  29. Jennifer M, Stephens MJS, Watkins PJ (1971) Relationship of blood acetoacetate and 3-hydroxybutyrate in diabetes. Diabetes 20(7):485–489

    Google Scholar 

  30. Lori L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15(6):412–426

    Article  Google Scholar 

  31. Abdelmegeed MA, Kim SK, Woodcroft KJ, Novak RF (2004) Acetoacetate activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in primary cultured rat hepatocytes: role of oxidative stress. J Pharmacol Exp Ther 310(2):728–736

    Article  CAS  PubMed  Google Scholar 

  32. Hoffman WH, Cheng C, Passmore GG, Carroll JE, Hess D (2002) Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells. Neurosci Lett 334(2):71–74

    Article  CAS  PubMed  Google Scholar 

  33. Jain SK, Kannan K, Lim G (1998) Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Radic Biol Med 25(9):1083–1088

    Article  CAS  PubMed  Google Scholar 

  34. Jain SK, Kannan K, Lim G, Matthews-Greer J, McVie R, Bocchini JA Jr (2003) Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes. Diabetes Care 26(7):2139–2143

    Article  CAS  PubMed  Google Scholar 

  35. Jain SK, Kannan K, Lim G, McVie R, Bocchini JA Jr (2002) Hyperketonemia increases tumor necrosis factor-{alpha} secretion in cultured u937 monocytes and type 1 diabetic patients and is apparently mediated by oxidative stress and cAMP deficiency. Diabetes 51(7):2287–2293

    Article  CAS  PubMed  Google Scholar 

  36. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE (2004) Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 53(8):2079–2086

    Article  CAS  PubMed  Google Scholar 

  37. Jain SK, McVie R (1999) Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients. Diabetes 48(9):1850–1855

    Article  CAS  PubMed  Google Scholar 

  38. Mossop R (1983) Effects of chromium III on fasting blood glucose, cholesterol and cholesterol HDL levels in diabetics. Cent Afr J Med 29(4):80–82

    CAS  PubMed  Google Scholar 

  39. Vincent JB (2004) Recent advances in the nutritional biochemistry of trivalent chromium. Proc Nutr Soc 63(01):41–47

    Article  CAS  PubMed  Google Scholar 

  40. Office of dietary supplements chromium and diabetes workshop summary (1999) http://odsodnihgov/pubs/conferences/chromium_diabetes.html Natcher Conference Center, National Institutes of Health

  41. Vincent JB (2000) Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev 58(3):67–72

    Article  CAS  PubMed  Google Scholar 

  42. Jain SK, Croad JL, Velusamy T, Rains JL, Bull R (2010) Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 in livers of zucker diabetic fatty rats. Mol Nutr Food Res 54(9):1371–1380

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are supported by grants from NIDDK and the Office of Dietary Supplements of the National Institutes of Health (RO1 DK072433) and the Malcolm Feist Endowed Chair in Diabetes. The authors thank Ms Georgia Morgan for excellent editing of this manuscript.

Conflict of interest

None of the authors has any financial interest in the publication of this manuscript, nor have they received any money from any other sources except the NIH or LSUHSC.

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  1. Departments of Pediatrics and Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, P.O. Box 33932, 1501 Kings Highway, Shreveport, LA, 71130, USA

    Justin L. Rains & Sushil K. Jain

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  1. Justin L. Rains
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  2. Sushil K. Jain
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Correspondence to Sushil K. Jain.

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Rains, J.L., Jain, S.K. Hyperketonemia decreases mitochondrial membrane potential and its normalization with chromium (III) supplementation in monocytes. Mol Cell Biochem 349, 77–82 (2011). https://doi.org/10.1007/s11010-010-0662-8

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