Al-Attas, Omar S., Al-Daghri , Nasser M., Al-Rubeaan , Khalid, da Silva, Nancy F., Sabico, Shaun, Kumar, Sudhesh, McTernan, P. G. (Philip G.) and Harte, A. L. (Alison L.). (2009) Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies. Cardiovascular Diabetology, Vol.8 (No.20). ISSN 1475-2840

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Abstract

Introduction Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue. Aims The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles. Methods Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined. Results Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall. Conclusion We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Diabetes -- Treatment, Endotoxins -- Physiological effect, Diabetes -- Complications, Obesity -- Complications
Journal or Publication Title:	Cardiovascular Diabetology
Publisher:	BioMed Central Ltd.
ISSN:	1475-2840
Date:	15 April 2009
Volume:	Vol.8
Number:	No.20
Identification Number:	10.1186/1475-2840-8-20
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	British Medical Association (BMA), Arden Medical Research Fund (AMRF), British Heart Foundation
References:	Dandona P, Aljada A, Bandyopadhyay A: Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004, 25:4-7. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005, 115:1111-1119. Deeg MA: Basic approach to managing hyperglycemia for the nonendocrinologist. Am J Cardiol 2005, 96:37E-40E. Sheehan MT: Current therapeutic options in type 2 diabetes mellitus: a practical approach. Clin Med Res 2003, 1:189-200. Calabro P, Yeh ET: Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Subcell Biochem 2007, 42:63-91. Brix-Christensen V, Vestergaard C, Andersen SK, Krog J, Andersen NT, Larsson A, Schmitz O, Tonnesen E: Evidence that acute hyperinsulinaemia increases the cytokine content in essential organs after an endotoxin challenge in a porcine model. Acta Anaesthesiol Scand 2005, 49:1429-1435. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M: IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005, 11:191-198. Trayhurn P, Wood IS: Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004, 92:347-355. Trayhurn P, Wood IS: Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 2005, 33:1078-1081. Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG: The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes. J Clin Endocrinol Metab 2007, 92:270-276. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112:1796-1808. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112:1821-1830. Stewart MW, Cirkel DT, Furuseth K, Donaldson J, Biswas N, Starkie MG, Phenekos C, Hamann A: Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Diabet Med 2006, 23:1069-1078. Weissman P, Goldstein BJ, Rosenstock J, Waterhouse B, Cobitz AR, Wooddell MJ, Strow LJ: Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin 2005, 21:2029-2035. Kim YW, Kim JY, Park YH, Park SY, Won KC, Choi KH, Huh JY, Moon KH: Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes 2006, 55:716-724. Chinetti G, Fruchart JC, Staels B: Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000, 49:497-505. Buckingham RE: Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. Hepatol Res 2005, 33:167-170. Murdolo G, Smith U: The dysregulated adipose tissue: a connecting link between insulin resistance, type 2 diabetes mellitus and atherosclerosis. Nutr Metab Cardiovasc Dis 2006, 16(Suppl 1):S35-38. van Doorn M, Kemme M, Ouwens M, van Hoogdalem EJ, Jones R, Romijn H, de Kam M, Schoemaker R, Burggraaf K, Cohen A: Evaluation of proinflammatory cytokines and inflammation markers as biomarkers for the action of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers. Br J Clin Pharmacol 2006, 62:391-402. Charalambous BM, Stephens RC, Feavers IM, Montgomery HE: Role of Bacterial Endotoxin in Chronic Heart Failure: the Gut of the Matter. Shock 2007, 28:15-23. Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S: Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 2007, 292:E740-747 Brun P, Castagliuolo I, Leo VD, Buda A, Pinzani M, Palu G, Martines D: Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007, 292:G518-525. Galal O: Nutrition-related health patterns in the Middle East. Asia Pac J Clin Nutr 2003, 12:337-343. Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world – a growing challenge. N Engl J Med 2007, 356:213-215. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27:1047-1053. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, et al.: Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56:1761-1772. Backhed F, Manchester JK, Semenkovich CF, Gordon JI: Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007, 104:979-984. Westergaard H: Insulin modulates rat intestinal glucose transport: effect of hypoinsulinemia and hyperinsulinemia. Am J Physiol 1989, 256:G911-918. Krogh-Madsen R, Moller K, Dela F, Kronborg G, Jauffred S, Pedersen BK: Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 2004, 286:E766-772. Yu WK, Li WQ, Li N, Li JS: Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. World J Gastroenterol 2003, 9:1824-1827. Byrne MM, Pluntke K, Wank U, Schirra J, Arnold R, Goke B, Katschinski M: Inhibitory effects of hyperglycaemia on fed jejunal motility: potential role of hyperinsulinaemia. Eur J Clin Invest 1998, 28:72-78. Cohen J: The detection and interpretation of endotoxaemia. Intensive Care Med 2000, 26(Suppl 1):S51-56. Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J, Vilardell F, Mourelle M, Moncada S: Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993, 18:1139-1143. Mitaka C: Clinical laboratory differentiation of infectious versus non-infectious systemic inflammatory response syndrome. Clin Chim Acta 2005, 351:17-29. Kannel WB: Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985, 110:1100-1107. Laakso M, Pyorala K: Adverse effects of obesity on lipid and lipoprotein levels in insulin-dependent and non-insulin-dependent diabetes. Metabolism 1990, 39:117-122. Hudgins LC, Parker TS, Levine DM, Gordon BR, Saal SD, Jiang XC, Seidman CE, Tremaroli JD, Lai J, Rubin AL: A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers. J Lipid Res 2003, 44:1489-1498. Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL: In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA 1993, 90:12040-12044. Eggesbo JB, Hjermann I, Lund PK, Joo GB, Ovstebo R, Kierulf P: LPS-induced release of IL-1 beta, IL-6, IL-8, TNF-alpha and sCD14 in whole blood and PBMC from persons with high or low levels of HDL-lipoprotein. Cytokine 1994, 6:521-529. Parker TS, Levine DM, Chang JC, Laxer J, Coffin CC, Rubin AL: Reconstituted high-density lipoprotein neutralizes gram-negative bacterial lipopolysaccharides in human whole blood. Infect Immun 1995, 63:253-258. Wurfel MM, Hailman E, Wright SD: Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med 1995, 181:1743-1754. Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD: Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med 1994, 180:1025-1035. Feingold KR, Staprans I, Memon RA, Moser AH, Shigenaga JK, Doerrler W, Dinarello CA, Grunfeld C: Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J Lipid Res 1992, 33:1765-1776. Fernandez-Real JM, Broch M, Richart C, Vendrell J, Lopez-Bermejo A, Ricart W: CD14 monocyte receptor, involved in the inflammatory cascade, and insulin sensitivity. J Clin Endocrinol Metab 2003, 88:1780-1784. Eichbaum EB, Harris HW, Kane JP, Rapp JH: Chylomicrons can inhibit endotoxin activity in vitro. J Surg Res 1991, 51:413-416. Harris HW, Grunfeld C, Feingold KR, Read TE, Kane JP, Jones AL, Eichbaum EB, Bland GF, Rapp JH: Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death. J Clin Invest 1993, 91:1028-1034. Rosenstock J, Rood J, Cobitz A, Biswas N, Chou H, Garber A: Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Diabetes Obes Metab 2006, 8:650-660. Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, Chrousos GP: Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998, 83:280-283. Bornstein SR, Preas HL, Chrousos GP, Suffredini AF: Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. J Infect Dis 1998, 178:887-890. Granowitz EV, Porat R, Dinarello CA: Circulating leptin during experimental endotoxemia in humans. J Infect Dis 1999, 179:1313-1314. Berkowitz DE, Brown D, Lee KM, Emala C, Palmer D, An Y, Breslow M: Endotoxin-induced alteration in the expression of leptin and beta3-adrenergic receptor in adipose tissue. Am J Physiol 1998, 274:E992-997. Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR: Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996, 97:2152-2157. Wu J, Lei MX, Chen HL, Sun ZX: [Effects of rosiglitazone on serum leptin and insulin resistance in patients with Type 2 diabetes]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004, 29:623-626. Lu H, Raptis M, Black E, Stan M, Amar S, Graves DT: Influence of diabetes on the exacerbation of an inflammatory response in cardiovascular tissue. Endocrinology 2004, 145:4934-4939.
URI:	http://wrap.warwick.ac.uk/id/eprint/643

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