Insulin resistance in relation to inflammatory gene expression and metabolic features in apparently healthy obese individuals
Abstract
The present study aimed to investigate the association of insulin resistance (IR) with inflammatory gene expression levels, metabolic health, lipid profile, and body composition in the apparently healthy obese. In this cross-sectional study, 88 apparently healthy obese subjects were recruited and divided into insulin-resistant and non-insulin-resistant (NIR) groups. Fasting blood samples were taken to determine serum metabolic features. mRNA expression of inflammatory genes were assessed in freshly isolated peripheral blood mononuclear cells (PBMCs), using quantitative real-time PCR (qPCR). Bioelectrical impedance analysis (BIA) was used to describe body composition. Among inflammatory genes, toll-like receptor 4 (TLR4) mRNA revealed significant upregulation in PBMCs of IR group compared with NIR individuals (p = 0.035). High-density lipoprotein cholesterol (HDL-C, p = 0.04), low-density lipoprotein cholesterol (LDL-C, p < 0.001), waist circumference (p = 0.025), and waist to hip ratio (p = 0.013) were significantly different between the two groups. A significant but weak correlation of HDL-C was observed with TLR4 (r = − 0.305; p = 0.011) and myeloid differentiation factor 88 (MyD88, r = − 0.27; p = 0.024) expression level. Also, LDL-C was found to be correlated with TLR4 (r = 0.302; p = 0.012) and MyD88 (r = 0.267; p = 0.027) expression levels. There was also a significant correlation between HOMA-IR and HDL-C (r = − 0.25; p = 0.019). The results of this study indicated the possible link between IR and TLR4. Also, there was a significant correlation between HDL-C and LDL-C as well as between TLR4 and MyD88. Some inflammatory genes and metabolic parameters were also significantly correlated.
Keywords
Insulin resistance Inflammatory genes Metabolic health Lipid profile Healthy obeseAbbreviations
- BP
Blood pressure
- BMI
Body mass index
- FBS
Fasting blood sugar
- HDL-C
High-density lipoprotein cholesterol
- HOMA-IR
Homeostasis model of insulin resistance
- IR
Insulin resistance
- LDL-C
Low-density lipoprotein cholesterol
- MetS
Metabolic syndrome
- MHO
Metabolically healthy obese
- MUO
Metabolically unhealthy obese
- MyD88
Myeloid differentiation factor 88
- NFĸB
Nuclear factor kappa B
- NIR
Non-insulin resistance
- PBMCs
Peripheral blood mononuclear cells
- QUICKI
Quantitative insulin sensitivity check index
- T2DM
Type 2 diabetes mellitus
- TC
Total cholesterol
- TRIF
TIR-domain containing adaptor-inducing interferon-β
- TLR2
Toll-like receptor 2
- TLR4
Toll-like receptor 4
- WC
Waist circumference
- WHR
Waist/hip ratio
Notes
Acknowledgments
Thanks are due to all who participated in the study.
Authors’ contribution
MSA and PA wrote the study protocol and study design. BB and DS helped with qPCR. MSA and PA analyzed and interpreted the data. PA, MN, and SM helped with the sampling. PA and MSA were involved in drafting the manuscript or revising it critically for content. All authors have given final approval of the version to be published.
Compliance with ethical standards
Competing interests
The authors declare that they have no conflict of interest.
References
- 1.Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289(1):76–9.CrossRefPubMedGoogle Scholar
- 2.Könner AC, Brüning JC. Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol Metab. 2011;22(1):16–23.CrossRefPubMedGoogle Scholar
- 3.Seidell JC. Obesity, insulin resistance and diabetes—a worldwide epidemic. Br J Nutr. 2000;83(S1):S5–8.CrossRefPubMedGoogle Scholar
- 4.Howard BV. Insulin resistance and lipid metabolism. Am J Cardiol. 1999;84(1):28–32.CrossRefGoogle Scholar
- 5.Engfeldt P, Arner P. Lipolysis in human adipocytes, effects of cell size, age and of regional differences. Horm Metab Res Suppl Ser. 1988;19:26–9.Google Scholar
- 6.Veilleux A, Caron-Jobin M, Noël S, Laberge PY, Tchernof A. Visceral adipocyte hypertrophy is associated with dyslipidemia independent of body composition and fat distribution in women. Diabetes. 2011;60(5):1504–11.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Banerji MA, Faridi N, Atluri R, Chaiken RL, Lebovitz HE. Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men. J Clin Endocrinol Metab. 1999;84(1):137–44.PubMedGoogle Scholar
- 8.Raji A, Seely EW, Arky RA, Simonson DC. Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. J Clin Endocrinol Metab. 2001;86(11):5366–71.CrossRefPubMedGoogle Scholar
- 9.Lundgren H, Bengtsson C, Blohme G, Lapidus L, Sjöström L. Adiposity and adipose tissue distribution in relation to incidence of diabetes in women: results from a prospective population study in Gothenburg, Sweden. Int J Obes. 1989;13(4):413–23.PubMedGoogle Scholar
- 10.Ohlson L-O, Larsson B, Svärdsudd K, Welin L, Eriksson H, Wilhelmsen L, et al. The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes. 1985;34(10):1055–8.CrossRefPubMedGoogle Scholar
- 11.Banerji M, Lebowitz J, Chaiken RL, Gordon D, Kral JG, Lebovitz HE. Relationship of visceral adipose tissue and glucose disposal is independent of sex in black NIDDM subjects. Am J Physiol Endocrinol Metab. 1997;273(2):E425–E32.CrossRefGoogle Scholar
- 12.Curtiss LK, Tobias PS. Emerging role of toll-like receptors in atherosclerosis. J Lipid Res. 2009;50(Supplement):S340–S5.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Investig. 2006;116(11):3015–25.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Jialal I, Kaur H, Devaraj S. Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J Clin Endocrinol Metab. 2014;99(1):39–48.CrossRefPubMedGoogle Scholar
- 15.Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003;52(12):2882–7.CrossRefPubMedGoogle Scholar
- 16.Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25(1):4–7.CrossRefPubMedGoogle Scholar
- 17.Poggi M, Bastelica D, Gual P, Iglesias M, Gremeaux T, Knauf C, et al. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia. 2007;50(6):1267–76.CrossRefPubMedGoogle Scholar
- 18.Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, et al. Loss-of-function mutation in toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56(8):1986–98.CrossRefPubMedGoogle Scholar
- 19.Caricilli AM, Nascimento PH, Pauli JR, Tsukumo DM, Velloso LA, Carvalheira JB, et al. Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet. J Endocrinol. 2008;199(3):399–406.CrossRefPubMedGoogle Scholar
- 20.Hardy OT, Kim A, Ciccarelli C, Hayman LL, Wiecha J. Increased toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents. Pediatr Obes. 2013;8(1):e19–23.CrossRefPubMedGoogle Scholar
- 21.Gómez-Ambrosi J, Catalán V, Rodríguez A, Andrada P, Ramírez B, Ibáñez P, et al. Increased cardiometabolic risk factors and inflammation in adipose tissue in obese subjects classified as metabolically healthy. Diabetes Care. 2014;37(10):2813–21.CrossRefPubMedGoogle Scholar
- 22.Telle-Hansen V, Halvorsen B, Dalen K, Narverud I, Wesseltoft-Rao N, Granlund L, et al. Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype. Genes Nutr. 2013;8(4):425–34.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Bollyky PL, Bice JB, Sweet IR, Falk BA, Gebe JA, Clark AE, et al. The toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury. PLoS One. 2009;4(4):e5063.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Hutton MJ, Soukhatcheva G, Johnson JD, Verchere CB. Role of the TLR signaling molecule TRIF in β-cell function and glucose homeostasis. Islets. 2010;2(2):104–11.CrossRefPubMedGoogle Scholar
- 25.Jialal I, Huet BA, Kaur H, Chien A, Devaraj S. Increased toll-like receptor activity in patients with metabolic syndrome. Diabetes Care. 2012;35(4):900–4.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Mirmiran P, Esmaillzadeh A, Azizi F. Detection of cardiovascular risk factors by anthropometric measures in Tehranian adults: receiver operating characteristic (ROC) curve analysis. Eur J Clin Nutr. 2004;58(8):1110–8.CrossRefPubMedGoogle Scholar
- 27.Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan LM, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006;91(8):2906–12.CrossRefPubMedGoogle Scholar
- 28.Saghafi-Asl M, Amiri P, Naghizadeh M, Ghavami SM, Karamzad N. Association of endotoxaemia with serum free fatty acids in metabolically healthy and unhealthy abdominally obese individuals: a case-control study in northwest of Iran. BMJ Open. 2017;7(5):e015910.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Katsuki A, Sumida Y, Gabazza EC, Murashima S, Furuta M, Araki-Sasaki R, et al. Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes Care. 2001;24(2):362–5.CrossRefPubMedGoogle Scholar
- 30.Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402–10.CrossRefPubMedGoogle Scholar
- 31.Devaraj S, Dasu MR, Rockwood J, Winter W, Griffen SC, Jialal I. Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. J Clin Endocrinol Metab. 2008;93(2):578–83.CrossRefPubMedGoogle Scholar
- 32.Dasu MRDS, Zhao L, Hwang DH, Jialal I. High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes. 2008;57:3090–8.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Faam B, Zarkesh M, Daneshpour MS, Azizi F, Hedayati M. The association between inflammatory markers and obesity-related factors in Tehranian adults: Tehran lipid and glucose study. Iran J Basic Med Sci. 2014;17(8):577.PubMedPubMedCentralGoogle Scholar
- 34.Ruderman NB, Schneider SH, Berchtold P. The “metabolically-obese,” normal-weight individual. Am J Clin Nutr. 1981;34(8):1617–21.CrossRefPubMedGoogle Scholar
- 35.Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res. 2007;100(11):1589–96.CrossRefPubMedGoogle Scholar
- 36.Dasu MR, Devaraj S, Park S, Jialal I. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care. 2010;33(4):861–8.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Reyna SM, Ghosh S, Tantiwong P, Meka CR, Eagan P, Jenkinson CP, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes. 2008;57(10):2595–602.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Creely SJ, McTernan PG, Kusminski CM, Da Silva N, Khanolkar M, Evans M, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292(3):E740–E7.CrossRefPubMedGoogle Scholar
- 39.Burchfiel CM, HAMMAN RF, MARSHALL JA, BAXTER J, KAHN LB, AMIRANI JJ. Cardiovascular risk factors and impaired glucose tolerance: the San Luis Valley Diabetes Study. Am J Epidemiol. 1990;131(1):57–70.CrossRefPubMedGoogle Scholar
- 40.Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S, et al. Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study. Arterioscler Thromb Vasc Biol. 1990;10(3):430–6.CrossRefGoogle Scholar
- 41.McKeigue PM, Miller G, Marmot M. Coronary heart disease in south Asians overseas: a review. J Clin Epidemiol. 1989;42(7):597–609.CrossRefPubMedGoogle Scholar
- 42.Modan M, Halkin H, Lusky A, Segal P, Fuchs Z, Chetrit A. Hyperinsulinemia is characterized by jointly disturbed plasma VLDL, LDL, and HDL levels. A population-based study. Arterioscler Thromb Vasc Biol. 1988;8(3):227–36.CrossRefGoogle Scholar
- 43.Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics. Metabolism. 1988;37(4):338–45.CrossRefPubMedGoogle Scholar
- 44.Wolfs MG, Rensen SS, Bruin-Van Dijk EJ, Verdam FJ, Greve J-W, Sanjabi B, et al. Co-expressed immune and metabolic genes in visceral and subcutaneous adipose tissue from severely obese individuals are associated with plasma HDL and glucose levels: a microarray study. BMC Med Genet. 2010;3(1):34.Google Scholar
- 45.Van Linthout S, Spillmann F, Graiani G, Miteva K, Peng J, Van Craeyveld E, et al. Down-regulation of endothelial TLR4 signalling after apo AI gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation. J Mol Med. 2011;89(2):151–60.CrossRefPubMedGoogle Scholar
- 46.Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med. 2011;17(11):1410–22.CrossRefPubMedGoogle Scholar
- 47.Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12(5):467–82.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, et al. Insulin resistance and cardiovascular events with low HDL cholesterol. Diabetes Care. 2003;26(5):1513–7.CrossRefPubMedGoogle Scholar
- 49.Shaikh AZ, Badade ZG, Thomas SS. Homa-Ir and Ratios of Tg/Hdl and Tc/Hdl as indicators of insulin resistance in patient with metabolic syndrome and type 2 diabetes mellitus. Indian J Appl Res. 2015;5(8):668–91.Google Scholar
- 50.Lemieux I, Pascot A, Couillard C, Lamarche BT, Tchernof A, Alméras N, et al. Hypertriglyceridemic waist. Circulation. 2000;102(2):179–84.CrossRefPubMedGoogle Scholar
- 51.Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res. 2005;2(3):105–12.CrossRefPubMedGoogle Scholar