AIM: Development of type 2 diabetes (T2DM) is associated with disturbances in immune and metabolic status that may be reflected by an altered gene expression profile of peripheral blood mononuclear cells (PBMC). To reveal a potential family predisposition to these alterations, we investigated the regulation of gene expression profiles in circulating CD14+ and CD14- PBMC in fasting conditions and in response to oral glucose tolerance test (OGTT) in glucose tolerant first-degree relatives (FDR) of T2DM patients and in control subjects. MATERIALS AND METHODS: This work is based on the clinical study LIMEX (NCT03155412). Non-obese 12 non-diabetic (FDR), and 12 control men without family history of diabetes matched for age and BMI underwent OGTT. Blood samples taken before and at the end of OGTT were used for isolation of circulating CD14+ and CD14- PBMC. In these cells, mRNA levels of 94 genes related to lipid and carbohydrate metabolism, immunity, and inflammation were assessed by qPCR. RESULTS: Irrespectively of the group, the majority of analyzed genes had different mRNA expression in CD14+ PBMC compared to CD14- PBMC in the basal (fasting) condition. Seven genes (IRS1, TLR2, TNFα in CD14+ PBMC; ABCA1, ACOX1, ATGL, IL6 in CD14- PBMC) had different expression in control vs. FDR groups. OGTT regulated mRNA levels of nine genes selectively in CD14+ PBMC and of two genes (ABCA1, PFKL) selectively in CD14-PBMC. Differences in OGTT-induced response between FDR and controls were observed for EGR2, CCL2 in CD14+ PBMC and for ABCA1, ACOX1, DGAT2, MLCYD, and PTGS2 in CD14- PBMC. CONCLUSION: This study revealed a different impact of glucose challenge on gene expression in CD14+ when compared with CD14- PBMC fractions and suggested possible impact of family predisposition to T2DM on basal and OGTT-induced gene expression in these PBMC fractions. Future studies on these putative alterations of inflammation and lipid metabolism in fractionated PBMC in larger groups of subjects are warranted.

Department for Pathophysiology Centre for Research on Nutrition Metabolism and Diabetes 3rd Faculty of Medicine Charles University Prague Czechia

Department of Internal Medicine 3rd Faculty of Medicine Charles University and Kralovske Vinohrady University Hospital Prague Czechia

Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine Prague and Inserm Toulouse France

Zobrazit více v PubMed

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol (2011) 11:98–107. 10.1038/nri2925 PubMed DOI

Manoel-Caetano FS, Xavier DJ, Evangelista AF, Takahashi P, Collares CV, Puthier D, et al. . Gene expression profiles displayed by peripheral blood mononuclear cells from patients with type 2 diabetes mellitus focusing on biological processes implicated on the pathogenesis of the disease. Gene (2012) 511:151–60. 10.1016/j.gene.2012.09.090 PubMed DOI

Kaizer EC, Glaser CL, Chaussabel D, Banchereau J, Pascual V, White PC. Gene expression in peripheral blood mononuclear cells from children with diabetes. J Clin Endocrinol Metab (2007) 92:3705–11. 10.1210/jc.2007-0979 PubMed DOI

Lenin R, Sankaramoorthy A, Mohan V, Balasubramanyam M. Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes. J Leukoc Biol (2015) 98:615–22. 10.1189/jlb.3A1214-609R PubMed DOI

Slieker RC, van der Heijden A, van Leeuwen N, Mei H, Nijpels G, Beulens JWJ, et al. . HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes. Diabetologia (2018) 61:138–46. 10.1007/s00125-017-4467-0 PubMed DOI PMC

Schnurr TM, Jakupovic H, Carrasquilla GD, Angquist L, Grarup N, Sorensen TIA, et al. . Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study. Diabetologia (2020) 63:1324–32. 10.1007/s00125-020-05140-5 PubMed DOI

Ali O. Genetics of type 2 diabetes. World J Diabetes (2013) 4:114–23. 10.4239/wjd.v4.i4.114 PubMed DOI PMC

Lihn AS, Ostergard T, Nyholm B, Pedersen SB, Richelsen B, Schmitz O. Adiponectin expression in adipose tissue is reduced in first-degree relatives of type 2 diabetic patients. Am J Physiol Endocrinol Metab (2003) 284:E443–8. 10.1152/ajpendo.00358.2002 PubMed DOI

Elgzyri T, Parikh H, Zhou Y, Dekker Nitert M, Ronn T, Segerstrom AB, et al. . First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle. J Clin Endocrinol Metab (2012) 97:E1332–7. 10.1210/jc.2011-3037 PubMed DOI

Palsgaard J, Brons C, Friedrichsen M, Dominguez H, Jensen M, Storgaard H, et al. . Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: differential regulation of insulin signaling pathways. PloS One (2009) 4:e6575. 10.1371/journal.pone.0006575 PubMed DOI PMC

Afman L, Milenkovic D, Roche HM. Nutritional aspects of metabolic inflammation in relation to health–insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols. Mol Nutr Food Res (2014) 58:1708–20. 10.1002/mnfr.201300559 PubMed DOI

O’Grada CM, Morine MJ, Morris C, Ryan M, Dillon ET, Walsh M, et al. . PBMCs reflect the immune component of the WAT transcriptome–implications as biomarkers of metabolic health in the postprandial state. Mol Nutr Food Res (2014) 58:808–20. 10.1002/mnfr.201300182 PubMed DOI

Kleiveland CR. Peripheral Blood Mononuclear Cells. In: Verhoeckx K, Cotter P, Lopez-Exposito I, Kleiveland C, Lea T, Mackie A, Requena T, Swiatecka D, Wichers H, Wichers H, editors. The Impact of Food Bioactives on Health: in vitro and ex vivo models. Cham: Springer; (2015). p. 161–7. 10.1007/978-3-319-16104-4_15 PubMed DOI

Kracmerova J, Czudkova E, Koc M, Malisova L, Siklova M, Stich V, et al. . Postprandial inflammation is not associated with endoplasmic reticulum stress in peripheral blood mononuclear cells from healthy lean men. Br J Nutr (2014) 112:573–82. 10.1017/S0007114514001093 PubMed DOI

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care (1999) 22:1462–70. 10.2337/diacare.22.9.1462 PubMed DOI

Leder L, Kolehmainen M, Narverud I, Dahlman I, Myhrstad MC, de Mello VD, et al. . Effects of a healthy Nordic diet on gene expression changes in peripheral blood mononuclear cells in response to an oral glucose tolerance test in subjects with metabolic syndrome: a SYSDIET sub-study. Genes Nutr (2016) 11 :3. 10.1186/s12263-016-0521-4 PubMed DOI PMC

Kempf K, Rose B, Herder C, Haastert B, Fusbahn-Laufenburg A, Reifferscheid A, et al. . The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression. J Mol Med (2007) 85:389–96. 10.1007/s00109-006-0132-7 PubMed DOI

Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik S, Fishilevich S, et al. . The GeneCards suite: From gene data mining to disease genome sequence analysis. Curr Protoc Bioinformatics (2016) 54:1.30.1–33. 10.1002/cpbi.5 PubMed DOI

Monaco G, Lee B, Xu W, Mustafah S, Hwang YY, Carre C, et al. . RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types. Cell Rep (2019) 26:1627–40 e7. 10.1016/j.celrep.2019.01.041 PubMed DOI PMC

Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K, et al. . A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J (2003) 17:1434–40. 10.1096/fj.02-1132com PubMed DOI

Chandak PG, Radovic B, Aflaki E, Kolb D, Buchebner M, Frohlich E, et al. . Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J Biol Chem (2010) 285:20192–201. 10.1074/jbc.M110.107854 PubMed DOI PMC

Schreiber R, Xie H, Schweiger M. Of mice and men: The physiological role of adipose triglyceride lipase (ATGL). Biochim Biophys Acta Mol Cell Biol Lipids (2019) 1864:880–99. 10.1016/j.bbalip.2018.10.008 PubMed DOI PMC

Howie D, Ten Bokum A, Necula AS, Cobbold SP, Waldmann H. The Role of Lipid Metabolism in T Lymphocyte Differentiation and Survival. Front Immunol (2017) 8:1949. 10.3389/fimmu.2017.01949 PubMed DOI PMC

Kharbanda S, Nakamura T, Stone R, Hass R, Bernstein S, Datta R, et al. . Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation. J Clin Invest (1991) 88:571–7. 10.1172/JCI115341 PubMed DOI PMC

Veremeyko T, Yung AWY, Anthony DC, Strekalova T, Ponomarev ED. Corrigendum: Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPbeta. Front Immunol (2018) 9:2923. 10.3389/fimmu.2018.02923 PubMed DOI PMC

Rull A, Camps J, Alonso-Villaverde C, Joven J. Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (or CCL2) in the regulation of metabolism. Mediators Inflam (2010) 2010:326580. 10.1155/2010/326580 PubMed DOI PMC

Tencerova M, Kracmerova J, Krauzova E, Malisova L, Kovacova Z, Wedellova Z, et al. . Experimental hyperglycemia induces an increase of monocyte and T-lymphocyte content in adipose tissue of healthy obese women. PloS One (2015) 10:e0122872. 10.1371/journal.pone.0122872 PubMed DOI PMC

Shanmugam N, Reddy MA, Guha M, Natarajan R. High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes (2003) 52:1256–64. 10.2337/diabetes.52.5.1256 PubMed DOI

Lopategi A, Lopez-Vicario C, Alcaraz-Quiles J, Garcia-Alonso V, Rius B, Titos E, et al. . Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction. Mol Cell Endocrinol (2016) 419:44–59. 10.1016/j.mce.2015.09.033 PubMed DOI

Ryan EP, Pollock SJ, Murant TI, Bernstein SH, Felgar RE, Phipps RP. Activated human B lymphocytes express cyclooxygenase-2 and cyclooxygenase inhibitors attenuate antibody production. J Immunol (2005) 174:2619–26. 10.4049/jimmunol.174.5.2619 PubMed DOI

Iniguez MA, Martinez-Martinez S, Punzon C, Redondo JM, Fresno M. An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes. J Biol Chem (2000) 275:23627–35. 10.1074/jbc.M001381200 PubMed DOI

Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. Diabetes (2002) 51:691–8. 10.2337/diabetes.51.3.691 PubMed DOI

Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta (2014) 1843:2563–82. 10.1016/j.bbamcr.2014.05.014 PubMed DOI

Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells. J Nutr Biochem (2016) 34:1–7. 10.1016/j.jnutbio.2015.11.002 PubMed DOI PMC

Yang Y, Shen F, Huang W, Qin S, Huang JT, Sergi C, et al. . Glucose Is Involved in the Dynamic Regulation of m6A in Patients With Type 2 Diabetes. J Clin Endocrinol Metab (2019) 104:665–73. 10.1210/jc.2018-00619 PubMed DOI

Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. . Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol (2013) 14:489–99. 10.1038/ni.2570 PubMed DOI PMC

Mauldin JP, Srinivasan S, Mulya A, Gebre A, Parks JS, Daugherty A, et al. . Reduction in ABCG1 in Type 2 diabetic mice increases macrophage foam cell formation. J Biol Chem (2006) 281:21216–24. 10.1074/jbc.M510952200 PubMed DOI

Mauerer R, Ebert S, Langmann T. High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages. Exp Mol Med (2009) 41:126–32. 10.3858/emm.2009.41.2.015 PubMed DOI PMC

Hedrick CC. Lymphocytes in atherosclerosis. Arterioscler Thromb Vasc Biol (2015) 35:253–7. 10.1161/ATVBAHA.114.305144 PubMed DOI PMC

Di Cara F, Andreoletti P, Trompier D, Vejux A, Bulow MH, Sellin J, et al. . Peroxisomes in Immune Response and Inflammation. Int J Mol Sci (2019) 20:3877. 10.3390/ijms20163877 PubMed DOI PMC

Violante S, Ijlst L, Te Brinke H, Koster J, Tavares de Almeida I, Wanders RJ, et al. . Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient. Biochim Biophys Acta (2013) 1831:1467–74. 10.1016/j.bbalip.2013.06.007 PubMed DOI

Villarreal-Perez JZ, Villarreal-Martinez JZ, Lavalle-Gonzalez FJ, Torres-Sepulveda Mdel R, Ruiz-Herrera C, Cerda-Flores RM, et al. . Plasma and urine metabolic profiles are reflective of altered beta-oxidation in non-diabetic obese subjects and patients with type 2 diabetes mellitus. Diabetol Metab Syndr (2014) 6:129. 10.1186/1758-5996-6-129 PubMed DOI PMC

Mauvais-Jarvis F. Gender differences in glucose homeostasis and diabetes. Physiol Behav (2018) 187:20–3. 10.1016/j.physbeh.2017.08.016 PubMed DOI PMC

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03155412