OBJECTIVE: This study tested the hypothesis that limited subcutaneous adipose tissue (SAT) expansion represents a primary predisposition to the development of type 2 diabetes mellitus (T2DM), independent of obesity, and identified novel markers of SAT dysfunction in the inheritance of T2DM. METHODS: First-degree relatives (FDR) of T2DM patients (n = 19) and control individuals (n = 19) without obesity (fat mass < 25%) were cross-sectionally compared. Body composition (bioimpedance, computed tomography) and insulin sensitivity (IS; oral glucose tolerance test, clamp) were measured. SAT obtained by needle biopsy was used to analyze adipocyte size, lipidome, mRNA expression, and inflammatory markers. Primary cultures of adipose precursors were analyzed for adipogenic capacity and metabolism. RESULTS: Compared with control individuals, FDR individuals had lower IS and a higher amount of visceral fat. However, SAT-derived adipose precursors did not differ in their ability to proliferate and differentiate or in metabolic parameters (lipolysis, mitochondrial oxidation). In SAT of FDR individuals, lipidomic and mRNA expression analysis revealed accumulation of triglycerides containing polyunsaturated fatty acids and increased mRNA expression of lysyl oxidase (LOX). These parameters correlated with IS, visceral fat accumulation, and mRNA expression of inflammatory and cellular stress genes. CONCLUSIONS: The intrinsic adipogenic potential of SAT is not affected by a family history of T2DM. However, alterations in LOX mRNA and polyunsaturated fatty acids in triacylglycerols are likely related to the risk of developing T2DM independent of obesity.

Department of Internal Medicine Královské Vinohrady University Hospital Prague Czech Republic

Department of Pathophysiology Center for Research on Nutrition Metabolism and Diabetes 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Radiology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine Charles University Prague Czech Republic

Institute of Physiology Czech Academy of Sciences Prague Czech Republic

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Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.

InterAct C, Scott RA, Langenberg C, et al. The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study. Diabetologia. 2013;56:60-69.

Bays HE, Chapman RH, Grandy S, Group SI. The relationship of body mass index to diabetes mellitus, hypertension and dyslipidaemia: comparison of data from two national surveys. Int J Clin Pract. 2007;61:737-747.

Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367-377.

Henninger AM, Eliasson B, Jenndahl LE, Hammarstedt A. Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes. PLoS One. 2014;9:e105262.

Alligier M, Gabert L, Meugnier E, et al. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab. 2013;98:802-810.

Levelt E, Pavlides M, Banerjee R, et al. Ectopic and visceral fat deposition in lean and obese patients with type 2 diabetes. J Am Coll Cardiol. 2016;68:53-63.

Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes. 2009;58:1550-1557.

Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000;43:1498-1506.

Arner P, Arner E, Hammarstedt A, Smith U. Genetic predisposition for type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis. PLoS One. 2011;6:e18284.

Smith U, Kahn BB. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J Intern Med. 2016;280:465-475.

Gustafson B, Gogg S, Hedjazifar S, Jenndahl L, Hammarstedt A, Smith U. Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am J Physiol Endocrinol Metab. 2009;297:E999-E1003.

Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome-an allostatic perspective. Biochim Biophys Acta. 2010;1801:338-349.

Barbagallo I, Li Volti G, Galvano F, et al. Diabetic human adipose tissue-derived mesenchymal stem cells fail to differentiate in functional adipocytes. Exp Biol Med (Maywood). 2017;242:1079-1085.

Gustafson B, Nerstedt A, Smith U. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nat Commun. 2019;10:2757.

Spinelli R, Florese P, Parrillo L, et al. ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics. Aging Cell. 2022;21:e13557.

Cizkova T, Stepan M, Dadova K, et al. Exercise training reduces inflammation of adipose tissue in the elderly: cross-sectional and randomized interventional trial. J Clin Endocrinol Metab. 2020;105:e4510-e4526.

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462-1470.

Stumvoll M, Van Haeften T, Fritsche A, Gerich J. Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times. Diabetes Care. 2001;24:796-797.

Lambert L, Novak M, Siklova M, Krauzova E, Stich V, Burgetova A. Hybrid and model-based iterative reconstruction influences the volumetry of visceral and subcutaneous adipose tissue on ultra-low-dose CT. Obesity (Silver Spring). 2020;28:2083-2089.

Brezinova M, Cajka T, Oseeva M, et al. Exercise training induces insulin-sensitizing PAHSAs in adipose tissue of elderly women. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865:158576.

Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose tissue hypoxia, inflammation, and fibrosis in obese insulin-sensitive and obese insulin-resistant subjects. J Clin Endocrinol Metab. 2016;101:1422-1428.

van Harmelen V, Skurk T, Rohrig K, et al. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int J Obes Relat Metab Disord. 2003;27:889-895.

Cederberg H, Stancakova A, Kuusisto J, Laakso M, Smith U. Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage? J Intern Med. 2015;277:540-551.

Nyholm B, Nielsen MF, Kristensen K, et al. Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients. Eur J Endocrinol. 2004;150:207-214.

Bergman RN, Kim SP, Catalano KJ, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring). 2006;14(Suppl 1):16S-19S.

Turner N, Kowalski GM, Leslie SJ, et al. Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia. 2013;56:1638-1648.

Vogelzangs N, van der Kallen CJH, van Greevenbroek MMJ, et al. Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht study. Int J Obes (Lond). 2020;44:1376-1386.

Mirra P, Desiderio A, Spinelli R, et al. Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa-mir-23a-5p, -193a-5p, and -193b-5p and insulin-like growth factor 2 expression. FASEB J. 2021;35:e21357.

Rossmeislova L, Malisova L, Kracmerova J, et al. Weight loss improves the adipogenic capacity of human preadipocytes and modulates their secretory profile. Diabetes. 2013;62:1990-1995.

Skurk T, Ecklebe S, Hauner H. A novel technique to propagate primary human preadipocytes without loss of differentiation capacity. Obesity (Silver Spring). 2007;15:2925-2931.

Baker NA, Muir LA, Washabaugh AR, et al. Diabetes-specific regulation of adipocyte metabolism by the adipose tissue extracellular matrix. J Clin Endocrinol Metab. 2017;102:1032-1043.

Smith RL, Soeters MR, Wust RCI, Houtkooper RH. Metabolic flexibility as an adaptation to energy resources and requirements in health and disease. Endocr Rev. 2018;39:489-517.

Lange M, Angelidou G, Ni Z, et al. AdipoAtlas: a reference lipidome for human white adipose tissue. Cell Rep Med. 2021;2:100407.

Li N, Lizardo DY, Atilla-Gokcumen GE. Specific triacylglycerols accumulate via increased lipogenesis during 5-FU-induced apoptosis. ACS Chem Biol. 2016;11:2583-2587.

Ibarguren M, Lopez DJ, Escriba PV. The effect of natural and synthetic fatty acids on membrane structure, microdomain organization, cellular functions and human health. Biochim Biophys Acta. 2014;1838:1518-1528.

Rodencal J, Dixon SJ. A tale of two lipids: lipid unsaturation commands ferroptosis sensitivity. Proteomics. 2023;23:e2100308.

Vallet SD, Ricard-Blum S. Lysyl oxidases: from enzyme activity to extracellular matrix cross-links. Essays Biochem. 2019;63:349-364.

Sotak M, Rajan MR, Clark M, et al. Healthy subcutaneous and omental adipose tissue is associated with high expression of extracellular matrix components. Int J Mol Sci. 2022;23:520.

Liu Y, Aron-Wisnewsky J, Marcelin G, et al. Accumulation and changes in composition of collagens in subcutaneous adipose tissue after bariatric surgery. J Clin Endocrinol Metab. 2016;101:293-304.

Huang A, Lin YS, Kao LZ, et al. Inflammation-induced macrophage lysyl oxidase in adipose stiffening and dysfunction in obesity. Clin Transl Med. 2021;11:e543.

Martinez-Revelles S, Garcia-Redondo AB, Avendano MS, et al. Lysyl oxidase induces vascular oxidative stress and contributes to arterial stiffness and abnormal elastin structure in hypertension: role of p38MAPK. Antioxid Redox Signal. 2017;27:379-397.

Bersani C, Xu L, Vilborg A, Lui W, Wiman KG. Correction to: Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3s. Oncogene. 2023;42:709.

Gasser E, Sancar G, Downes M, Evans RM. Metabolic messengers: fibroblast growth factor 1. Nat Metab. 2022;4:663-671.

Patel S, Alvarez-Guaita A, Melvin A, et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 2019;29(3):707-718.e8.

Zhao R, Liu W, Wang M, et al. Lysyl oxidase inhibits TNF-alpha induced rat nucleus pulposus cell apoptosis via regulating Fas/FasL pathway and the p53 pathways. Life Sci. 2020;260:118483.

Fu M, Rao M, Bouras T, et al. Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem. 2005;280:16934-16941.

Li Q, Hagberg CE, Silva Cascales H, et al. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. Nat Med. 2021;27:1941-1953.

Belligoli A, Compagnin C, Sanna M, et al. Characterization of subcutaneous and omental adipose tissue in patients with obesity and with different degrees of glucose impairment. Sci Rep. 2019;9:11333.

Klimcakova E, Roussel B, Kovacova Z, et al. Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat. Diabetologia. 2011;54:876-887.