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Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men

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Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men Original Article Basic Research Diabetes Metab J 2020;44:326-335 https://doi.org/10.4093/dmj.2019.0031 pISSN 2233-6079 · eISSN 2233-6087 DIABETES & METABOLISM JOURNAL Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men Laura G.M. Janssen1,2, Andrea D. van Dam1,2, Mark J.W. Hanssen3, Sander Kooijman1,2, Kimberly J. Nahon1,2, Hanneke Reinders1,2, Ingrid M. Jazet1, Wouter D. van Marken Lichtenbelt3, Patrick C.N. Rensen1,2, Natasha M. Appelman-Dijkstra1,4, Mariëtte R. Boon1,2 1Division of Endocrinology, Department of Medicine, 2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 3 Department of Human Biology and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, 4Center for Bone Quality, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Background: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is as- sociated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians. Methods: Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458). Results: Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P<0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signal- ing and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced. Conclusion: South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians. Keywords: Adiposity; Insulin resistance; SOST protein, human; Wnt signaling pathway INTRODUCTION a high socioeconomical burden [1]. In the South Asian popu- lation, originally deriving from the Indian subcontinent and The incidence of type 2 diabetes mellitus is increasing world- comprising approximately one fifth of the world population, wide and its morbidity and mortality rates are accompanied by the prevalence of type 2 diabetes mellitus is particularly high Corresponding author: Laura G.M. Janssen https://orcid.org/0000-0002-7247-1018 This is an Open Access article distributed under the terms of the Creative Commons Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) P.O. Box 9600, 2300 RC Leiden, The Netherlands which permits unrestricted non-commercial use, distribution, and reproduction in any E-mail: [email protected] medium, provided the original work is properly cited. Received: Feb. 9, 2019; Accepted: Apr. 15, 2019 Copyright © 2020 Korean Diabetes Association https://e-dmj.org Wnt signaling and metabolism in South Asian men [2,3]. This may at least partly be explained by a disadvanta- via advertisements in local hospitals and universities. Ethnicity geous metabolic phenotype, including central obesity and in- was defined as having four grandparents of South Asian or sulin resistance [4-6]. The underlying cause of this metabolic white Caucasian origin. To define South Asian ethnicity, we phenotype is not yet fully elucidated, but may be related to a here adopted the geographical area of South Asia applied by difference in energy metabolism favouring energy storage. the United Nations, with the exception of Iran (i.e., Afghani- The Wnt family is well-known for its function in embryonic stan, Bangladesh, Bhutan, India, The Maldives, Nepal, Paki- development and oncogenesis. The canonical route of this sig- stan, and Sri Lanka) [18]. Participants underwent a medical nal transduction pathway comprises endogenous Wnt ligands screening including their medical history, a physical examina- that bind to Wnt coreceptors named Frizzleds (FZD) and low- tion, blood chemistry tests and an oral glucose tolerance test density lipoprotein receptor-related proteins 5 (LRP5) and 6 (OGTT) to exclude individuals with undiagnosed type 2 dia- (LRP6). Upon binding of Wnt ligands to these receptors, betes mellitus according to 2014 American Diabetes Associa- β-catenin is rescued from being degraded, facilitating its nu- tion criteria. Prediabetes was defined as having either a fasting clear translocation and ultimately inducing transcription of plasma glucose level between 5.6 and 6.9 mmol/L or a plasma Wnt target genes [7,8]. glucose level between 7.8 and 11.1 mmol/L at 2 hours after the Evidence has emerged that Wnt signaling also plays a role in OGTT [19]. Exclusion criteria included uncontrolled hyper- metabolism, since an impairing mutation in the gene encoding tension, hyper- or hypothyroidism, liver or kidney dysfunc- for LRP6 was found in a family with hyperlipidaemia, type 2 tion, rigorous exercise, smoking and use of β-blockers. Three diabetes mellitus and early coronary artery disease [9]. Muta- South Asians were using antihypertensive medication before tions in various Wnt genes have also been associated with an and during the study, two of whom used an angiotensin-con- increased risk for insulin resistance and type 2 diabetes melli- verting enzyme inhibitor and one of whom used an angioten- tus [10-12]. Moreover, circulating levels of the Wnt inhibitor sin II-receptor blocker. The Medical Ethical Committee of the sclerostin were shown to be higher in individuals with predia- Leiden University Medical Center (LUMC) and Maastricht betes and type 2 diabetes mellitus compared with normoglyce- University Medical Center (MUMC) approved the study pro- mic individuals [13]. Additionally, the Wnt pathway is in- tocol (P14-252). The study was undertaken in accordance with volved in adiposity, as mutations that probably impair Wnt sig- the principles of the revised Declaration of Helsinki (2013) and naling are associated with obesity and an increased waist cir- in accordance with the Medical Research Involving Human cumference [14-16]. In vitro studies have indeed shown that Subjects Act (WMO). All volunteers provided written in- Wnt signaling suppresses adipogenesis and favors precursor formed consent prior to participation. cell commitment to other lineages, such as osteoblasts [17]. Altogether, we hypothesized that reduced Wnt signaling Study design contributes to the increased risk to develop an impaired glu- This study was part of a randomized clinical trial aiming to in- cose homeostasis and high body fat percentage in South vestigate the effects of L-arginine on brown adipose tissue me- Asians. Therefore, we investigated expression levels of both tabolism (clinical trial registration number: NCT02291458). Wnt and insulin signaling genes in subcutaneous white adi- The study was conducted between November 2014 and Octo- pose tissue (WAT) and skeletal muscle as well as plasma ber 2015 at the LUMC and MUMC. Participants were instruct- sclerostin levels in South Asian and white Caucasian men with ed to refrain from intense physical exercise for 48 hours prior prediabetes and overweight or obesity. to the experiment and consumed a standardized evening meal the day before the experiment. After a 10-hour overnight fast, METHODS body composition was determined by dual X-ray absorptiom- etry (Discovery A; Hologic, Marlborough, MA, USA) and a Participants cannula was placed into the right antecubital vein for blood Ten Dutch South Asian males with prediabetes and overweight withdrawal. A fasting skeletal muscle biopsy from the muscu- or obesity (body mass index [BMI] 25 to 35 kg/m2, age 40 to 55 lus vastus lateralis and a subcutaneous WAT biopsy from the years) and 10 age- and BMI-matched Dutch white Caucasian umbilical region were obtained under localized anaesthesia. males were enrolled in this study. Participants were recruited Biopsies were frozen and stored at −80°C until further analyses. https://e-dmj.org Diabetes Metab J 2020;44:326-335 327 Janssen LGM, et al. Quantitative reverse transcription polymerase chain separately by including ethnicity as a covariate. No adjust- reaction ments (for e.g., BMI or age) were made, as participants were Skeletal muscle and WAT biopsies were homogenized in 1 mL matched for these parameters. Data are presented as mean± TriPure RNA Isolation reagent (Roche, Mannheim, Germany) standard error of the mean, unless states otherwise. A P<0.05 and RNA was extracted according to the manufacturer’s in- was considered
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