Diabetes Metab J.  2020 Apr;44(2):326-335. 10.4093/dmj.2019.0031.

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

• Janssen LG
• Dam ADv
• Hanssen MJ
• Kooijman S
• Nahon KJ
• Reinders H
• Jazet IM
• Lichtenbelt WDvM
• Rensen PC
• Appelman-Dijkstra NM
• Boon MR

• KMID: 2502414
• DOI: http://doi.org/10.4093/dmj.2019.0031

Abstract

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 associated 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 signaling 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.

Keyword

Adiposity; Insulin resistance; SOST protein, human; Wnt signaling pathway

Figure

• 

  Fig. 1 Plasma sclerostin levels in white Caucasian and South Asian men. Data are expressed as mean. Error bars show standard error of the mean. aP<0.01 South Asians vs. white Caucasians.

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  Fig. 2 Gene expression of key players in Wnt and insulin signaling in (A, B) white adipose tissue (WAT) and (C, D) skeletal muscle (SM) in white Caucasian and South Asian men. Data are expressed as mean. Error bars show standard error of the mean. Black bars are South Asians and white bars are white Caucasians. WNT10B, wingless-type MMTV integration site family; FZD, Frizzleds; LRP, low-density lipoprotein receptor-related protein; DVL2, dishevelled segment polarity protein 2; GSK3B, glycogen synthase kinase 3 beta; CTNNB1, catenin beta 1; TCF7L2, transcription factor 7 like 2; INSR, insulin receptor; TBC1D4, TBC1 domain family member 4; SLC2A4, solute carrier family 2 member 4; GYS1, glycogen synthase 1. aP<0.05, bP<0.001, cP<0.1, South Asians vs. white Caucasians.

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  Fig. 3 Correlations between expression of Wnt signaling coreceptors low-density lipoprotein receptor-related proteins 5 (LRP5) and 6 (LRP6) and insulin signaling genes (A, B) insulin signaling receptor (INSR), (C, D) TBC1 domain family member 4 (TBC1D4), (E, F) solute carrier family 2 member 4 (SLC2A4), and (G, H) glycogen synthase 1 (GYS1) in white adipose tissue (WAT) in South Asian and white Caucasian men. Correlations are shown for both groups combined, black circles are South Asians and white circles are white Caucasians. Dotted lines represent 95% confidence interval.

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