Ethnic Disparities in Lipid Metabolism and Clinical Outcomes between Dutch South Asians and Dutch White Caucasians with Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated lipidomic changes in plasma of Dutch South Asians (DSA) and Dutch white Caucasians (DwC) with and without T2DM and explore their associations with clinical features. Using a targeted quantitative lipidomics platform, monitoring over 1000 lipids across 17 classes, along with ¹H NMR based lipoprotein analysis, we studied 51 healthy participants (21 DSA, 30 DwC) and 92 T2DM patients (47 DSA, 45 DwC) from the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction in type 2 dIAbetes mellitus (MAGNA VICTORIA) study. This comprehensive mapping of the circulating lipidome allowed us to identify relevant lipid modules through unbiased weighted correlation network analysis, as well as disease and ethnicity related key mediatory lipids. Significant differences in lipidomic profiles, encompassing various lipid classes and species, were observed between T2DM patients and healthy controls in both the DSA and DwC populations. Our analyses revealed that healthy DSA, but not DwC, controls already exhibited a lipid profile prone to develop T2DM. Particularly, in DSA-T2DM patients, specific lipid changes correlated with clinical features, particularly diacylglycerols (DGs), showing significant associations with glycemic control and renal function. Our findings highlight an ethnic distinction in lipid modules influencing clinical outcomes in renal health. We discover distinctive ethnic disparities of the circulating lipidome and identify ethnicity-specific lipid markers. Jointly, our discoveries show great potential as personalized biomarkers for the assessment of glycemic control and renal function in DSA-T2DM individuals.

Keywords: Dutch South Asian; Dutch white Caucasian; diabetic nephropathy; lipidomics; type 2 diabetes mellitus.

Figure 1

Study workflow and design. Abbreviations: T2DM type 2 diabetes mellitus; WGCNA Weighted Correlation Network Analysis.

Figure 2

Lipid class abundance between patients with T2DM and healthy controls. (A) Stack plot with the hierarchical cluster in Dutch South Asian. (B) Stack plot with the hierarchical cluster in Dutch white Caucasian. Abbreviations: CE cholesteryl ester; CER ceramide; DCER dihydroceramide; DG diacylglyceride; FA fatty acid; HC healthy control; HexCER hydroxyceramide; LacCER lactosylceramide; LPC lysophosphatidylcholine; LPE lysophosphatidylethanolamine; PA phosphatidic acid; PC phosphatidylcholine; PE phosphatidylethanolamine; PI phosphatidylinositol; PS phosphatidylserine; SM sphingomyelin; T2DM type 2 diabetes mellitus, TG triglyceride.

Figure 3

Comparison of differential lipids between patients with T2DM and healthy controls in two ethnicities. (A) Differential lipids per lipid class between patients with T2DM and healthy controls, as well as a comparison across two ethnicities. The colour grey represents lipids with non-significant associations (FDR > 0.05), the colour blue represents lipids lower in T2DM, and the colour red represents lipids higher in T2DM. The dot size represents −log₂FDR. Venn diagram of (B) lipids lower in T2DM and (C) higher in T2DM than healthy controls (HC) in DSA and DwC. Heatmap of lipids that are commonly/uncommonly (D) lower and (E) higher in DSA and DwC with T2DM. Abbreviations: CE cholesteryl ester; CER ceramide; DCER dihydroceramide; DG diacylglyceride; DwC Dutch white Caucasian; DSA Dutch South Asian; FA fatty acid; FDR false discovery rate; HexCER hydroxyceramide; LacCER lactosylceramide; LPC lysophosphatidylcholine; LPE lysophosphatidylethanolamine; PA phosphatidic acid; PC phosphatidylcholine; PE phosphatidylethanolamine; PI phosphatidylinositol; PS phosphatidylserine; SM sphingomyelin, TG triglyceride.

Figure 4

Association of lipid correlation network modules with clinical features in (A) Dutch South Asians with T2DM and (B) Dutch white Caucasians with T2DM. The colour grey denotes a lipid cluster with no significant associations with clinical features, the colour blue denotes a lipid cluster with a negative association with clinical features, and the colour red denotes a lipid cluster with a positive association with clinical features. The correlation coefficients are represented by the size of the dots (Spearman’s rank correlation test). Abbreviations: BP blood pressure; BMI body mass index; HbA1c hemoglobin A1c; HDL high-density lipoprotein; LBM lean body mass; LDL low-density lipoprotein; SAT subcutaneous adipose tissue, VAT visceral adipose tissue.

Figure 5

Correlations between key mediatory lipids in diabetic nephropathy-associated module of Dutch South Asians and lipoproteins, kidney function, and glycemic control. (A) Bubble plot depicting the correlations of lipids with lipoproteins, kidney function, and glycemic control in Dutch South Asians with T2DM. (B) Violin plots of lipids between T2DM with and without diabetic nephropathy in Dutch South Asians. (C) Bubble plot depicting the correlations of lipids with lipoproteins, kidney function, and glycemic control in Dutch white Caucasians with T2DM. (D) Violin plots of lipids between T2DM with and without DN in Dutch white Caucasians. Lipids in bold indicated that they were specifically different in Dutch South Asians. The colour grey indicates no significant correlations with clinical features; the colour blue indicates a negative correlation with clinical features, and the colour red indicates a positive correlation with clinical features. The size of the dots represents the correlation coefficients (Pearson’s correlation). The Wilcoxon signed-rank test was performed; * p < 0.05, ** p < 0.01, ns not significant. Abbreviations: DG diacylglyceride; DN diabetic nephropathy; HbA1c hemoglobin A1c; HDL high-density lipoprotein; LDL low-density lipoprotein, T2DM type 2 diabetes mellitus.