Circulating FGF21 is lower in South Asians compared with Europids with type 2 diabetes mellitus

Abstract

Objective: Inflammation contributes to the development of type 2 diabetes mellitus (T2DM). While South Asians are more prone to develop T2DM than Europids, the inflammatory phenotype of the South Asian population remains relatively unknown. Therefore, we aimed to investigate potential differences in circulating levels of inflammation-related proteins in South Asians compared with Europids with T2DM.

Method: In this secondary analysis of three randomized controlled trials, relative plasma levels of 73 inflammation-related proteins were measured using an Olink Target Inflammation panel and the serum fibroblast growth factor 21 (FGF21) concentration using an ELISA kit in Dutch South Asians (n = 47) and Dutch Europids (n = 49) with T2DM.

Results: Of the 73 inflammation-related proteins, the relative plasma levels of six proteins were higher (stem cell factor, caspase-8, C-C motif chemokine ligand 28, interferon-gamma, sulfotransferase 1A1 and cystatin D; q-value <0.05), while relative levels of six proteins were lower (FGF21, human fibroblast collagenase, interferon-8, C-C motif chemokine ligand 4, C-X-C motif chemokine ligand 6 and monocyte chemoattractant protein-1; q-value <0.05) in South Asians compared with Europids. Of these, the effect size of FGF21 was the largest, particularly in females. We validated this finding by assessing the FGF21 concentration in serum. The FGF21 concentration was indeed lower in South Asians compared with Europids with T2DM in both males (-42.2%; P < 0.05) and females (-58.5%; P < 0.001).

Conclusion: Relative plasma levels of 12 inflammation-related proteins differed between South Asians and Europids with T2DM, with a significantly pronounced reduction in FGF21. In addition, the serum FGF21 concentration was significantly lower in South Asian males and females compared with Europids. Whether low FGF21 is an underlying cause or consequence of T2DM in South Asians remains to be determined.

Clinical trial registration: ClinicalTrials.gov (NCT01761318, registration date 20-12-2012; NCT02660047, registration date 21-03-2018; and NCT03012113, registration date 06-01-2017).

Keywords: FGF21; South Asian; inflammation; obesity.

Figure 1

Comparison of plasma levels of inflammation-related proteins in South Asian (SA) and Europid (EU) males and females with type 2 diabetes mellitus. A volcano plot showing the comparison of relative plasma levels of 73 inflammation-related proteins in all SAs (n = 47) compared with all EUs (n = 48) with type 2 diabetes mellitus (A). Additionally, comparisons are shown for SA (n = 19) versus EU (n = 27) males with type 2 diabetes mellitus (B) and for SA (n = 28) versus EU (n = 20) females with type 2 diabetes mellitus (C). The x-axes show the log 2 fold change (log 2 FC) between SAs and EUs; the y-axes show the q-value on a log scale. P values were obtained from a Mann–Whitney U test and then corrected using Benjamini–Hochberg’s false discovery rate to yield q-values. Red circles represent significantly higher relative protein levels in SAs and blue circles represent significantly lower relative protein levels in SAs, compared with EUs (q < 0.05). The value of one EU male was excluded because of failure of the quality control of Olink, one EU male was excluded as insufficient plasma was available to perform protein analysis, and data of 23 proteins were omitted from the 96-inflammation panel because their levels were below the detection limit in more than 75% of the samples.

Figure 2

Comparison of the serum fibroblast growth factor 21 concentration in South Asian and Europid males and females with type 2 diabetes mellitus. Box plots showing the serum concentration of fibroblast growth factor 21 (FGF21) in all South Asians (n = 47, orange circles) compared with that of all Europids (n = 49, green circles) with type 2 diabetes mellitus (A). In addition, FGF21 concentrations are shown for South Asian (n = 19, orange circles) and Europid (n = 29, green circles) males (B) and South Asian (n = 28, orange circles) and Europid (n = 20, green circles) females (C). Circles represent individual values, boxes represent means and deviations represent standard deviations.