Contribution of Circulating Mfge8 to Human T2DM and Cardiovascular Disease

MFGE8 is a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal studies. However, its role in the pathophysiology of human T2DM, obesity, and cardiovascular disease has been controversial and less explored. Earlier, we reported a rare Asian Indian population-specific missense variant (rs371227978; Arg148His) in the MFGE8 associated with increased circulating Mfge8 and T2DM. Here, we have further investigated the role of Mfge8 with T2DM risk in additional Asian Indians (n=4917) and Europeans and other multiethnic cohorts from UK Biobank (UKBB) (n= 455,808) and the US (n=1150). We also evaluated the exposure of Mfge8-enriched human EVs (with and without mutation) in zebrafish (ZF) for their impact on the cardiometabolic organ system. Most individual carriers of Arg148His variant not only had high circulating Mfge8 but also showed a positive significant correlation with glucose (r= 0.42; p = 4.9x10-04), while the non-carriers showed a negative correlation of Mfge8 with glucose (r = -0.38; p = 0.001) in Asian Indians. However, the same variant was monomorphic in Europeans and other ethnic groups of UKBB and US cohorts. Even in the absence of Arg148His variant, serum Mfge8 correlated significantly with blood glucose both in Caucasians (r = 0.56; p = 8.4x10-10) and individuals from other ethnicities (African Americans, Hispanics, and others) (r = 0.31; p = 5.8x10-4). Since Mfge8 is an EV marker, the exposure of Mfge8-enriched human EVs to ZF larvae rapidly developed fatty liver disease and heart hypertrophy and exhibited redundant growth with poor muscular architecture with and without the high-fat diet (HFD), while the control group fishes developed fatty liver disease and heart hypertrophy only after the HFD feeding. With strong evidence from animal studies supporting the role of Mfge8 in obesity, insulin resistance, and the development of atherosclerosis in T2DM, the current research suggests that circulating Mfge8 may be a potential marker for preventing or reducing the risk of T2DM and cardiovascular disease.