We conducted an observational study to compare the serum FGF19 levels between the patients with T2D and healthy controls and to analyse the association of serum FGF19 levels with baPWV and FGF19 levels with AIP in patients with T2D. The main findings of our study are as follows: first, serum FGF19 levels of T2D patients were significantly lower than those in healthy controls; second, arteriosclerosis parameters, including baPWV and AIP, significantly decreased across ascending tertiles of serum FGF19 levels in patients with T2D; and third, after adjusting for other clinical covariates, the serum FGF19 levels were independently and inversely associated with baPWV in patients with T2D.
Evidence from previous studies has shown that FGF19 participates in the synthesis of BA, the balance of glucose metabolism, and the reduction of weight in mice [20-23]. In accordance with our data, J. Zhang et al. showed that serum FGF19 levels were significantly lower in normal glucose tolerance (NGT) subjects than in isolated-impaired glucose tolerance (I-IGT) subjects and isolated-impaired fasting glucose (I-IFG) participants based on glucose effectiveness (GE) and hepatic glucose production (HGP) [24]. Meanwhile, in T2D patients with MetS, serum FGF19 levels were significantly lower than they were in other T2D patients. Moreover, FGF19 levels were significantly negatively related to AIP and TG in T2D patients with MetS [25]. In a study of 315 Chinese patients with suspected or established CAD, the serum FGF19 level was an independent predictor of the Gensini score, which represents the presence and severity of CAD [16]. In our study, the FGF19 levels in the T2D group decreased significantly compared with those in the control group. In the T2D group, lnFGF19 levels were negatively related to baPWV and AIP values.
Arterial stiffness was considered to be an independent predictor of atherosclerotic diseases and can be measured by baPWV, a simple, noninvasive and convenient tool [26,27]. Previous studies revealed that baPWV was broadly used and generally accepted in China [28]. BaPWV was associated with blood pressure, diabetes status [29], HbA1c [7], inflammation [30] and obesity [31]. We considered baPWV as a risk factor for CVD and investigated its association with serum FGF19 levels. Finally, our study found that in the fully adjusted model 3, lnFGF19 was still independently associated with baPWV (β = –0.20, t = –2.23, p = 0.029, adjusted R2 = 0.599).
AIP is a main marker for the presence of atherosclerosis and CAD [32,33]. In postmenopausal women with CAD, the values of AIP were higher than those in the control group. After multivariate logistic regression analysis, AIP was shown to be independently related to CAD, which indicated that AIP was a significant marker for the incidence of CAD [34]. Gaojun Cai et al found that in the Han Chinese population, AIP was a predictor for the incidence of CAD [33]. The patients with diabetic neuropathy and MetS had significantly higher AIP levels than their counterparts [35]. In our study, the levels of AIP in the T2D group were higher than those in the controls, and AIP was independently associated with the serum FGF19 levels in T2D patients. In agreement with our study, P. Song et al. revealed that the AIP was obviously higher in T2D participants than in non-T2D participants [12]. However, more research should be conducted to analyse the relationship between FGF19 levels and arterial lesions.
Several possible mechanisms may explain the link between FGF19 levels and atherosclerosis in T2D patients. FGF19 regulates glucolipid homeostasis and nutrient metabolism via the FGFR4-β-Klotho complex. In rodent studies, FXR-/- mice showed a pro-atherogenetic lipoprotein profile and defects in the formation of any detectable plaques associated with a high-fat (HF) diet. FXR agonists protect against the formation of aortic plaques in murine models that have a pro-atherogenetic lipoprotein profile and accelerated atherosclerosis [36]. In hepatic FXR-knockout and FXR-knockdown mice, the reconstitution of FXR expression upregulated the transport of cholesterol. Consistent with its role of phosphorylating FXR, the nonreceptor tyrosine kinase Src regulated the formation of cholesterol and ameliorated arterial lesions. Therefore, the phosphorylation of hepatic FXR induced Src via FGF15/19 and then played a role in the balance of cholesterol homeostasis, preventing the formation of atherosclerosis [37]. In transgenic human apolipoprotein(a) (APOA) mice (tg-APO mice), the FGF19 influence APOA biosynthesis by attenuating transfection of primary hepatocytes with siRNA against the FGFR4 [38]. Moreover, Mei Zhou, R. et al. revealed that NGM282, an FGF19 analogue, regulated cholesterol in mice by activating MEK1 and reduced atherosclerosis in Apoe-/- mice with dyslipidaemia. Furthermore, the HDL-c levels of healthy volunteers improved after the administration of NGM282 for a week [39]. Therefore, our research revealed that baPWV and AIP were all independently associated with FGF19 levels after adjusting for other clinical covariates via multiple linear regression analysis, which indicates that decreased FGF19 may be accompanied by several unfavourable metabolic alterations and can be implicated in increased arterial stiffness.
This study had several limitations that should be addressed. First, this study had a cross-sectional design based on a small sample size and could not explain any causal connection between the decreased serum FGF19 level and increased risk of atherosclerosis and CAD as assessed by baPWV and AIP. Second, our research was a single-centre study conducted among Chinese participants, and the generalizability of our data needs to be assessed. Third, the influence of diabetic and hypertensive treatment on the formation of atherosclerosis is unknown, and the influence of medication history on baPWV and AIP values has not been determined. However, lnFGF19 levels were closely related to baPWV and AIP, even after adjusting for age, gender, duration, BMI, hypertension, diabetic treatment and NAFLD. Meanwhile, baPWV was not measured among controls, but the present research showed that diabetes was significantly correlated with an increased risk of baPWV compared with normal glucose [29]. Moreover, other confounding factors affecting baPWV, such as alcohol consumption, smoking status and health behaviour, were not completely assessed at the beginning of this study. Finally, the relationships between FGF19 levels and CAD measured by other vascular markers, such as carotid intima-media thickness (CIMT) or flow-mediated dilatation (FMD), were not assessed. All limitations were fully considered when selecting the appropriate statistical approach. Therefore, larger, prospective follow-up studies need to be conducted to better investigate the correlation between FGF19 levels and the risk of CAD in T2D patients.