We conducted a cross-sectional study of 200 T2D patients to analyse the relationship between serum FGF19 levels and the AIP. In patients with T2D, across the tertiles of AIP, the serum FGF19 concentrations and HDL-c levels decreased significantly and BMI, NAFLD, FPG and TG levels increased. Spearman’s bivariate correlation analyses showed that serum FGF19 levels were significantly negatively related to TG and AIP levels in T2D patients, even after adjusting for age, sex, duration, BMI, hypertension, and diabetic treatment and again after further adjusting for NAFLD and NFS. However, a negative relationship between AIP values and FGF19 levels was detected only among nonobese T2D patients. Finally, multiple linear regression analysis showed that AIP was an important risk factor for FGF19 levels. Moreover, serum FGF19 levels decreased significantly across increasing tertiles of AIP.
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 [18-21]. 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 [22] via glucose effectiveness (GE) and hepatic glucose production (HGP). In our study, the FGF19 levels of the T2D group decreased significantly from Q1 to Q2 to Q3. Our previous study showed that the decrease in FGF19 in T2D patients correlated with endogenous beta cell function, as assessed by the insulin secretion-sensitivity index-2 (ISSI-2). In T2D patients with MetS, serum FGF19 levels are significantly lower than they are in other T2D patients. Moreover, FGF19 levels were significantly negatively related to AIP and TG in T2D patients with MetS [12]. Most T2D patients had higher body fat percentages and weight, and we found that FGF19 levels were negatively correlated with AIP tertiles among nonobese T2D patients. However, P. Song et al. found that T2D patients had abnormal body fat levels and higher AIP values. AIP was also positively correlated with the visceral fat area [7]. FGF19 may regulate the lipid balance at the beginning of obesity and may be a protective factor. The reason for this discrepancy may be related to diabetic treatments. FGF19 levels were also lower in patients with postbariatric hypoglycemia and may be related to GLP-1 secretion [23].
AIP is a main marker for the presence of atherosclerosis and CAD [24,25]. The patients with diabetic neuropathy and MetS had significantly higher AIP levels than their counterparts. Increased AIP levels were correlated with the risk of hypertension and were associated with insulin resistance (HOMA-IR) [26]. Insulin resistance and dyslipidemia promote the development of NAFLD. In our study, the level of AIP was closely correlated with serum FGF19 levels in T2D patients. The correlation still existed after adjusting for age, sex, duration, BMI, hypertension, diabetic treatment and even after further adjusting for NAFLD and NFS. In postmenopausal women with CAD, the values of non-HDL-c, TC/HDL-c, LDL-c/HDL-c, AC, AIP, and LCI were all higher than 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 [27]. In agreement with our study, P. Song et al. revealed that the AIP was obviously higher in T2D participants than in non-T2D participants. Meanwhile, the AIP level was higher in patients with a VFA ≥ 100 cm2 than in patients with a VFA < 100 cm2. The AIP was positively related to VAF in patients with T2D [7]. In a cohort study of diabetic foot patients with and without osteomyelitis, diabetic foot patients with osteomyelitis had higher AIP values than those without. AIP could be a marker for the diagnosis of diabetic foot osteomyelitis [28]. In elderly women with hypertension, the AIP level was higher and was positively related to the risk of all-cause mortality after an analysis of ten years of follow-up [29]. Wei Ni et al. showed that in Chinese people, the AIP level was different between coronary heart disease (CHD) patients with multivessel lesions and healthy controls. Simultaneously, AIP was independently correlated with CHD in males but not in females [30]. Similarly, Gaojun Cai et al found that in the Han Chinese population, AIP was a predictor for the incidence of CAD [31]. 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 [11]. As shown in our research, the serum FGF19 level decreased with increasing tertiles of AIP and was independently associated with the AIP value in patients with T2D. Therefore, serum FGF19 levels may be a predictor of atherosclerosis and CAD in patients with T2D. However, more research should be conducted to analyse the relationship between FGF19 levels and arterial lesions.
Several possible mechanisms may explain the link between decreased 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 on 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 [32]. 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 [33]. 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 dyslipidemia. Furthermore, the HDL-c levels of healthy volunteers improved after the administration of NGM282 for a week [34]. Our research revealed that FGF19 levels were closely related to AIP in the T2D group even after adjusting for age, sex, duration, BMI, SBP, DBP, diabetic treatment (lifestyle intervention alone, insulin injection, insulin secretagogues and insulin sensitizers), hypertension, NAFLD, and NFS. Meanwhile, the mechanism of the relationship underlying the relationship between FGF19 and atherosclerosis in T2D patients, especially in nonobese T2D patients, remains unclear, and more clinical and basic studies are needed to explore this relationship.
This study had several limitations that should be addressed. 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 AIP. Our research was a single-centre study conducted among Chinese participants, and the generalizability of our data needs to be assessed. The influence of diabetic and hypertensive treatment on the formation of atherosclerosis is unknown, and the influence of medication history on AIP has not been determined. However, FGF19 levels differed significantly based on the tertiles of AIP and were closely related to AIP even after adjusting for age, sex, duration, BMI, SBP, DBP, diabetic treatment, hypertension, NAFLD, and NFS. 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.
In our study, we revealed that serum FGF19 levels decreased significantly in the T2D group as the tertiles of the AIP increased. The AIP was closely associated with the FGF19 level. A correlation existed among nonobese T2D patients. The AIP was independently associated with the concentration of FGF19 after multiple stepwise regression analysis. Serum FGF19 levels might be a useful predictor of the risk of atherosclerosis and CAD in T2D patients.