Background
Type 2 diabetes (T2D) is a major cause of death with an estimated 5 million death worldwide in 2019 [
1]. The prevalence of T2D increased 16-fold over the past 3 decades and reached 10.9% in China [
1,
2]. Previous study indicated that lipoproteins exerted key effects on the pathogenesis of diabetes [
3]. Therefore, the exploration of lipoprotein markers levels for T2D intervention is of high priority.
Traditional lipid concentrations are known to predict T2D, such as total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein (LDL) particles [
4]. There is growing interest in which lipid markers best assess diabetes risk [
5‐
7]. Circulating apolipoproteins, which relate to the total number of lipoprotein particles, are superior to standard lipoprotein cholesterol measures for evaluating T2D risk [
8,
9]. Apolipoproteins exert important roles in the metabolism of lipoprotein and blood glucose [
10,
11]. Apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) are two major types of apolipoprotein that had been well investigated. ApoA1 is the main lipoprotein associated with high-density lipoprotein cholesterol (HDL-C) [
12]. ApoB is a single molecule that is presented as in low-, intermediate-, and very low-density lipoproteins [
13]. In vitro and animal studies revealed that ApoA1 and ApoB modulated fasting blood glucose (FBG) level via improving insulin level [
14‐
16]. Several studies have assessed the association of ApoA1, ApoB, and ApoB/A1 ratio with the FBG level showing inverse or null association with ApoA1 [
17‐
19] but positive association with ApoB and ApoB/A1 ratio [
11,
20,
21]. Notably, studies observed inverse and even positive association between ApoA1 and T2D presence [
22‐
28], and positive association between T2D presence and ApoB as well as ApoB/A1 ratio [
5,
23,
26,
28‐
30]. These results suggested that ApoA1, ApoB, and ApoB/A1 ratio may play important roles in maintaining FBG and T2D pathological process. Previous studies showed that Chinese adults had lower levels of ApoA, ApoB, and lipoprotein compared to Caucasians [
31], however, little data is available for Chinese adults [
24,
28] who differ from their Western counterparts in levels of lipoprotein [
31]. Moreover, the different prevalence of obesity between Chinese and Western populations may have impact on the apolipoprotein-T2D association because body fat can affect the circulating glycometabolism [
32,
33]. The apolipoprotein-T2D/FBG association in Chinese population remains unclear.
Obesity is an important risk factor for the pathogenesis of T2D [
34]. Accumulating evidence support a significant association between circulating apolipoprotein level and obesity [
35]. No study, however, investigated whether or not the association between apolipoproteins and T2D is mediated by obesity.
In this cross-sectional study, we investigated the association of ApoA1, ApoB, and ApoB/A1 ratio with T2D and FBG level, and analyzed the mediating effects of body mass index (BMI) for these associations, thus to find potential indicators for predicting T2D in Chinese population.
Discussion
In this community-based cross-sectional study, we estimated the association of serum levels of ApoA1 and ApoB as well as the ratio of ApoB/A1 with T2D prevalence and FBG level. We found that serum ApoA1 was favorably associated with a decreased prevalence of T2D, whereas ApoB and ApoB/A1 ratio were positively associated with T2D prevalence. Consistent with these findings, we observed an inverse association of serum ApoA1 with FBG, and positive association of ApoB and ApoB/A1 ratio with FBG. Moreover, ApoB and ApoB/A1 ratio performed better than ApoA1 in predicting T2D prevalence in a Chinese population.
ApoA1, a major protein component of HDL with anti-inflammatory and immunomodulatory effect [
12,
39], is found in significant amounts on chylomicron remnants [
40]. The protective effect of HDL is due to lipoprotein(a) particles, especially ApoA1 [
41]. Our results demonstrated that both ApoA1 and HDL-C were inversely associated with the T2D prevalence and an intermediate ApoA1 concentration showed a lower T2D prevalence compared with HDL-C. Similarly, ApoA1 has been observed to be equivalent or better than HDL-C as a risk marker for cardiovascular or atherosclerosis events [
42,
43]. Previous studies reported that ApoA1 had cardio- and bone mass-protective roles [
39,
44]. Although ApoA1 can modulate FBG, the association of ApoA1 with T2D prevalence and FBG level in Chinese populations is ill-characterized. Based on data from 1514 males participated in the ATTICA 2001–2012 surveys, the 10-year T2D risk decreased 1.02% with every 1 mg/dL increase of apoA1 [
22]. FINRISK97 cohort consisted of 7827 middle aged persons found that ApoA were significantly associated with incident diabetes in Finland [
45]. Wu et al. observed that low level of ApoA1 was independently associated with T2D (OR: 0.51, 95% CI: 0.33, 0.76) [
24]. TwSHHH indicated the inverse association between ApoA1 and incident T2D among 4223 adults in Taiwan, Chinese (hazard ratio [HR]: 0.59, 95% CI: 0.38, 0.92) [
28]. But fasting plasma glucose level was adjusted in multivariate analysis of this prospective study, which might be more likely to obtain inverse associations. Similar results were also reported by other groups [
23,
25,
26]. Consistent with these findings, we observed a beneficial effect of ApoA1 on T2D presence. In contrast, null and even positive association was observed in western population [
22,
27,
46]. Mellor et al. reported that serum ApoA1 was not associated with the risk of diabetes in a prospective cohort composed of 759 females in Greek population [
22]. In a 13.5 years prospective study with 110 incident T2D and 741 non-T2D subjects within the Rotterdam Study, Brahimaj et al. [
46] found null association between serum ApoA1 and T2D risk in the Dutch population. Onat et al. even found the positive association of serum ApoA1 with diabetes in Turkish population (OR: 1.85, 95% CI: 1.03, 3.32) [
27]. In addition, several studies assessed the association of ApoA1 with FBG level showing inconsistent results (inverse or null association) [
18,
19,
47]. Similar to our results, previous studies found plasma glucose levels were negatively correlated to ApoA1 in Chinese and Dutch population (r: − 0.1182 and − 0.013) [
18,
46]. The heterogeneity among different studies can be caused by different mechanisms. Significant results were more likely to be obtained in cross-sectional study (vs. prospective study [
22]). The lower ApoA1 concentration that was found in The Rotterdam Study (7.4 μmol/L) [
46] than in the present study (39.0 μmol/L) might provide a potential explanation for the null findings of the prior one study. ApoA1 might turn to enhance risk of diabetes due to dysfunctional adiponect in prevailing among Turks (vs. this study) [
27]. Moreover, favorable association is readily to be found in large sample size, non-obesity population, and Asian population as observed in the present study and previously reported. Although we were unable to characterize the shape of the exposure–outcome relation due to the limited number of samples, our results implied that an intermediate ApoA1 level was important in FBG regulation. Large prospective study is needed to confirm this speculation.
A series of studies have shown the association of serum ApoB and ApoB/A1 ratio with T2D prevalence and FBG level [
5,
7,
20‐
23,
27,
28,
30,
48]. A large multiethnic cohort study of kidney transplant recipients found that serum ApoB and ApoB/A1 ratio were positively associated with post-transplantation diabetes mellitus with an OR of 12.2 (95%CI: 3.13, 47.5) for ApoB and OR of 8.25 (95%CI: 1.72, 39.5) for ApoB/A1 ratio, respectively [
23]. A retrospective longitudinal study in Korea also observed that ApoB level and ApoB/A1 ratio were positively associated with T2D, the OR values were 1.262 (95%CI: 1.107, 1.438) for ApoB and 1.292 (95%CI: 1.137, 1.468) for ApoB/A1 ratio, respectively [
5]. TwSHHH study also pointed out the risk of T2D associated with serum levels of ApoB and ApoB/A1 ratio among adults in Taiwan, China (OR
ApoB: 2.21, 95% CI
ApoB: 1.12, 4.16; OR
ApoB/A1: 2.46, 95% CI
ApoB/A1: 1.32, 4.58) [
28]. But fasting plasma glucose level was adjusted in this prospective study. In addition, a cross-sectional study with 70,063 subjects found a positive association of ApoB/A1 ratio with T2D (OR: 1.31, 95%CI: 1.17, 1.46) [
30]. Similar to these findings, the present study found positive association of ApoB level and ApoB/A1 ratio with T2D prevalence. Our study also confirmed the positive association of ApoB and ApoB/A1 ratio with FBG level as previously reported [
20,
21]. However, the Atherosclerosis Risk in Communities (ARIC) study of 9026 American populations reported the null effects of ApoB and ApoB/A1 ratio on diabetes [
7]. Analogous findings were seen in Turkish population [
27], Australian women with previous gestational diabetes mellitus [
48] and Greek population [
22]. The inconsistent results of the present and previous studies might be attributable to some factors. Interestingly, the positive association was more likely to be observed in persons with higher ApoB concentration ([116 mg/dL] for this study) than lower concentration (99.58 mg/dL for American [
7] and 106.36 mg/dL for Greece [
22]), in studies with relative large sample size ([
5,
23,
30] & this study vs. small sample size [
48]). Additionally, other reasons such as the differences in design of study (cross-sectional vs. prospective), different obesity (Chinese vs. Western population), and covariates that were adjusted might also provide an explanation for the inconsistent findings among these studies.
It is worth noting that ApoB and ApoB/A1 ratio showed higher OR for T2D, compared with the TC, TG and LDL-C. These findings were supported by previous study results. An aboriginal Canadian study indicated that plasma ApoB concentration was positively associated with T2D risk and was superior to LDL-C in predicting the disease in aboriginal Canadian population [
49]. Additionally, ApoB showed a stronger association with the incident T2D compared with conventional lipid measurements in Korean populations [
50]. Previous study revealed that ApoB/A1 ratio added significant information for predicting insulin resistance [
51]. Indeed, ApoB was contained in each of very low LDL, intermediate-density lipoprotein, LDL-C, and lipoprotein(a) particles [
8]. Taken together, these finds suggested that Apo levels either separately for ApoB or together as calculated ApoB/A1 ratio might provide additional information for predicting the incident T2D.
Mechanisms
The association of serum ApoA1, ApoB, and ApoB/A1 ratio with T2D may be through various mechanisms. First, ApoA1 can reduce lipid binding capability, alter protein structure, and attenuate ability of catalyzing cholesterol efflux from macrophages [
17]. In addition, ApoA1 is able to improve glucose tolerance via increasing glucose uptake into skeletal muscle and heart by adenosine monophosphate-activated protein kinasecomplex [
52]. Second, ApoB inhibits lipolysis in adipocytes by acting as a metabolic pathway from liver to peripheral fat [
53]. Dysregulation of ApoB metabolism can consequently cause insulin resistance [
54]. Furthermore, path analyses in the present study confirmed an impact of ApoB on BMI. Third, oxidative stress and inflammation exert important roles in T2D pathophysiology. Several studies have demonstrated that ApoA1 protects mice against inflammation and oxidative stress-induced damage via clearing pro-inflammatory lipids and decreasing plasma malondialdehyde levels and intestinal inflammation in a Cyclooxygenase 2 total knockout and myeloid knockout/ cholate-containing high fat diet model [
55,
56]. Finally, ApoB can aggravate inflammation by binding to enolase-1 and releasing more inflammatory cytokines (e.g., tumor necrosis factor-α, IL-1β, and IL-6) [
57].
Strengths and limitations
This study comprehensively assessed the association of ApoA1, ApoB, and ApoB/A1 ratio with T2D prevalence and FBG level. Importantly, to the best of our knowledge, this is the first report that analyzes the mediating effects of BMI on the association of ApoA1, ApoB, and ApoB/A1 ratio with T2D prevalence in Chinese adults. Next, the relatively large sample size allows us to be able to evaluate potential association among variables. Third, the availability of individual information (e.g., medication records and lifestyles) allows us to adjust for more potential confounders. Fourth, we further evaluated the effect of the interactions between ApoA1, ApoB, ApoB/A1 ratio and individual information (e.g., sex, age, BMI, smoking, and drinking status) on T2D prevalence. Finally, by comparing apolipoprotein indicators, we found that ApoB and ApoB/A1 ratio performed better in predicting T2D, which may provide specific guidance for large epidemiological surveys for T2D. Notwithstanding, the present study also has a few limitations. First, the causality was not determined due to the cross-sectional study design. However, apolipoprotein levels reached a steady-state in adults, and this state was mainly influenced by diets rather than glucose metabolism indices. Therefore, cause-and-effect association is less likely to be inverted. Second, although all subjects were recruited from urban communities in China, it had little influence on the association of ApoA1, ApoB and ApoB/A1 ratio with T2D prevalence or FBG level. Third, previous study reported dietary nutrients were related to Apo concentrations [
58], however, we did not rule out the effects of dietary nutrients, which might attenuate the underlying associations. Fourth, although daily physical activity was assessed by a physical activity questionnaire, subjective recall bias and day-to-day fluctuations from daily physical activity in our study were possible, but which might have minimal impact on the present results due to daily physical activity was relative stable in participants with an average age of 60.3 years. Finally, although attempts to control for the potential confounders have been made, residual confounding may not be ruled out as reported by other observational studies.
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