In this large longitudinal cohort study based on a Chinese adult population, we revealed for the first time a positive correlation of the LDL:HDL ratio with the risk of prediabetes. Sensitivity analysis results further confirmed that this association was very robust.
Prediabetes is the pathological stage that must go through to develop from normal blood glucose levels to type 2 DM and it is estimated that the annual conversion rate of prediabetes to DM is 5–10% [6]. IR and islet β-cell dysfunction are the pathological basis of the occurrence and development of prediabetes, and IR is also an important cause of “diabetic dyslipidemia” in patients with prediabetes and DM [10, 22, 23]. In prediabetic patients, dyslipidemia is usually manifested as elevated levels of LDL-C, TC, TG, and reduced HDL-C levels [22, 24]; among them, abnormally elevated LDL-C and decreased HDL-C levels will damage the function of pancreatic islet β cells to further aggravate IR, which will form a vicious cycle, and accelerate the progression from prediabetes to type 2 DM [25]. A series of clinical studies that have been completed have also confirmed that both LDL-C and HDL-C were important lipid parameters associated with the risk of glycemic metabolism [26,27,28]. In a recent study, Pan et al. using a two-sample Mendelian randomization analysis demonstrated that elevated LDL-C levels can significantly increase the risk of developing type 2 DM [27]; while in the study of the Chinese hypertensive population by Liu et al., it was found a U-shaped correlation between the level of LDL-C and the incidence of DM [26]. In contrast to LDL-C, HDL-C was inversely associated with the risk of glycemic metabolism. According to Drew BG et al., in their recent double-blind, placebo-controlled clinical trial, they recruited 13 patients with type 2 DM, and each patient was given intravenous injections of recombinant high-density lipoprotein (rHDL) and placebo saline at different times, with a 4-week interval between the two injections; the results showed that compared with a placebo injection, subjects injected with rHDL had significantly higher plasma HDL levels as well as apolipoprotein AI (ApoA-I) levels and plasma insulin levels, significantly enhanced β-cell function, while FPG levels decreased significantly. In further studies, the researchers found that HDL and ApoA-I can reduce FPG levels by activating AMP-activated protein kinase in skeletal muscle and enhancing the ability of skeletal muscle cells to uptake glucose [28]. In addition, studies have shown that in patients with type 2 DM, infusion of cholesteryl ester transfer protein inhibitor significantly reduced blood glucose levels by indirectly increasing plasma HDL levels [29, 30]. The above studies have shown that HDL-C is a favorable factor for blood glucose metabolism and can have a positive impact on patients with glucose metabolism disorders.
Recently, some researchers have found that the LDL:HDL ratio, a combined index which is calculated as LDL-C divided by HDL-C, was also closely related to DM, NAFLD, and many other metabolic-related diseases, and this parameter was also regarded as a potential IR surrogate marker [15,16,17, 31,32,33]. However, the relationship of LDL:HDL ratio with the incidence of prediabetes has not been clarified. This study found that the LDL:HDL ratio was an independent risk factor for prediabetes. To our knowledge, our research first revealed the relationship of LDL:HDL ratio with prediabetes, a finding that may provide a valuable reference for the primary prevention of prediabetes.
The underlying mechanism of the relationship of LDL:HDL ratio with prediabetes remains unclear, and there are several possible explanations. In prediabetic patients, a high LDL:HDL ratio is usually caused by normal or elevated plasma LDL-C levels and significantly decreased plasma HDL-C levels [22]. The elevated LDL-C levels may exert potential prediabetic effects by reducing both the maximum glucose-stimulated insulin secretion and the basal proliferation of human islet β-cells; whereas reduced HDL-C levels could weaken its protective effect on islet β-cells apoptosis, resulting in lower islet β-cell numbers and insulin secretion; the occurrence and development of prediabetes may be the outcome of the combined action of the two [25]. Moreover, from Table 1 we can find that people with a high LDL:HDL ratio generally have higher TG levels; previous studies have shown that elevated TG levels in skeletal muscle increased skeletal muscle IR and systemic IR, which means that high TG levels may further promote the occurrence of prediabetes [34]. We also further evaluated the role of TG in LDL:HDL ratio-related prediabetes risk in subgroup analysis, and the results showed that no significant interaction was found, and further studies are needed to explore the potential association.
Some interesting results were also found in the stratified analysis of the current study. The LDL:HDL ratio-related prediabetes risk diminished with increasing age and BMI, and the mechanisms behind this age- and BMI-related effect heterogeneity may be explained in several ways. On the one hand, age-associated increases in IR and the number of comorbidities, as well as the decline in general health, may result in a relatively weakened association of the LDL:HDL ratio with prediabetes [35]; with the increase of BMI, the IR will be significantly enhanced, making overweight and even obesity a major risk factor for prediabetes [36]. On the other hand, poor diet and lifestyle may increase prediabetes risk associated with LDL:HDL ratio in younger age groups [37]; the risk of prediabetes associated with LDL:HDL ratio is higher in non-obese people with lower BMI may be attributed to ectopic fat deposition, insulin secretion disorders, low birth weight due to uterine malnutrition, and epigenetic changes in the human genome, which can lead to severe glucose metabolism disorders and more prevalent in Asian population [38]. At the same time, we found that in the sex subgroups women had a significantly higher LDL:HDL ratio-related prediabetes risk, which was confusing. Because in the current study, there was a significantly higher proportion of women than men in the low LDL:HDL ratio categories, and the incidence of prediabetes in women was found to be lower than in men in the sex subgroups (9.58% vs 14.84%), therefore it is oddly that women showed higher LDL:HDL ratio-related risk of prediabetes than men (P-interaction < 0.0001). The reason for this phenomenon may be suggested by the age subgroups in the stratified analysis. We can find that about 70% of all subjects with new-onset prediabetes are older than 50 years old, which indicated that prediabetes in most women occurred after menopause [39]. Based on some available evidence, we speculate that the increased risk of prediabetes in postmenopausal women may be associated with changes in ovarian aging-related hormone levels. It is well known that postmenopausal women experience accelerated ovarian aging, markedly decreased estrogen levels, and markedly increased androgen levels; the most immediate effects of these changes are further increased adipose tissue mass, fat redistribution, decreased skeletal muscle mass, and decreased insulin sensitivity [40]; most notable of which is the redistribution of body fat in women after menopause. According to existing studies, estrogen and androgen play different roles in fat deposition, among which estrogen is mainly related to peripheral fat storage in the subcutaneous region of the buttocks and femur, while androgen is mainly related to the accumulation of visceral abdominal fat [41]. In postmenopausal women, the levels of sex hormones in the body are significantly changed, and the ratio of androgen to estradiol is significantly increased, which may be an important reason for central fat accumulation, visceral fat increase, and abdominal obesity [40, 42]. These deleterious patterns of fat deposition all significantly increase the risk of prediabetes in postmenopausal women. In the subgroup of family history of DM, those with a family history of DM showed a higher risk of LDL:HDL ratio-related prediabetes. This discrepancy may be because the occurrence of DM is influenced by genetic factors, and only a single gene mutation such as PPARgamma, ATK2, and insulin receptor gene can cause severe IR [43]. Furthermore, there was a lot of evidence that the adiponectin gene, HFE hereditary hemochromatosis gene, etc. may also affect the susceptibility to type 2 DM; individuals with the susceptibility genes were more likely to develop prediabetes if environmental factors altered the expression of these genes [44].
Strengths and limitations
This study has some notable merits: (1) This is the first study to explore the relationship between LDL:HDL ratio and prediabetes, several special populations were found in the stratified analyses, which can provide a new strategy for the accurate screening of prediabetes as well as the prevention and intervention of DM. (2) The study population comes from multiple regions in China, with a huge number and a wide age distribution, which is well representative of the Chinese population. (3) Strict statistical analysis was performed in this study, and multiple sensitivity analyses and subgroup analyses were conducted. The positive correlation of the LDL:HDL ratio with the incidence of prediabetes is stable among all populations, so the conclusions of this research are relatively reliable.
Of course, this study also has some limitations: (1) As the diagnostic criteria for prediabetes recommended by ADA were adopted in the current study [12], its relatively low diagnostic threshold for IFG may include more patients with new-onset prediabetes. Nevertheless, we applied the WHO-recommended diagnostic criteria for prediabetes in the sensitivity analysis, based on a higher diagnostic threshold of IFG (FPG: 6.1–6.9 mmol/L) [21], and also obtained results consistent with the main analysis. (2) The diagnosis of prediabetes in the present study was only based on FPG levels, which may cause us to miss some new cases of prediabetes. However, we still demonstrated a significant correlation of LDL:HDL ratio with prediabetes in a smaller number of cases. (3) As the study design of the retrospective cohort, even if we adjusted for a large number of confounders, residual confounding due to measurement error in the assessment of confounders and the unavailability of data for some unmeasured factors could not be ruled out. (4) The results obtained in this study are based on a Chinese population cohort, most of which are from cities in southern China, so our results are more suitable for generalization in southern Chinese populations, while further research is needed in northern populations and non-Chinese populations. (5) Since this study did not distinguish between different types of HDL-C, the effect of dysfunctional HDL-C on blood glucose metabolism could not be excluded, which may affect the correlation between LDL:HDL ratio and prediabetes, and further analyses of the different roles of HDL-C and its subpopulations are required in future studies [45].