Abstract
BackgroundThe identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up.MethodsIn the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110–125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman’s coefficients. Kaplan–Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models.ResultsDuring a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan–Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds.ConclusionsThe plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations.Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509
Highlights
The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients
We found such an inverse association between low High-density lipoprotein (HDL)-C levels and the risk of new-onset T2D by univariate analysis, it did not remain after further adjustments for body mass index (BMI) and glucose homeostasis (FPG, HbA1C)
After adjustment for classical diabetes risk factors, glucose parameters (FPG, HbA1C), and plasma TG, we identified 4 apolipoproteins amongst 16 that remain significantly associated with new-onset T2D in individuals with prediabetes: apoE, apoF, apoJ, and apoL1
Summary
The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. The identification of early biomarkers associated with T2D risk is required for improving the current prevention strategies and for gaining a better understanding of the disease [6]. Low concentrations of high-density lipoprotein cholesterol (HDL-C) and high concentrations of plasma triglycerides (TG) are associated with an increased risk of T2D, and they are usually preceded by the gradual onset of insulin resistance [7, 8]. Clinical trials have reported that the statin-induced reduction of low-density lipoprotein cholesterol (LDL-C) slightly increases the risk of newonset T2D [9,10,11]. T2D prevalence is halved in patients with familial hypercholesterolemia, especially in carriers of the most severe LDL receptor mutations [13], suggesting a direct association between the prevalence of T2D and the upregulation of the LDL receptor pathway
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