Triglyceride-Rich Lipoprotein and LDL Particle Subfractions and Their Association With Incident Type 2 Diabetes: The PREVEND Study.

Abstract

Background: Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, and evaluated their associations with incident T2D in the general population.Methods: We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.Results: In subjects without T2D at baseline, very large TRLP, large LDLP and LDL size were inversely associated with HOMA-β, whereas large TRLP, medium TRLP and TRL size were positively associated with HOMA-β taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 individuals developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP and TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and LDL size were associated with a lower risk of developing T2D.Conclusions: Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.

The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus

“…Excess cholesterol is also able to induce endoplasmic reticulum stress and mitochondrial dysfunction and promote reactive oxygen species (ROS) production in pancreatic β-cells, ultimately leading to structural changes in insulin-containing granules [34]. RC is more abundant, larger, and carries more cholesterol than LDL-C particles; hence, it can be inferred that RC is more harmful to pancreatic β-cells [8]. Furthermore, unlike LDL-C, the unique pro-inflammatory characteristics of RC may significantly contribute to abnormal glucose metabolism by exacerbating insulin resistance and a systemic pro-inflammatory state [20,42].…”

“…Furthermore, unlike LDL-C, the unique pro-inflammatory characteristics of RC may significantly contribute to abnormal glucose metabolism by exacerbating insulin resistance and a systemic pro-inflammatory state [20,42]. Apart from these effects, the particle size of TRLs has drawn great interest from researchers, and an increasing body of evidence suggests that the particle size of TRLs is the key factor that contributes to its pathogenicity [8,43]. Specific particle properties of TRLs and LDL-C are associated with β-cell function and incident DM [8].…”

“…There has been increasing evidence in recent years that TRLs are associated with the onset of diabetes [7]. A molecular lipid analysis showed that plasma TG levels were the only variable associated with DM in high-risk groups [8], and a high-fat diet increased the synthesis of TG in the liver, reduced relative high-density lipoprotein cholesterol (HDL-C), and accelerated the onset of DM [9]. In population cohort studies, a higher TG-related indicators were associated with DM independent of insulin resistance, highlighting the importance of TRLs in the development of DM [10][11][12].…”

“…Cholesterol content in TRLs contributed more directly to cardiovascular disease (CVD) rather than TG, thus, RC was highlighted in the lipids management in recent years [14]. RC is more abundant, larger, and carries more cholesterol than LDL-C particles, so it can be inferred that RC is more harmful to pancreatic β-cells [8]; In addition, unlike LDL-C, TRLs exert their pathogenic effects through inflammatory pathways [15,16]. Epidemiological evidence has suggested that higher RC levels were not only significantly associated with the development of DM, but also contributed to the comorbidities such as hypertension [17,18].…”

“…It will become increasingly important to investigate the discordance/concordance of LDL-C and RC, especially in the context of the increasing prevalence of DM, as both are on the rise in DM patients. Specific TRLs and LDL-C particles have been linked to DM based on the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study [8], but the association between the discordant/concordant LDL-C and RC and DM requires further elucidation.…”