Positive Association between Triglyceride-Rich Lipoprotein Cholesterol and Diabetes Mellitus in Hypertensive Patients

Background. The association between triglyceride-rich lipoprotein cholesterol (TRL-C) and diabetes mellitus (DM) remains unclear because of limited research and data. The aim of this study was to explore the independent association between TRL-C and DM in hypertensive patients and to examine whether a healthy lifestyle would have an impact on this relationship. Methods. In this study, data from 13,721 hypertensive patients who were not treated with lipid-lowering drugs were analyzed. TRL-C was calculated from total cholesterol (TC) minus [LDL cholesterol + HDL cholesterol]. DM was defined as fasting plasma glucose of ≥7.0 mmol/L and/or self-reported history of hypoglycemic drug use. Results. After adjusting for potential confounding factors, the TRL-C was significantly positively associated with elevated DM (odds ratio (OR): 1.73 and 95% confidence interval (CI): 1.54–1.94). In subgroup analysis, a healthy lifestyle (HL) failed to modify the positive association between TRL-C and DM (HL: OR 1.93, 95%CI 1.58–2.36; non-HL: OR 1.72, 95%CI 1.50–1.98; P for interaction = 0.38). Conclusion. The results showed a positive association between TRL-C and DM in hypertensive patients. A healthy lifestyle failed to diminish the relationship between TRL-C and DM. The novel findings indicate that TRL-C might be a reliable marker of DM and may provide a new strategy for the prevention and treatment of DM.

Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3

Angiopoietin-like protein 3 (ANGPTL3) is a key physiological regulator of plasma lipid and lipoprotein metabolism that involves the control of enzymes, lipoprotein and endothelial lipases. Inhibition of ANGPTL3 offers a new approach for correcting the health risks of dyslipidemia, including familial hypercholesterolemia, mixed hyperlipidemia, metabolic syndrome and/or severe hypertriglyceridemia. ANGPTL3 inhibition with nucleic acid-based antisense oligonucleotide and siRNA can correct dyslipidemia chiefly by reducing production and increasing catabolism of triglyceride-rich lipoprotein and LDL particles. Early clinical trials have demonstrated that these agents can safely and effectively lower plasma triglyceride and LDL-cholesterol levels by up to 70 and 50%, respectively. However, the long-term safety and cost–effectiveness of these agents await to be confirmed in an ongoing and future clinical trials.

HNF4g invalidation prevents diet-induced obesity via intestinal lipid malabsorption

Changes in dietary habits have occurred concomitantly with a rise of type 2 diabetes (T2D) and obesity. Intestine is the first organ facing nutrient ingestion and has to adapt its metabolism with these dietary changes. HNF-4γ, a transcription factor member of the nuclear receptor superfamily and mainly expressed in intestine has been suggested involved in susceptibility to T2D. Our aim was to investigate the role of HNF-4γ in metabolic disorders and related mechanisms. Hnf4g-/- mice were fed high-fat/high-fructose (HF-HF) diet for 6 weeks to induce obesity and T2D. Glucose homeostasis, energy homeostasis in metabolic cages, body composition and stool energy composition, as well as gene expression analysis in jejunum were analyzed. Despite an absence of decrease in calorie intake, of increase in locomotor activity or energy expenditure, Hnf4g-/- mice fed HF-HF are protected against weight gain after 6 weeks of HF-HF diet. We showed that Hnf4g-/- mice fed HF-HF display an increase in fecal calorie loss, mainly due to intestinal lipid malabsorption. Gene expression of lipid transporters, Fatp4 and Scarb1 and of triglyceride-rich lipoprotein secretion proteins, Mttp and ApoB are decreased in gut epithelium of Hnf4g-/- mice fed HF-HF, showing the HNF-4γ role in intestine lipid absorption. Furthermore, plasma GLP-1 and jejunal GLP-1 content are increased in Hnf4g-/- mice fed HF-HF, which could contribute to the glucose intolerance protection. The loss of HNF-4γ leads to a protection against a diet-induced weight gain and to a deregulated glucose homeostasis, associated with lipid malabsorption.

The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19

A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides. However, a detailed characterization of the particle counts and sizes of the different plasma lipoproteins in patients with COVID-19 has yet to be reported. In this pilot study, NMR spectroscopy was used to characterize lipoprotein particle numbers and sizes, and various metabolites, in 32 patients with severe COVID-19 admitted to the intensive care unit. Our study revealed markedly reduced HDL particle (HDL-P) numbers at presentation, especially low numbers of small HDL-P (S-HDL-P), and high counts of triglyceride-rich lipoprotein particle (TRL-P), particularly the very small and small TRL subfractions. Moreover, patients with severe COVID-19 were found to have remarkably elevated GlycA levels, and elevated levels of branched-chain amino acids and beta-hydroxybutyrate. Finally, we detected elevated levels of lipoproteins X and Z in most participants, which are distinct markers of hepatic dysfunction, and that was a novel finding.

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

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, estimated as HOMA-β, 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, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater 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 greater 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.

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

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.