Association between liver insulin resistance and cardiovascular risk factors

Abstract. Vangipurapu J, Stan?áková A, Kuulasmaa T, Soininen P, Kangas AJ, Ala‐Korpela M, Kuusisto J, Laakso M (University of Eastern Finland and Kuopio University Hospital, Kuopio; University of Oulu and Biocenter Oulu, Oulu, Finland). Association between liver insulin resistance and cardiovascular risk factors. J Intern Med 2012; 272: 402–408. Objectives. The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole‐body insulin sensitivity and different cardiovascular disease (CVD) risk factors. Design and subjects. A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m^?2) were included in this study from the population‐based cross‐sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole‐body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. Results. Total cholesterol (r = ?0.088 vs. r = 0.020; P < 0.0019), high‐sensitivity C‐reactive protein (CRP) (r = 0.284 vs. r = ?0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = ?0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = ?0.234 and r = ?0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. Conclusions. Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.     

Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population‐based study of 9399 Finnish men

Abstract. Wang J, Stan?áková A, Soininen P, Kangas AJ, Paananen J, Kuusisto J, Ala‐Korpela M, Laakso M (University of Eastern Finland and Kuopio University Hospital, Kuopio; Institute of Clinical Medicine, University of Oulu, Oulu; University of Eastern Finland, Kuopio; and Clinical Research Center, University of Oulu, Oulu; Finland). Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population‐based study of 9399 Finnish men. J Intern Med 2012; doi: 10.1111/j.1365‐2796.2012.02562.x. Objectives. We investigated serum concentrations of lipoprotein subclass particles and their lipid components determined by proton nuclear magnetic resonance spectroscopy in a population‐based study. Design and methods. A total of 9399 Finnish men were included in the study: 3034 men with normal fasting glucose and normal glucose tolerance; 4345 with isolated impaired fasting glucose (IFG); 312 with isolated impaired glucose tolerance (IGT); 1058 with both IFG and IGT; and 650 with newly diagnosed type 2 diabetes (New DM). Lipoprotein subclasses included chylomicrons (CM) and largest VLDL particles, other VLDL particles (five subclasses), intermediate‐density lipoprotein (IDL), LDL (three subclasses) and HDL (four subclasses). The phospholipid, triglyceride (TG), cholesterol, free cholesterol and cholesterol ester levels of the lipoprotein particles were measured. Results. Abnormal glucose tolerance (especially IGT and New DM) was significantly associated with increased concentrations of VLDL subclass particles and their components (with the exception of very small VLDL particles). After further adjustment for total TGs and HDL cholesterol, increased lipid concentrations in the CM/largest VLDL particles and in most of the other VLDL particles remained significant in individuals with isolated IGT, IFG+IGT and New DM. There was a consistent trend towards a decrease in large and an increase in small HDL particle concentrations in individuals with hyperglycaemia even after adjustment for serum total TGs and HDL cholesterol. Conclusions. Abnormal glucose tolerance modifies the concentrations of lipoprotein subclass particles and their lipid components in the circulation and is also related to compositional changes in these particles.     

内皮脂肪酶与高密度脂蛋白及动脉粥样硬化的关系

高密度脂蛋白具有一定的抗动脉粥样硬化的作用,而内皮脂肪酶可水解高密度脂蛋白,进而影响动脉粥样硬化的进展,故深入探讨三者关系,可能为动脉粥样硬化相关疾病的防治提供崭新的靶点.     

Methylenetetrahydrofolate reductase homozygosis and low-density lipoproteins in patients with genotype 1 chronic hepatitis C

Methylenetetrahydrofolate reductase status, homocysteine and lipoproteins levels have been associated with severity of disease and both rapid and sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C (CHC). We aimed to assess the association of homocysteine and MTHFR status with serum cholesterol levels and their potential links to both histological findings and virological response, in patients with genotype 1 hepatitis C virus (HCV). A total of 119 consecutive patients were evaluated by biopsy and metabolic measurements. A total of 103 healthy blood donors were used as controls. Serum homocysteine and MTHFR C677T mutation were also evaluated. All patients underwent antiviral therapy with PEG-IFN alfa-2a plus ribavirin. HCV-RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. Mean serum values of homocysteine were higher in patients than in controls (15.8 ± 5.8 μg/L vs 12.5 ± 5.8 μg/L; P < 0.001), with a similar CC, CT and TT MTHFR distribution (23.6%, 48.7% and 27.7% in G1-CHC vs 34%, 48.5% and 17.5% in controls; P = 0.14). In genotype 1, HCV MTHFR TT homozygosis was independently linked to higher LDL (OR 1.016; CI 1.002-1.031; P = 0.03), but not to homocysteine. No association were found between homocysteine, MTHFR and histological features or both rapid virological response (RVR) and SVR. Low cholesterol (OR 0.988, 95%CI 0.975-0.999, P = 0.04) was independently linked to severe fibrosis, and high LDL was the only independent positive predictors of both RVR and SVR (OR 1.036; 95%CI 1.017-1.055; P < 0.001; and OR 1.016; 95%CI 1.001-1.031; P = 0.04 respectively). In patients with genotype 1 hepatitis C, showing higher homocysteine serum levels than controls, MTHFR C677T homozygosis, via modulating cholesterol levels, could interfere with liver fibrosis and response to antiviral therapy.     

Utility of non-high-density lipoprotein cholesterol in assessing incident type 2 diabetes risk

Aims: Traditional lipid indices have been associated with type 2 diabetes, but limited data are available regarding non‐high‐density lipoprotein (non‐HDL) cholesterol. In view of recent guidelines for the clinical management of dyslipidemia recommending the monitoring of non‐HDL cholesterol as a secondary target after achieving the low‐density lipoprotein (LDL) cholesterol goal, we aimed to assess the association of non‐HDL cholesterol with incident type 2 diabetes and compare its utility as a risk predictor with traditional lipid variables in Aboriginal Canadians. Methods: Of 606 diabetes‐free participants at baseline, 540 (89.1%) returned for 10‐year follow‐up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipids were measured. Fasting and 2‐h postload glucose were obtained at baseline and follow‐up to determine the incidence of type 2 diabetes. Results: The cumulative incidence of type 2 diabetes was 17.5%. Higher non‐HDL cholesterol, total‐to‐HDL cholesterol ratio, apolipoprotein B, triglyceride and LDL cholesterol and lower HDL cholesterol concentrations were individually associated with incident type 2 diabetes in univariate analyses (all p < 0.05). Non‐HDL cholesterol was a superior determinant of incident diabetes compared with LDL cholesterol (comparing C‐statistics of univariate models p = 0.01) or HDL cholesterol (p = 0.004). With multivariate adjustment including waist circumference, non‐HDL cholesterol remained associated with incident diabetes [odds ratio (OR) 1.42 (95% confidence interval, CI 1.07–1.88)], while LDL cholesterol and HDL cholesterol became non‐significant. Conclusions: Non‐HDL cholesterol was associated with incident type 2 diabetes and was superior to LDL cholesterol as a risk predictor in this population. Further studies are required to establish the utility of non‐HDL cholesterol in non‐Aboriginal populations.     

Toll‐like receptor 2‐mediated modulation of growth and functions of regulatory T cells by oral streptococci

This study was designed to determine whether oral streptococci modulate the growth and functions of regulatory T cells. Heat‐killed cells of wild‐type strains of Streptococcus gordonii and Streptococcus mutans induced the Toll‐like receptor 2 (TLR2) ‐mediated nuclear factor‐κB (NF‐κB) activation, but their lipoprotein‐deficient strains did not. Stimulation with these streptococci resulted in a significant increase in the frequency of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in splenocytes derived from both TLR2^+/+ and TLR2^?/? mice, but the level of increase in TLR2^+/+ splenocytes was stronger than that in TLR2^?/? splenocytes. Both strains of S. gordonii enhanced the proliferation of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells isolated from TLR2^+/+ mice at the same level as those from TLR2^?/? mice in an interleukin‐2‐independent manner. However, wild‐type and lipoprotein‐deficient strains of both streptococci did not enhance the suppressive activity of the isolated regulatory T cells in vitro, but rather inhibited it. TLR ligands also inhibited the suppressive activity of the regulatory T cells. Inhibition of the suppressive activity was recovered by the addition of anti‐IL‐6 antibody. Pretreatment of antigen‐presenting cells with the NF‐κB inhibitor BAY11‐7082 enhanced the suppressive activity of the regulatory T cells. These results suggested that interleukin‐6 produced by antigen‐presenting cells inhibits the suppressive activity of the regulatory T cells. Wild‐type strain, but not lipoprotein‐deficient strain, of S. gordonii reduced the frequency of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in the acute infection model, whereas both strains of S. gordonii increased it in the chronic infection model mice. Hence, this study suggests that oral streptococci are capable of modulating the growth and functions of regulatory T cells in vitro and in vivo.     

Mild hypercholesterolemia blunts the proinflammatory and prothrombotic effects of hypertension on the cerebral microcirculation

Although an increased leukocyte and platelet adhesion is observed in cerebral venules of mice with either hypertension (HTN) or hypercholesterolemia (HCh), it remains unclear whether the combination of HTN and HCh exerts a comparable effect on leukocyte and platelet recruitment in the cerebral microvasculature. Thus, we examined whether HCh alters platelet and leukocyte adhesion, and blood–brain barrier (BBB) permeability, in cerebral venules in two models of murine HTN: DOCA salt-induced and angiotensin II (Ang II) induced. In both models, the mice were placed on either a normal or cholesterol-enriched diet. An enhanced recruitment of adherent leukocytes and platelets in cerebral venules was noted in both HTN models in the absence of HCh, but not in its presence. The Ang II-induced increase in BBB permeability was attenuated by HCh as well. Both total and high-density lipoprotein (HDL) cholesterol levels were elevated in the HCh mice. The HTN-induced increase in leukocyte and platelet adhesion was attenuated in apolipoprotein A-I transgenic mice (ApoA1-Tg) and blunted in wild-type mice treated with the ApoA1 mimetic peptide, 4F. Our findings indicate that mild HCh significantly blunts the cerebral microvascular responses to HTN and that HDL may have a role in mediating this beneficial effect of HCh.