Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis

Background

Free fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA).

Methods

Clinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analyses.

Results

Serum FFAs did not differ significantly in patients with RA and controls (0.56 mmol/L [0.38–0.75] and 0.56 mmol/L [0.45–0.70] respectively, p = 0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p = 0.035 and p = 0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p = 0.011), CRP (p = 0.01), triglycerides (p = 0.005) and Framingham risk score (p = 0.048) in RA, but not with IL-6 (p = 0.48) or coronary artery calcium score (p = 0.62).

Conclusions

Serum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.     

Free fatty acids and pathogenesis of type 2 diabetes mellitus.

Plasma free fatty acids (FFA) might mediate the insulin resistance and impaired glucose tolerance associated with central obesity. Central adipocytes are resistant to insulin, suggesting that FFA delivery to the liver via the portal vein is increased when visceral triglyceride (TG) stores are increased. Muscle insulin resistance might result from the 'Randle' mechanism, from downregulation of the insulin signaling pathway, and/or reduced access of insulin to skeletal muscle owing to changes in blood flow or insulin transport across capillary endothelium. TG storage within muscle might interfere with insulin action, but a causal relationship between myocellular lipid and glucose disposal remains to be demonstrated. Basal levels of FFA appear to be permissive for insulin secretion; however, elevated FFA have a minor effect on insulin secretion in vivo. In humans, prolonged hyperlipidemia engenders an insulin response matched to the degree of insulin resistance, leaving open the question of whether lipotoxicity of islet cells contributes to glucose intolerance and diabetes in humans. Elevated portal FFA might account for overproduction of liver glucose output with visceral adiposity. Additionally, portal FFA might reduce hepatic extraction of insulin, diminishing the necessity of increased beta-cell response to compensate for FFA-driven insulin resistance. Overall, effects of FFA can lead to several components of the insulin resistance syndrome and risk for diabetes. Reduction in FFA might be the appropriate therapy for these disorders.     

Extended afternoon naps are associated with hypertension in women but not in men

BackgroundThe impact of afternoon napping duration on the risk of hypertension has not been well established, particularly with regards to sex and age differences.ObjectiveTo examine the association between afternoon napping duration and hypertension stratified by sex and age among Chinese adults over 45 years of age.MethodsThe 2011–2012 survey of the China Health and Retirement Longitudinal Study (CHARLS) was used, including 7,980 participants. We conducted logistic regression models in the overall sample, and then stratified by sex and age groups.ResultsMiddle-aged and older women who napped over 90 min were 39% and 54% more likely to have hypertension, respectively; however, the associations were not significant in middle-aged and older men.ConclusionExtended afternoon napping (≥90 min) was associated with hypertension in both the middle-aged women and older women but not in men. Future studies are needed to further examine the association and possible mechanisms.     

Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men

Aims/hypothesis  

Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting.     

Elevated serum ceruloplasmin levels are associated with albuminuria in Korean men with type 2 diabetes mellitus

The aim of this study was to examine the possible association between serum ceruloplasmin, a copper carrying protein, and albuminuria in 456 males with type 2 diabetes. Multivariate regression analysis demonstrated that elevated serum ceruloplasmin was a determinant of albuminuria independently of conventional risk factors.     

Advanced glycation end products are associated with pulse pressure in type 1 diabetes: the EURODIAB Prospective Complications Study

We investigated the associations of pulse pressure (a measure of arterial stiffness) with the early glycation products hemoglobin A1c (HbA1c) and Amadori albumin and the advanced glycation end products pentosidine, Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine in a large group of type 1 diabetic individuals of the EURODIAB Prospective Complications Study. We did a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 543 (278 men) European individuals with type 1 diabetes diagnosed at <36 years of age. We used linear regression analyses to investigate the association of pulse pressure with glycation products. Pulse pressure was significantly associated with plasma levels of Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine but not with HbA1c, Amadori albumin, and urinary levels of pentosidine. Regression coefficients adjusted for age, sex, mean arterial pressure, and duration of diabetes were 0.09 mm Hg (P=0.003) per 1 microM/M lysine Nepsilon-(carboxymethyl)lysine; 0.24 mm Hg (P=0.001) and -0.03 mm Hg (P=0.62) per 1 microM/M lysine Nepsilon-(carboxyethyl)lysine (in individuals with and without complications, respectively; P interaction=0.002); and 0.50 mm Hg (P=0.16) per 1% HbA1c; 0.07 mm Hg (P=0.12) per 1 U/mL Amadori albumin; and 0.77 mm Hg (P=0.48) per 1 nmol/mmol creatinine pentosidine. In young type 1 diabetic individuals, arterial stiffness is strongly associated with the advanced glycation end products Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine. These findings suggest that the formation of advanced glycation end products is an important pathway in the development of arterial stiffness in young type 1 diabetic individuals.     

Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with Type I diabetes mellitus

Aims/hypothesis. To investigate the association between glycaemic control and hypertensive pregnancy complications. Methods. From 1988 to 1997, we followed up 683 consecutive non-selected pregnancies in women with Type I (insulin-dependent) diabetes mellitus. Glycaemic control was assessed by assay of HbA_{1 c}. Pre-eclampsia was defined as diastolic blood pressure of 90 mmHg or more at the end of pregnancy after an increase of 15 mmHg or more, combined with proteinuria of 0.3 g or more for 24 h. Pregnancy-induced hypertension was defined similarly but without proteinuria. The same criteria were applied to a control group of 854 non-selected non-diabetic women. Results. Pre-eclampsia developed in 12.8 % of the women with diabetes (excluding those with nephropathy before pregnancy) and in 2.7 % of the control women (odds ratio 5.2; 95 % CI 3.3–8.4). In multiple logistic regression, glycaemic control, nulliparity, retinopathy and duration of diabetes emerged as statistically significant independent predictors of pre-eclampsia. The adjusted odds ratios for pre-eclampsia were 1.6 (95 % CI 1.3–2.0) for each 1 % increment in the HbA_{1 c} value at 4–14 (median 7) weeks of gestation and 0.6 (0.5–0.8) for each 1 % decrement achieved during the first half of pregnancy. Changes in glycaemic control during the second half of pregnancy did not significantly alter the risk of pre-eclampsia. Unlike pre-eclampsia, the risk of pregnancy-induced hypertension was not associated with glycaemic control. Conclusion/interpretation. In women with Type I diabetes, poor glycaemic control is associated with an increased risk of pre-eclampsia but not with a risk of pregnancy-induced hypertension. [Diabetologia (2000) 43: 1534–1539] Received: 23 June 2000 and in revised form: 9 August 2000     

Reproductive history and hormonal birth control use are associated with coronary calcium progression in women with type 1 diabetes mellitus

CONTEXT: Coronary artery disease is increased in women with type 1 diabetes (T1D), compared with nondiabetic (Non-DM) women. Women with T1D have more menstrual dysfunction and are less likely to use hormonal birth control (BC) than Non-DM women. OBJECTIVE: The purpose of this study was to determine whether coronary artery calcium (CAC) is associated with menstrual dysfunction and BC use in women with T1D. MATERIALS AND METHODS: This was a prospective cohort study, and participants were followed up for an average of 2.4 yr. PATIENTS: Patients included 612 women (293 T1D, 319 Non-DM) between the ages of 19 and 55 yr who had CAC measured twice by electron beam tomography. RESULTS: Irregular menses and amenorrhea were more common in T1D than Non-DM women (22.1 vs. 14.9%, P < 0.05 and 16.6 vs. 7.0%, P < 0.001). T1D women reported less BC use than Non-DM women (79.8 vs. 89.9%, P < 0.001) and reached menarche at an older age (13.1 +/- 1.8 vs. 12.8 +/- 1.5 yr, P < 0.05). Use of BC was associated with less CAC progression in all women, but this association was stronger in T1D women (P value for interaction = 0.02). Irregular menses were associated with greater CAC progression only among T1D women. CONCLUSIONS: A prior history of BC use is associated with reduced CAC progression among all women, with a stronger association in T1D than in Non-DM women. Women with T1D who report irregular menses have increased CAC progression, compared with those with regular menses.     

Hematocrit is associated with carotid atherosclerosis in men but not in women

BACKGROUND: It is known that blood and plasma viscosities are associated with clinical manifestations of atherosclerosis, though evidence is not conclusive particularly in women. OBJECTIVE: To verify whether hematocrit and blood and plasma viscosities are independently associated with carotid atherosclerosis and whether their measurement can improve the definition of the global coronary heart disease (CHD) risk. METHOD: Eight hundred and ninety-two participants in a cardiovascular disease prevention campaign were examined with regard to conventional CHD risk factors (age, blood pressure, lipids, glucose, body mass index, waist/hip ratio, cigarette smoking and diabetes), hematocrit and blood and plasma viscosities. According to the degree of carotid atherosclerosis, investigated by echo-Doppler, participants were divided in three groups: those without atherosclerosis, those with a low degree of atherosclerosis and those with a high degree of atherosclerosis. RESULTS: In men, age, blood pressure, intima-media thickness (IMT), hematocrit (47.4+/-3.7%, 47.8+/-3.7%, 48.4+/-3.7%, P<0.05) and blood viscosity (4.69+/-0.51 cP, 4.77+/-0.55 cP, 4.82+/-0.51 cP, P=0.05) increased with increasing degree of carotid atherosclerosis. In women, age, blood pressure, total cholesterol and low-density lipoprotein-cholesterol, IMT and plasma viscosity (1.42+/-0.12 cP, 1.44+/-0.11 cP, 1.46+/-0.13 cP, P<0.05) increased with increasing carotid score. Analysis of covariance (ANCOVA) showed that after adjusting for hematocrit, blood viscosity was no longer different in the three groups. In discriminant analysis, hematocrit, among the hemorheological variables investigated, was independently associated with carotid score in men (F=3.66, P<0.05). Neither hematocrit nor blood and plasma viscosities were significantly associated with carotid score in women. CONCLUSION: These findings suggest that in men, both hematocrit and blood viscosity are related to carotid atherosclerosis but hematocrit would appear to have an independent effect over and above that mediated by viscosity.     

Free fatty acids suppress growth hormone, but not luteinizing hormone, secretion in sheep

An experiment was conducted to determine the effects of exogenously administered FFA on GH and LH secretion in sheep. Ovariectomized ewes received iv infusions of a mixture of FFA (166 mg/min; n = 5) or 0.9% saline (n = 4) for 10 h. Jugular blood was sampled every 15 min for 14 h, beginning 4 h before initiation of infusion. After 8 h of FFA or saline treatment, each ewe received a pituitary challenge of 10 micrograms GRF and 1 microgram GnRH, administered together as an iv bolus. Lipid infusion increased (P less than 0.01) serum FFA concentrations to levels characteristic of those in fasted sheep [23.0 +/- 0.8 mg/100 ml (mean +/- SE)]. Frequency of GH pulses (P less than 0.01) and the GH response to GRF (P less than 0.0001) were suppressed by FFA treatment. Mean serum GH concentrations increased gradually (P less than 0.01) during the 10-h infusion period in saline-treated but not lipid-treated, ewes. This finding may reflect diurnal changes in somatotrope secretory activity that are blocked by FFA. Mean serum LH concentrations, LH pulse frequency and amplitude, and the LH secretory response to GnRH were unaffected by FFA or saline infusion. In agreement with previous work in sheep and other species, these results provide evidence for an inhibitory effect of FFA on GH release. The exact mechanism responsible for this action, however, remains to be elucidated. Finally, acutely elevated FFA levels do not appear to influence LH secretion in the ovariectomized ewe.     

绝经后女性2型糖尿病合并高尿酸血症的相关因素研究

目的探讨绝经后女性2型糖尿病(T2DM)患者合并高尿酸血症(HUA)的相关因素。方法选取绝经后女性T2DM患者365例,依据女性血尿酸是否≥360μmol/L,分为正常尿酸(NUA)组316例和HUA组49例。分析2组临床相关指标及糖尿病慢性并发症和合并症的差异。结果与NUA组比较,HUA组糖尿病视网膜病变(61.2%vs 45.6%)、糖尿病肾病(67.3%vs 12.3%)、颈动脉粥样硬化斑块(65.3%vs 44.9%)、高血压(73.5%vs52.5%)、冠心病(34.7%vs 18.7%)及脂肪肝(61.2%vs 47.5%)的发病率明显升高(P0.05,P0.01)。多元线性回归分析显示,糖化血红蛋白(β=-0.207,P=0.026)、糖尿病病程(β=0.166,P=0.018)、LDL-C(β=0.184,P=0.009)、肌酐(β=0.356,P=0.002)是HUA的独立影响因素。结论绝经后女性T2DM合并HUA患者有较高的大小血管并发症的发生率。     

Plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women

Objectives To investigate the associations of the plasma homocysteine (HCY) levels with the alterations in arterial stiffness in a community-based cohort. The gender differences in these associations were examined. Methods We evaluated the relationship between plasma HCY levels to three measures of vascular function [carotid-femoral pulse wave velocity (CF-PWV), carotid-ankle PWV (CA-PWV) and heart rate corrected augmentation index (AI)] in 1680 participants (mean age: 61.5 years; 709 men, 971 women) from communities of Beijing, China. Results In univariate analysis, plasma HCY levels was positively related to the CF-PWV (r = 0.211, P < 0.0001) and CA-PWV (r = 0.148, P < 0.0001), whereas inversely associated with AI (r = ?0.052, P = 0.016). In multiple linear regression models adjusting for covariants, plasma HCY remained positively related to the CF-PWV (standardized β = 0.065, P = 0.007) in total cases. When the groups of men and women were examined separately, plasma HCY remained positively associated with the CF-PWV (standardized β = 0.082, P = 0.023) in men, whereas the relations between HCY and any of the arterial stiffness indices were not further present in women. Conclusions In Chinese population, plasma HCY levels are independently associated with alterations of large artery stiffness in men but not in women.     

Association of pulse pressure with carotid atherosclerosis in patients with type 2 diabetes mellitus

Pulse pressure is known to be a potent risk factor for cardiovascular disease. However, it has not been determined whether pulse pressure is associated with cerebrovascular disease in patients with diabetes mellitus. The purpose of the present study was to investigate association of pulse pressure with carotid atherosclerosis in patients with diabetes and to determine whether age and gender affect the association. A cross-sectional study was performed using outpatients with type 2 diabetes. Carotid atherosclerosis and arterial stiffness were evaluated by intima-media thickness of common carotid arteries (IMT) and aortic pulse wave velocity (a-PWV), respectively. The relationship of brachial pulse pressure with IMT was analyzed. Pulse pressure was significantly correlated with age, duration of diabetes, systolic blood pressure, serum sialic acid, a-PWV and IMT. The mean IMT in the highest tertile group of pulse pressure after adjustment for gender was significantly higher than the mean IMT in the lowest tertile group. In analysis using subgroups of gender, a significant correlation between pulse pressure and IMT was shown in women but not in men. In multiple regression analysis, there was a significant correlation between pulse pressure and IMT in women independently of age, body mass index, systolic blood pressure, hemoglobin A1c, atherogenic index, a-PWV, history of therapy for hypertension and history of nephropathy. The results of this study suggest that pulse pressure is a major age-independent predictor of carotid atherosclerosis in female patients with diabetes.     

Immunoglobulin heavy chain switch region polymorphisms are not associated with type 1 diabetes

In order to ascertain whether the immunoglobulin heavy chain genes are important in the aetiology of Type 1 diabetes, we have used restriction fragment length polymorphism (RFLP) analysis of genomic DNA to study 148 Caucasoid subjects with Type 1 diabetes and 146 normal Caucasoid subjects. A DNA probe homologous to the switch regions for the IgM (S mu) and IgA1 (S alpha 1) genes when used in conjunction with the restriction endonuclease Sst I detects RFLPs at both these loci. There were no significant differences in phenotype or gene frequencies for the alleles of S mu or S alpha 1 in the patients when compared with control subjects; nor were there significant associations of S mu or S alpha 1 with HLA-DR type or gender.