Elevated plasma non-esterified fatty acid levels and insulin secretion in non-diabetic relatives of type 2 diabetic patients

OBJECTIVE: High non-esterified fatty acid (NEFA) levels impair glucose-stimulated insulin secretion from islets derived from non-diabetic Zucker rats that are genetically predisposed to diabetes. We therefore examined the effect of elevated plasma NEFA levels on insulin secretion in non-diabetic first-degree relatives of type 2 diabetic patients who are at increased risk of developing diabetes. SUBJECTS AND STUDY DESIGN: Normal glucose tolerant relatives (n = 9) and control subjects with no family history of diabetes were pair-matched for age, sex, body mass index (BMI), insulin sensitivity and early insulin response during an oral glucose tolerance test (OGTT). Plasma NEFA levels were raised from 0 to 340 minutes by the infusion of 20% Intralipid and heparin. From 180 minutes, insulin secretion rates (IRSs) were assessed by stepped low-dose glucose infusion. RESULTS: The mean (geometric mean +/- 95% CI) NEFA levels were comparable between relatives and control subjects (2.7 [2.1-3.6] and 2.1 [1.7-2.7] mmol/l, paired analysis, NS). Similarly, plasma glucose levels achieved at each glucose infusion step were comparable between the groups. However, there were no significant differences between the groups for ISR throughout the study. CONCLUSIONS: Sustained elevation of plasma non-esterified fatty acid levels does not decrease insulin secretion in non-diabetic relatives of type 2 diabetic patients, and is therefore unlikely to be important in the development of the impaired pancreatic beta-cell function in type 2 diabetes mellitus.     

Effect of omega-3 fatty acids on lipid peroxidation and antioxidant enzyme status in type 2 diabetic patients

BACKGROUND: This study was conducted to investigate the effect of omega-3 fatty acids on lipid peroxidation and antioxidant enzyme activities in non-insulin dependent diabetic patients. METHODS: Thirty-four non-insulin dependent diabetic patients were selected for this study and they were initially treated with antidiabetic drugs alone for one month. This was followed by supplementation with omega-3 fatty acids (1,080 mg of EPA and 720 mg of DHA per day) along with the antidiabetic drugs for a period of two months. RESULTS: No change in glycaemic control was observed in diabetic patients at the end of two months of omega-3 fatty acids therapy along with antidiabetic drugs. The combined treatment significantly reduced serum triglycerides (2.07 +/- 0.94 mmol/l, before combined therapy vs 1.54 +/- 0.49 mmol/l after combined therapy, P<0.05) and increased HDL-cholesterol levels (0.93 +/- 0.099 mmol/l, before combined therapy vs 1.04 +/- 0.098 mmol/l after therapy, P<0.01). The raised lipid peroxide levels (5.14 +/- 0.61 micromol MDA/l in controls vs 6.36 +/- 1.56 micromol MDA/l in diabetic patients, P<0.001) were significantly decreased in these patients after the combined therapy (6.36 +/- 1.56 micromol MDA/l, before combined therapy vs 5.16 +/- 0.7 micromol MDA/l, after combined therapy, P<0.01). Among the erythrocyte antioxidant enzymes, the Glutathione peroxidase activity was increased (32.5 +/- 9.9 U/g Hb/min, before combined therapy vs 42.25 +/- 4.6 U/g Hb/min, after combined therapy, P<0.01) while no change was observed in Catalase (99.7 +/- 30.4 KU/g Hb before combined therapy vs 85.35 +/- 23.41 KU/g Hb, after combined therapy) and Superoxide dismutase activities (2.6 +/- 1.04 U/mg Hb/min, before therapy vs 3.01 +/- 1.08 U/mg Hb/min, after combined therapy) after the 2 months of combined treatment with antidiabetic agents and omega-3 fatty acids. CONCLUSION: Supplementation with omega-3 fatty acids has beneficial effects on serum triglycerides, HDL-cholesterol, lipid peroxidation and antioxidant enzymes, which may lead to decreased rate of occurrence of vascular complications in diabetes.     

Clinical studies of omega-3 fatty acid supplementation in patients who have rheumatoid arthritis

Several studies have now demonstrated reproducible clinical benefits of rheumatoid arthritis disease activity after ingestion of n-3 fatty acids. Biologic changes induced by fish oils include decreases in the production of leukotriene B4, platelet activating factor and interleukin-1. Investigations now focus on the proper dose and duration of fish-oil dietary intervention in order to obtain optimum clinical effects. Their ultimate therapeutic role has not yet been determined.     

Gender-specific inhibition of platelet aggregation following omega-3 fatty acid supplementation

Background and AimsIncreased platelet aggregation is a major risk factor for heart attacks, stroke and thrombosis. Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) reduce platelet aggregation; however studies in the published literature involving EPA and/or DHA supplementation have yielded equivocal results. Recent in vitro studies have demonstrated that inhibition of platelet aggregation by LCn-3PUFA is gender specific. We examined the acute effects of dietary supplementation with EPA or DHA rich oils on platelet aggregation in healthy male and females.Methods and ResultsA blinded placebo controlled trial involving 15 male and 15 female subjects. Platelet aggregation was measured at 0, 2, 5 and 24 h post-supplementation with a single dose of either a placebo or EPA or DHA rich oil capsules. The relationship between LCn-3PUFA and platelet activity at each time point was examined according to gender vs. treatment. EPA was significantly the most effective in reducing platelet aggregation in males at 2, 5 and 24 h post-supplementation (?11%, ?10.6%, ?20.5% respectively) whereas DHA was not effective relative to placebo. In contrast, in females, DHA significantly reduced platelet aggregation at 24 h (?13.7%) while EPA was not effective. An inverse relationship between testosterone levels and platelet aggregation following EPA supplementation was observed.ConclusionInteractions between sex hormones and omega-3 fatty acids exist to differentially reduce platelet aggregation. For healthy individuals, males may benefit more from EPA supplementation while females are more responsive to DHA.     

Dietary omega-3 fatty acid supplementation and naproxen treatment in patients with rheumatoid arthritis.

In a controlled, double blind, clinical trial we tested the effect of dietary omega-3 fatty acid supplementation with and without naproxen and placebo, respectively, in 67 patients with active rheumatoid arthritis. The patients were randomized into 3 groups that received the following treatment: Group 1, corn oil ("placebo omega-3 fatty acids"), 7 g/day for 16 weeks, and naproxen, 750 mg/day for 10 weeks followed by a stepwise reduction to 0 mg/day during the following 3 weeks; Group 2, omega-3 fatty acids, 3.8 g of eicosapentaenoic acid plus 2.0 g of docosahexaenoic acid, and naproxen, 750 mg/day for 16 weeks; and Group 3, omega-3 fatty acids as Group 2 and naproxen as Group 1. At the end of the trial, patients in Group 2 had improved with respect to duration of morning stiffness and global assessment by physician and patient. In Groups 1 and 3 there was a significant deterioration for most of the variables measured. However, for duration of morning stiffness the deterioration was significantly less pronounced in Group 3 compared with Group 1. These effects might be ascribed to the dietary omega-3 fatty acid supplementation.     

Correlations between homocysteine levels and atherosclerosis in Japanese type 2 diabetic patients

Elevated total plasma homocysteine (tHcy) level and aortic stiffness are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that tHcy correlates with aortic stiffness and insulin resistance in type 2 diabetic patients. The study consisted of 40 Japanese patients with type 2 diabetes mellitus and high tHcy levels (mean age +/- SD, 57 +/- 7 years) and a control group of 45 age-matched patients with normal tHcy levels (mean age +/- SD, 57 +/- 6 years). Brachial-ankle pulse wave velocity (BaPWV) was measured by an automatic oscillometric method. Brachial-ankle pulse wave velocity was used as an index of atherosclerosis. Body mass index values (P < .05), waist circumferences (P < .05), and the waist-to-hip ratios (P < .05) were larger in the high-tHcy group than in the normal-tHcy group. The BaPWV was higher in the high-tHcy group than in the normal-tHcy group (P < .0001). Fasting plasma glucose (P < .005) and insulin concentrations (P < .0001), and the homeostasis model assessment (HOMA) index (P < .0001) were higher in the high-tHcy group than in the normal-tHcy group. Multiple regression analysis showed that tHcy levels were independently predicted by BaPWV and the HOMA index. In conclusion, our results indicate that the elevated level of tHcy in Japanese patients with type 2 diabetes mellitus is characterized by increased aortic stiffness and insulin resistance, and that the BaPWV and the HOMA index are independent predictors of tHcy.     

2型糖尿病患者血浆脂联素、同型半胱氨酸水平与血管内皮功能的关系

目的探讨2型糖尿病患者的血浆脂联素、同型半胱氨酸（Hcy）水平及其与血管的内皮功能的关系。方法选择2型糖尿病患者56例和健康体检者48例为对照组,用酶联免疫吸附法（ELISA）测定患者血浆Hcy和脂联素水平,用Celermajer法测定血管内皮功能。结果2型糖尿病组血浆Hcy水平明显高于对照组（P〈0．01）;而血浆脂联素水平、内皮依赖性血管舒张功能（EDD）及非内皮依赖性血管舒张功能（EID）分别低于对照组（P〈0．01）。EED与血浆Hcy呈负相关,而与脂联素呈正相关。结论2型糖尿病患者血浆Hcy水平升高,而脂联素水平减低,提示血浆Hcy升高以及脂联素的降低是2型糖尿病内皮功能损伤的重要的因素,测定血浆Hcy、脂联素和EDD可以反映2型糖尿病患者血管病变情况。     

血浆同型半胱氨酸水平与2型糖尿病合并脑梗死的关系

本研究评估空腹血浆总同型半胱氨酸 (tHcy)水平与 2型糖尿病合并脑梗塞的关系 ,并分析影响糖尿病患者血浆Hcy水平的因素 ,结果显示 ,血浆同型半胱氨酸水平升高是 2型糖尿病合并脑梗塞的独立危险因素 ;血清叶酸、VitB12 和血肌酐均为tHcy的影响因素。     

Effect of metabolic control on homocysteine levels in type 2 diabetic patients: a 3-year follow-up

OBJECTIVES: Hyperhomocysteinaemia has emerged as a novel risk factor for cardiovascular disease. The determinants of total homocysteine (tHcy) levels in type 2 diabetic patients (D2p) have not been studied in detail. We examined prospectively the effect of different degrees of metabolic control on plasma tHcy in D2p with preserved kidney function. SUBJECTS AND MAIN OUTCOME MEASUREMENTS: Ninety-five D2p were studied. Clinical parameters, fasting plasma glucose, HbA1c, serum lipids, blood urea nitrogen (BUN) and creatinine, vitamin B12 and folate and tHcy were measured at the baseline and after 36 months. The methylentetrahydrofolate reductase (MTHFR) C677T polymorphism was also determined. Subjects were categorized according to deltaHbA1c into group A (+/-1 point), B (>1 point increase) or C (>1 point decrease). RESULTS: Total homocysteine was reduced in subjects whose HbA1c decreased with time, whilst patients showing a worsened metabolic control had an increased tHcy in respect to baseline. A larger response to the improved metabolic control in terms of tHcy reduction was noted in wild type patients versus those homozygous for the mutation. A multivariate analysis revealed MTHFR polymorphism and HbA1c as strong determinants of changes in tHcy with time. CONCLUSIONS: The findings suggest that in D2p tHcy decreases even with modest improvement of glycaemic control; moreover patients homozygous for the MTHFR C677T mutation show the largest changes in tHcy levels with concomitant changing of HbA1c. These results define a further mechanism through which hyperglycaemia might promote cardiovascular damage in diabetic patients.     

An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia

A remarkable reduction of plasma concentrations of high-density lipoproteins (HDL), especially of the HDL(2) subfraction, is one of the typical lipoprotein alterations found in patients with familial combined hyperlipidemia (FCHL). Fourteen FCHL patients received 4 capsules daily of Omacor (an omega-3 polyunsaturated fatty acid [omega3 FA] concentrate providing 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day; Pronova Biocare, Oslo, Norway) or placebo for 8 weeks in a randomized, double-blind, crossover study. Plasma triglycerides were 44% lower, and LDL cholesterol and apoliporpotein (apo)B were 25% and 7% higher after Omacor than placebo. HDL cholesterol was higher (+8%) after Omacor than placebo, but this difference did not achieve statistical significance. Omacor caused a selective increase of the more buoyant HDL(2) subfraction; plasma HDL(2) cholesterol and total mass increased by 40% and 26%, respectively, whereas HDL(3) cholesterol and total mass decreased by 4% and 6%. Both HDL(2) and HDL(3) were enriched in cholesteryl esters and depleted of triglycerides after Omacor. No changes were observed in the plasma concentration of major HDL apolipoproteins, LpA-I and LpA-I:A-II particles, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP). The plasma concentration of the HDL-bound antioxidant enzyme paraoxonase increased by 10% after Omacor. Omacor may be helpful in correcting multiple lipoprotein abnormalities and reducing cardiovascular risk in FCHL patients.     

Effects of riboflavin and folic acid supplementation on plasma homocysteine levels in healthy subjects

BACKGROUND: Observational studies have shown an inverse relationship between vitamin B2 status and total homocysteine levels, a risk factor for cardiovascular disease. We hypothesize that intervention with riboflavin will lower total homocysteine levels. The total homocysteine lowering by the three genotypes (CC, CT, TT) of methylenetetrahydrofolate reductase polymorphism (677C-->T) was also studied. METHODS: The decrease in total homocysteine levels after supplementation with riboflavin (10 mg/d) or folic acid (1 mg/d) for 3 weeks was compared in two groups of healthy subjects (17 per group, matched by age and gender) (Phase 1). Then, both groups received supplementation with folic acid and riboflavin for an additional 3 weeks (Phase 2). RESULTS: During Phase 1, total homocysteine levels were lowered by 2% or 4% after supplementation with riboflavin or folic [corrected] acid, respectively, although neither decrease was statistically significant (P=0.50 and 0.19). Compared to subjects of CC genotype, total homocysteine lowering in subjects of CT genotype was approaching significance (P=0.059) for the folic acid group, but not for the riboflavin group. After Phase 2, total homocysteine levels were not lowered significantly in either the folic acid (1%) or the riboflavin (2%) group. However, in the folic acid-riboflavin combined group, total homocysteine lowering in subjects of TT type was larger when compared to subjects of CC and CT types (P=0.007). CONCLUSIONS: Riboflavin supplementation did not lower total homocysteine levels in healthy subjects with CC type of C677T polymorphism. However, supplementation with folic acid or with both folic acid and riboflavin may be important for CT and TT subjects in optimizing their homocysteine metabolism. These findings are relevant in characterizing the factors controlling the high total homocysteine levels for subjects of CT and TT genotypes.     

Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis

Objective. To study the long-term effects of supplementation with omega-3 fatty acids (ω3) in patients with active rheumatoid arthritis. Methods. Ninety patients were enrolled in a 12-month, double-blind, randomized study comparing daily supplementations with either 2.6 gm of ω3, or 1.3 gm of ω3 + 3 gm of olive oil, or 6 gm of olive oil. Results. Significant improvement in the patient's global evaluation and in the physician's assessment of pain was observed only in those taking 2.6 gm/day of ω3. The proportions of patients who improved and of those who were able to reduce their concomitant antirheumatic medications were significantly greater with 2.6 gm/day of ω3. Conclusion. Daily supplementation with 2.6 gm of ω3 results in significant clinical benefit and may reduce the need for concomitant antirheumatic medication.     

Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure

We investigated the effects of omega-3 fatty acids administration on endothelium-dependent vasodilation in patients > or =65 years old who received treatment for chronic heart failure (CHF). Twenty patients (mean age 73 years; 15 men) with grade II and III CHF who were on maximal medical management were recruited. Patients were randomized in a double-blind, crossover fashion to 6 weeks of omega-3 fatty acid (1.8 g ecosapentaenoic acid and 1.2 g docosahexaenoic acid) or olive oil. Forearm blood flow (FBF) responses to incremental doses of intra-arterial sodium nitroprusside, acetycholine (ACH), angiotensin-II, and N(g)-nitro-L-arginine methyl ester were assessed by venous occlusion strain gauge plethysmography. The endothelium-dependent increase in FBF was greater in response in ACH infusion after omega-3 fatty acid administration (7.9, 95% confidence interval [CI] 4.81 to 11.08 to 11.3, 95% CI 7.31 to 15.23 arbitrary units (p <0.05) compared with baseline (7.95, 95% CI 4.8 to 11.08 arbitrary units) and olive oil administration (7.27, 95% CI 4.66 to 9.88 arbitrary units) (p = NS for both). Neither omega-3 fatty acid nor olive oil altered endothelium-independent vasodilation in response to infusion of sodium nitroprusside, nor did they influence vasoconstrictor responses to angiotensin-II or N(g)-nitro-L-arginine methyl ester. Dietary omega-3 fatty acid supplementation was accompanied by an increase in FBF response to ACH, which represents enhanced endothelium-dependent vasodilation in CHF. Further studies are warranted to assess the mechanism responsible for the beneficial actions of omega-3 fatty acids in CHF.     

The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients

The effect of 3 days of intensive treatment with acipimox, an antilipolytic nicotinic acid derivative, on plasma leptin levels was studied in eight patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, cross-over study. Acipimox reduced plasma free fatty acids (FFA) markedly and lowered plasma triglycerides, glucose and insulin. Plasma leptin levels were elevated in all eight patients during 3 days of acipimox treatment (mean increase+/-s.e.: 2.38+/-0.57ng/ml, P<0.005) and the 24h mean effect of acipimox on leptin levels increased during the experimental period (P<0.03). The effect on plasma insulin and glucose resembled a mirror image of the effect on plasma leptin during 3 days of treatment. The suggestion that leptin mediates insulin resistance and may be involved in the development of the diabetic syndrome cannot be supported by the present results. It has been reported that FFA stimulates leptin secretion. Surprisingly, despite a markedly reduced FFA level, leptin concentration increased in the present study. We suggest that a primary acipimox effect is to increase leptin secretion, and that this prevails over the reduced FFA stimulus.     

Effects of omega-3 fatty acid supplementation and exercise on low-density lipoprotein and high-density lipoprotein subfractions

The purpose of this study was to examine the effect of combining exercise with omega-3 fatty acids (n-3fa) supplementation on lipoprotein subfractions and associated enzymes. Subjects were 10 recreationally active males, aged 25 +/- 1.5 years (mean +/- SE), who supplemented n-3fa (60% eicosapentaenoic acid [EPA] and 40% docosahexaenoic [DHA]) at 4 g/d for 4 weeks. Before and after supplementation, subjects completed a 60-minute session of treadmill exercise at 60% Vo(2)max. Following a 24-hour diet and activity control period, blood was collected immediately before and after the exercise session to assess lipid variables: high-density lipoprotein cholesterol (HDL-C) and subfractions, low-density lipoprotein cholesterol (LDL-C) and subfractions and particle size, lecithin:cholesterol acyltransferase (LCAT) activity, and cholesterol ester transfer protein (CETP) activity. Supplementation with n-3fa alone increased total HDL-C and HDL(2)-C, while exercise alone increased total HDL-C, HDL(3)-C, and total LDL-C. LDL subfractions, particle size, and LCAT and CETP activities were not affected by supplementation. Combination treatment resulted in an additive effect for HDL(3)-C only and also increased LDL(1)-C versus baseline. LCAT and CETP activities were not affected by treatments. These results suggest that n-3fa supplementation or an exercise session each affect total HDL-C and subfractions but not LDL-C or subfractions. In addition, the combination of n-3fa and exercise may have additional effects on total HDL-C and LDL-C subfractions as compared to either treatment alone in active young men.     

血浆同型半胱氨酸与2型糖尿病外周神经病变的相关性

目的 探讨血浆总同型半胱氨酸浓度与糖尿病外周神经病变的关系.方法 入选2型糖尿病患者227例,进行横断面研究.用临床表现及肌电图诊断外周糖尿病神经病变,并测定血浆同型半胱氨酸水平及与糖尿病神经病变相关或可能影响血浆同型半胱氨酸水平的指标.结果 糖尿病外周神经病变患者80例,糖尿病无神经病变者147例.糖尿病神经病变组血浆总同型半胱氨酸水平(12.6±3.6)μmol/L,高于糖尿病非神经病变组(8.2±0.9)μmol/L(P＜0.01).在校正外周神经病变传统危险因素(糖尿病病程、糖化血红蛋白)及高同型半胱氨酸浓度的影响因素(年龄、性别、血清叶酸和维生素B12、肾功能状态和双胍类使用)后,同型半胱氨酸与糖尿病神经病变仍相关[OR1.15(1.02～1.28),P＜0.05].在校正每单位上述混杂因素增加后,每增加4.0 μmol/L的血浆同型半胱氨酸也与神经病变发生密切相关[OR 1.17(0.94～1.33),P＜0.05].结论 高血浆总同型半胱氨酸浓度与糖尿病神经病变的发生相关,为糖尿病外周神经病变的独立危险因素.

Abstract：

Objective To explore the relationship between plasma homocysteine levels and diabetic peripheral neuropathy (DPNP). Methods A crossectional analysis was conducted on 227 patients with type 2 diabetes. Peripheral neuropathy was confirmed using electromyography (EMG). The risk factors possibly associated with diabetic neuropathy or plasma homocysteine levels were analyzed in relation to likelihood of occurrence of DPNP. Results Eighty patients with neuropathy and 147 patients without neuropathy were included. Plasma homocysteine levels were significantly higher in patients with diabetic neuropathy [( 12. 6 ± 3.6 ) μmol/ L] than without diabetic neuropathy [( 8. 2 ± 0. 9 ) μmol/L] ( P ＜0. 001 ), and the relationship remained significant after adjusting for duration of diabetes, glycosylated hemoglobin A1c (HbA1c), age, renal status, serum folate acid and vitamin B12, and metformin [OR 1.15( 1.02-1.28 ) ,P ＜ 0. 05]. In addition, per increase of 4. 0 μmol/L plasma homocysteine was closely related to the occurrence of neuropathy after controlling for per unit increase of other confounding factors [OR 1.17(0. 94-1.33), P ＜ 0. 05]. Conclusions Hyperhomocysteinemia was an independent risk factor for the occourence of diabetic peripheral neuropathy.