Increasing the fat-to-carbohydrate ratio in a high-fat diet prevents the development of obesity but not a prediabetic state in rats

Metabolic disorders induced by high-fat feeding in rodents evoke some, if not all, of the features of human metabolic syndrome. The occurrence and severity of metabolic disorders, however, varies according to rodent species, and even strain, as well as the diet. Therefore, in the present study, we investigated the long-term obesogenic and diabetogenic effects of three high-fat diets differing by their fat/carbohydrate ratios. Sprague-Dawley rats were fed a control high-carbohydrate and low-fat diet [HCD; 3:16:6 ratio of fat/carbohydrate/protein; 15.48 kJ/g (3.7 kcal/g)], a high-fat and medium-carbohydrate diet [HFD1; 53:30:17 ratio of fat/carbohydrate/protein; 19.66 kJ/g (4.7 kcal/g)], a very-high-fat and low-carbohydrate diet [HFD2; 67:9:24 ratio of fat/carbohydrate/protein; 21.76 kJ/g (5.2 kcal/g)] or a very-high-fat and carbohydrate-free diet [HFD3; 75:0:25 ratio of fat/carbohydrate/protein; 24.69 kJ/g (5.9 kcal/g)] for 10 weeks. Compared with the control diet (HCD), rats fed with high-fat combined with more (HFD1) or less (HFD2) carbohydrate exhibited higher BMI (body mass index; +13 and +10% respectively; P<0.05) and abdominal fat (+70% in both HFD1 and HFD2; P<0.05), higher plasma leptin (+130 and +135% respectively; P<0.05), lower plasma adiponectin levels (-23 and -30% respectively; P<0.05) and impaired glucose tolerance. Only the HFD1 group had insulin resistance. By contrast, a very-high-fat diet devoid of carbohydrate (HFD3) led to impaired glucose tolerance, insulin resistance and hypoadiponectinaemia (-50%; P<0.05), whereas BMI, adiposity and plasma leptin did not differ from respective values in animals fed the control diet. We conclude that increasing the fat-to-carbohydrate ratio to the uppermost (i.e. carbohydrate-free) in a high-fat diet prevents the development of obesity, but not the prediabetic state (i.e. altered glucose tolerance and insulin sensitivity).     

A fat-enriched,glucose-enriched diet markedly attenuates adiponectin mRNA levels in rat epididymal adipose tissue

Adiponectin levels are decreased in subjects with obesity, diabetes and coronary artery disease. In the present study, we have investigated whether the decrease in the levels and mRNA expression of adiponectin is due to obesity or to the diet itself. Wistar rats were either fed standard laboratory chow throughout (controls) or given a fat-enriched, glucose-enriched diet (diet-fed) for 2 days or 16 weeks. After 2 days of diet feeding, total body weight, fat pad masses and the plasma levels of glucose, insulin and leptin were all comparable between the two groups, while plasma NEFA (non-esterified fatty acid) and triacylglycerol levels were increased in the diet-fed animals (P<0.01 for both). There was a marked (P<0.01) decrease in plasma adiponectin levels. After 16 weeks of diet feeding, diet-fed rats had significantly higher body weight, fat pad mass and plasma levels of leptin, adiponectin, NEFA and triacylglycerol (P<0.001 for all) compared with chow-fed controls, whereas plasma levels of glucose and insulin were similar in the two groups. After 2 days of diet feeding, there were no significant changes in Ob mRNA levels in epididymal fat, whereas there was a marked decrease in adiponectin mRNA levels. After 16 weeks of diet feeding, rats had significantly increased levels of Ob mRNA, but decreased adiponectin mRNA levels, in epididymal fat compared with the chow-fed group (P<0.001 for both). These findings suggest that obesity per se is not a factor in the decreased adiponectin levels observed in obese subjects. We propose that the lipid profile of the plasma and/or the constituents of the diet consumed by rats may contribute to adiponectin levels more than obesity per se.     

Adipocytokines and metabolic syndrome--molecular mechanism and clinical implication

Recent progress in adipocyte-biology shows that adipocytes are not merely fat-storing cells but that they secrete a variety of hormones, cytekines, growth factors and other bioactive substabces, conceptualized as adipocytokines. These include plasminogen activator inhibitor 1(PAI-1), tumor necrosis factor(TNF-alpha), leptin and adiponectin. Dysregulated productions of these adipocytekines participate in the pathogenesis of obesity-associated metabolic syndrome such as insulin resistance, type 2 diabetes, hyperlipidemia, and vascular diseases. Increased productions of PAI-1 and TNF-alpha from accumulated fat contribute to the formation of thrombosis and insulin resistance in obesity, respectively. Lack of leptin causes metabolic syndrome. Adiponectin exerts insulin-sensitizing and anti-atherogenic effects, hence decrease of plasma adiponectin is causative for insulin resistance and atherosclerosis in obesity.     

Plasma adiponectin and leptin levels,body composition,and glucose utilization in adult women with wide ranges of age and obesity

OBJECTIVE: The purpose of this study was to determine the relationships between plasma adiponectin and leptin levels, total and central obesity, and glucose utilization across the adult age span. RESEARCH DESIGN AND METHODS: We studied 148 women aged 18-81 years with a BMI range of 17.2-44.3 kg/m(2). Total percent body fat was determined by dual-energy X-ray absorptiometry and abdominal fat by computed tomography. Glucose tolerance in non-type 2 diabetic volunteers was determined with an oral glucose tolerance test. Glucose utilization (M) was measured during the last 60 min of hyperinsulinemic-euglycemic clamps (240 pmol x m(-2) x min(-1)). Plasma adiponectin levels were measured by radioimmunoassay. The women were separated into three age-groups: young, middle, and old (<40, 40-59, and >or=60 years, respectively), as well as by glucose tolerance status. RESULTS: Adiponectin concentrations did not differ by age-groups. There were significant age effects for BMI, percent body fat, visceral fat, subcutaneous abdominal fat, VO(2max), and M. Adiponectin levels were lower in the prediabetic women (n = 18) than in the normal glucose-tolerant women (n = 108) and the women with type 2 diabetes (n = 22) (both P < 0.05). Univariate correlations revealed significant negative relationships between plasma adiponectin levels and BMI, percent body fat, visceral fat, subcutaneous abdominal fat, fasting leptin, and fasting insulin and positive relationship with M (all P < 0.05). In a multiple stepwise regression model to predict adiponectin, only M remained in the model at P < 0.001. Multivariate analyses revealed a significant relation for M as a function of adiponectin, insulin, and VO(2max). CONCLUSIONS: The data suggest that plasma adiponectin does not change with age but levels are negatively associated with percent body fat, visceral fat, subcutaneous abdominal fat, insulin, and leptin levels in women. Adiponectin is positively associated with M across the age span in women.     

Analysis of candidate genes in Polish families with obesity.

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.     

Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus

OBJECTIVE: Women with prior gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes and associated vasculopathy. Because increased fat mass and inflammatory processes are angiopathic risk factors, the relationship between insulin sensitivity, parameters of subclinical inflammation, and plasma concentrations of adipocytokines was investigated in pGDM both at 3 months and 12 months after delivery. RESEARCH DESIGN AND METHODS: Insulin sensitivity (through a frequently sampled intravenous glucose tolerance test) and plasma concentrations of ultrasensitive C-reactive protein (CRP), adiponectin, plasminogen activator inhibitor (PAI)-1, tumor necrosis factor-alpha, leptin, and interleukin-6 were measured in 89 pGDM (BMI 26.9 +/- 0.5 kg/m(2), age 32 +/- 0.5 years) and in 19 women with normal glucose tolerance during pregnancy (NGT) (23.7 +/- 0.9 kg/m(2), 31 +/- 1.3 years). RESULTS: pGDM showed lower (P < 0.0001) plasma adiponectin (6.7 +/- 0.2 microg/ml) than NGT (9.8 +/- 0.6 microg/ml) and a decreased (P < 0.003) insulin sensitivity index (S(i)) and disposition index (P < 0.03), but increased plasma leptin (P < 0.003), PAI-1 (P < 0.002), and CRP (P < 0.03). After adjustment for body fat mass, plasma adiponectin remained lower in pGDM (P < 0.004) and correlated positively with S(i) (P < 0.003) and HDL cholesterol (P < 0.0001) but negatively with plasma glucose (2-h oral glucose tolerance test [OGTT]) (P < 0.0001), leptin (P < 0.01), CRP (P < 0.007), and PAI-1 (P < 0.0001). On regression analysis, only HDL cholesterol, postload (2-h OGTT) plasma glucose, and S(i) remained significant predictors of plasma adiponectin, explaining 42% of its variability. Of note, adiponectin further decreased (P < 0.05) only in insulin-resistant pGDM despite unchanged body fat content and distribution after a 1-year follow-up. CONCLUSIONS: Lower plasma adiponectin concentrations characterize women with previous GDM independently of the prevailing insulin sensitivity or the degree of obesity and are associated with subclinical inflammation and atherogenic parameters.     

Effects of a 3‐day low‐fat diet on metabolic control,insulin sensitivity,lipids and adipocyte hormones in Norwegian subjects with hypertriacylglycerolaemia and type 2 diabetes

The metabolic and hormonal impact of rapid dietary changes in type 2 diabetes has not been clarified. The objective of this study was to test whether a short‐term, low‐fat diet affected metabolic control, insulin sensitivity, lipids and adipocyte hormones in patients with type 2 diabetes with hypertriacylglycerolaemia. Nineteen outpatient subjects (10 M, 9 F) with type 2 diabetes and triacylglycerols >2.2?mmol/L at screening were included in the study. Dietary intake was assessed by weighing during two periods of 3‐day baseline diet followed by a 3‐day low‐fat dietary intervention. The two periods of baseline diet did not differ with respect to relevant variables during intervention. Subjects were advised to increase fibre‐rich and low‐fat foods and to decrease intake of visible fat in an isoenergetic manner. The percentage of energy from fat was reduced from 39 to 22 (p<0.0001), median values. Daytime blood glucose did not change and fasting insulin and fasting glucose to insulin ratios were unaffected. Total cholesterol decreased from 6.3 to 6.2?mmol/L (p<0.005), high‐density lipoprotein cholesterol from 1.13 to 1.10?mmol/L (p<0.048) and the ratio of n‐6 to n‐3 fatty acids in phospholipids from 2.5 to 1.9 (p<0.003). Concentrations of leptin decreased from 12.1 to 9.9?ng/mL (p<0.005) and adiponectin increased from 8.6 to 10.5?μg/mL (p<0.024). The effect on leptin was confined to women. A low‐fat diet intervention for 3 days in insulin‐resistant type 2 diabetes affects lipid, adiponectin and leptin levels but fails to improve insulin sensitivity and metabolic control.     

Effects of a 3-day low-fat diet on metabolic control, insulin sensitivity, lipids and adipocyte hormones in Norwegian subjects with hypertriacylglycerolaemia and type 2 diabetes

The metabolic and hormonal impact of rapid dietary changes in type 2 diabetes has not been clarified. The objective of this study was to test whether a short-term, low-fat diet affected metabolic control, insulin sensitivity, lipids and adipocyte hormones in patients with type 2 diabetes with hypertriacylglycerolaemia. Nineteen outpatient subjects (10 M, 9 F) with type 2 diabetes and triacylglycerols >2.2 mmol/L at screening were included in the study. Dietary intake was assessed by weighing during two periods of 3-day baseline diet followed by a 3-day low-fat dietary intervention. The two periods of baseline diet did not differ with respect to relevant variables during intervention. Subjects were advised to increase fibre-rich and low-fat foods and to decrease intake of visible fat in an isoenergetic manner. The percentage of energy from fat was reduced from 39 to 22 (p < 0.0001), median values. Daytime blood glucose did not change and fasting insulin and fasting glucose to insulin ratios were unaffected. Total cholesterol decreased from 6.3 to 6.2 mmol/L (p < 0.005), high-density lipoprotein cholesterol from 1.13 to 1.10 mmol/L (p < 0.048) and the ratio of n-6 to n-3 fatty acids in phospholipids from 2.5 to 1.9 (p < 0.003). Concentrations of leptin decreased from 12.1 to 9.9 ng/mL (p < 0.005) and adiponectin increased from 8.6 to 10.5 microg/mL (p < 0.024). The effect on leptin was confined to women. A low-fat diet intervention for 3 days in insulin-resistant type 2 diabetes affects lipid, adiponectin and leptin levels but fails to improve insulin sensitivity and metabolic control.     

Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.

Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.     

针灸对单纯性肥胖症瘦素和胰岛素抵抗的影响

目的探讨针灸对单纯性肥胖病瘦素和胰岛素抵抗的作用. 方法采用 RT-PCR和 Northern Blot技术测定瘦素受体( OB-R)基因表达水平,放射免疫分析测定血清和下丘脑瘦素( Leptin)和胰岛素( INS)的含量.观察针灸治疗前后单纯性肥胖患者血清瘦素、 INS、脂质水平的变化;还观察针刺治疗前后肥胖大鼠体质量、 Lee's指数、体脂、血清和下丘脑瘦素和 INS的含量以及下丘脑 OB-R基因表达的变化. 结果 单纯性肥胖患者瘦素、 INS、总胆固醇( TC)、三酰甘油( TG)、低密度脂蛋白-胆固醇( LDL-C)的含量均显著高于正常人水平;而高密度脂蛋白-胆固醇( HDL-C)却显著低于正常人水平,针灸治疗后患者瘦素、 INS、 TC、 TG、 LDL-C的含量均明显回降,而 HDL-C含量却明显回升,这种变化与减肥疗效有关.肥胖大鼠体质量、 Lee's指数、体脂及血清瘦素和 INS水平均显著高于正常大鼠,而下丘脑瘦素和 INS水平及 OB-R基因表达水平均明显低于正常大鼠.针刺治疗取得良好减肥疗效的同时,肥胖大鼠血清瘦素和 INS均明显回降,而下丘脑瘦素和 INS水平以及 OB-R基因表达水平却明显升高. 结论 针灸对肥胖机体中枢和外周瘦素和 INS水平的良性调整作用以及促进下丘脑 OB-R基因表达可能是针灸纠正瘦素和胰岛素抵抗以及异常的内分泌代谢的重要机制.     

肥胖儿童并发症及综合干预20例疗效观察

目的:了解单纯性肥胖儿胰岛素抵抗、脂肪肝及其他并发症的发生情况,观察综合干预治疗对控制肥胖儿体重的效果。方法:对40例单纯性肥胖儿做糖耐量及胰岛素释放试验,检测血脂、血清瘦素、肝肾功能,随机分为两组各20例,干预组给予饮食、运动、药物等综合干预治疗。结果:本组血清瘦素均升高,血甘油三酯升高6例、基础胰岛素增高11例、胰岛素抵抗指数(IR)增高10例、脂肪肝18例,黑棘皮病13例。干预组体重、腰围、体重指数均明显降低,差异有显著性。结论:儿童肥胖者与高瘦素血症、胰岛素抵抗及脂肪肝发病相关,综合干预治疗对控制肥胖者体重有重要意义。     

老年慢性肾衰竭患者胰岛素抵抗情况及分析

目的了解老年慢性肾衰竭（CRF）时胰岛素抵抗的情况,及其与白蛋白（Alb）、血脂、肾功能、瘦素（Leptin）浓度的关系。方法测定首都医科大学宣武医院23例老年CRF患者及28例正常老年对照组的空腹血糖（Glu）、胰岛素、瘦素、血脂、白蛋白、体重指数（BMI）等指标。计算胰岛素敏感指数（ISI）-空腹血糖与空腹胰岛素浓度乘积的倒数。分析ISI与其它参数的关系。结果老年CRF组ISI显著低于正常老年对照组[（-4.24±0.78）对（-3.81±0.47）,取自然对数值,P〈0.05];老年CRF组Leptin水平显著高于对照组（P〈0.01）;直线相关分析显示老年CRF组ISI的自然对数值与血肌酐（Scr）、瘦素、脂肪容量和BMI呈显著负相关,与内生肌酐清除率（Ccr）呈正相关。结论老年CRF时存在明显的胰岛素抵抗,可能与肾功能减退、瘦素抵抗、肥胖和β细胞对胰岛素抵抗的代偿能力下降有关。     

Evaluation of genetic predisposition to insulin resistance by nutrient-induced insulin output ratio (NIOR).

BACKGROUND: New tools to identify genotype-phenotype interactions need to be described and implemented. The aim of this study was to identify correlation between the risk originating from gene variation and diet-dependent development of insulin resistance. METHODS: Insulin output in terms of area under the curve after an oral glucose tolerance test (AUC Ins OGTT) and lipid tolerance tests (AUC Ins OLTT) were measured in 167 overweight/obese patients. Estimation of the 18 common gene polymorphisms for obesity risk and standard phenotyping were performed. RESULTS: Insulin output (AUC Ins OGTT) correlated strongly between both insulin treatments across the whole group. However, within the genotype sub-groups, correlation was lower or did not exist. Using a nutrient-induced insulin output ratio (NIOR), calculated as AUC Ins OLTT/AUC Ins OGTT, values ranged from 0.42 to 5.83 and correlated significantly with body mass index (BMI) and leptin, but not with age, gender, waist-to-hip ratio (WHR) and homeostasis model assessment of insulin resistance (HOMA-IR) or plasma adiponectin. High NIOR was found in a subgroup of carriers of rare allelic variants of genes characteristic for poorer tolerance to lipids in the diet. Low NIOR values were found within a sub-group with rare genetic variants regulating carbohydrate metabolism. Thus, the new insulin index NIOR may distinguish gene variant carriers into groups of glucose- or lipid-sensitive phenotypes. CONCLUSIONS: We suggest that the OLTT/OGTT insulin output ratio (NIOR) may be predictive for identifying individuals who are phenotypically susceptible to insulin resistance in response to high fat or carbohydrate in their habitual diet.     

Plasma levels of tumor necrosis factor-alpha, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance

OBJECTIVE: To investigate the relationship between insulin resistance and plasma concentrations of free fatty acids (FFAs), leptin, and potential agonists of the insulin receptor substrate (IRS) system, including tumor necrosis factor-alpha (TNF-alpha), IGF-I, growth hormone (GH), and angiotensin II in individuals with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Because glucose toxicity per se leads to insulin resistance, the determination of the primary metabolic alterations leading to insulin resistance is best accomplished in individuals who are at an increased risk to develop type 2 diabetes. Therefore, 48 subjects with IGT and insulin resistance (IR), characterized by hyperinsulinemic-euglycemic clamps, were compared with 52 healthy insulin-sensitive (IS) control subjects with respect to the relationship between the plasma levels of TNF-alpha, IGF-I, GH, angiotensin II, FFA, leptin, and insulin resistance. RESULTS: Between the IR and the IS groups, there were no significant differences in the plasma concentrations of TNF-alpha, GH, angiotensin II, IGF-I, and leptin. However, plasma FFA levels were significantly elevated in the IR group compared with the IS group after matching for BMI. CONCLUSIONS: The plasma concentrations of FFA, but not TNF-alpha, IGF-I, GH, and angiotensin II, are elevated in patients at an early stage of insulin resistance, suggesting that FFAs, but not the other modulators of the IRS system, may be a primary metabolic abnormality leading to insulin resistance.     

Ethnicity, insulin resistance, and inflammatory adipokines in women at high and low risk for vascular disease

OBJECTIVE: We sought to compare the relationship between body composition, insulin resistance, and inflammatory adipokines in Aboriginal Canadian women, who are at high risk of vascular disease, with white women. RESEARCH DESIGN AND METHODS: A subgroup of the First Nations Bone Health Study population, consisting of 131 Aboriginal women and 132 matched white women, was utilized. Body composition was determined by whole-body dual X-ray absorptiometry, and blood analytes were measured after an overnight fast. RESULTS: After excluding individuals with diabetes, A1C, BMI, percent trunk fat, and homeostasis model assessment of insulin resistance (HOMA-IR) were greater in First Nation women compared with white women, whereas adiponectin, retinol binding protein (RBP)4, and insulin-like growth factor binding protein-1 (IGFBP-1) were lower. First Nation women had more trunk fat for any given level of total fat than white women. There were no differences in resistin, leptin, tumor necrosis factor (TNF)-alpha, or C-reactive protein (CRP) levels between First Nation and white women. Insulin resistance correlated with leptin and inversely with adiponectin levels in both First Nation and white women. There were weak correlations between insulin resistance and TNF-alpha, interleukin-6, and CRP, but these were not significant after correction for body fat. No correlation was found between RBP4 and insulin resistance. ANCOVA revealed a higher HOMA-IR adjusted for total body fat in First Nation women than in white women (P = 0.015) but not HOMA-IR adjusted for trunk fat (P > 0.2). CONCLUSIONS: First Nation women are more insulin resistant than white women, and this is explained by trunk fat but not total fat. Despite the increased insulin resistance, inflammatory adipokines are not significantly increased in First Nation women compared with white women.     

The TNF-alpha gene NcoI polymorphism at position -308 of the promoter influences insulin resistance, and increases serum triglycerides after postprandial lipaemia in familiar obesity.

Tumour necrosis factor alpha (TNF-alpha), acting as a modulator of gene expression in adipocytes, has been linked to the development of insulin resistance and obesity. The aim of this study was to investigate whether the A/G variation at position -308 in the TNF-alpha promoter influences the body weight, insulin resistance, and postprandial lipaemia in Polish Caucasians. One hundred twenty one subjects, 38 men and 83 women, representing 40 obese families, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). TNF-1 (GG) and TNF-2 (GA and AA) allele carriers were compared with respect to body mass index, fat/lean body mass composition, waist-to-hip ratio, as well as fasting lipids, glucose, leptin, and insulin fasting, and during the oral glucose tolerance test (4 points within 2 hours) and oral lipid tolerance test (OLTT; 5 points within 8 hours). The insulin sensitivity indices HOMA-IR (homeostasis model assessment of insulin resistance), ISI-COMP (whole body insulin sensitivity index), ISI-HOMA (hepatic insulin sensitivity), and DELTA (early secretory response to an oral glucose load) were calculated. We detected 64 GG, 56 GA, and 1 AA genotypes. Significant increases of insulin resistance parameters in obese female TNF-2 allele carriers were observed (significantly increased HOMA-IR and decreased ISI-HOMA, ISI-composite). The male TNF-2 carriers were characterised by significantly increased levels of triglyceride and free fatty acids during OLTT as well as fasting glucose. The A/G variation at position -308 in the promoter region of the TNF-alpha gene could be an important genetic factor predisposing to insulin resistance in obese women and increased levels of glucose, triglyceride, and free fatty acids in men.     

肥胖与高血压患者血清瘦素水平与胰岛素抵抗的相关性研究

目的探讨肥胖和高血压患者血清瘦素水平与胰岛素抵抗(IR)的关系及在肥胖和高血压发病机制中的作用。方法选择男性合并肥胖或非肥胖的高血压患者和正常血压者,测定血糖、胰岛素、血脂、尿酸(Ur)、胰岛素敏感性指数(ISI)、24h尿蛋白定量和血清瘦素浓度,分析瘦素水平与IR的相关性及与体重指数(BMI)、血压和其它各项指标的关系。结果血清瘦素水平在高血压组高于正常血压组,肥胖者高于非肥胖者。ISI则为正常血压组的非肥胖者高于肥胖者,而无论肥胖与否,正常血压组均高于高血压组。在高血压组中,ISI降低程度肥胖与非肥胖者无显著差异。在合并肥胖的高血压和正常血压组中,血清瘦素水平与ISI呈显著负相关(r=－0.51,P<0.01)和(r="－"0.38,P<0.05)。BMI、腰臀比、ISI是影响两组瘦素水平的最显著因素,影响ISI的因素依次为BMI、SBP、DBP、TG、Ur和瘦素。BMI是影响瘦素水平和ISI的共同因素。多元逐步回归分析发现,BMI与瘦素、ISI、TG密切相关。结论肥胖者血清瘦素水平升高与IR高度相关,并与脂代谢有关。瘦素抵抗在高血压的发生中可能起间接促进作用,但与IR的关联尚待探讨。     

Effects of a superselective beta1-adrenoblocker nebivolol on the course of coronary heart disease and insulin resistance in patients with diabetes mellitus type 2 after coronary artery bypass grafting

AIM: To study safety and effects of nebivolol on the course of coronary heart disease (CHD) and insulin resistance (IR) in patients with diabetes mellitus type 2 (DM-2) after coronary artery bypass grafting. MATERIAL AND METHODS: The study included 53 CHD patients with DM-2 (mean age 56.7 +/- 1.3 years). All the patients were divided into two groups: 22 patients with IR (group 1) and 31 patients free of IR (group 2). All the patients received an 8 week course of nebivolol the efficacy of which was assessed by changes in coronary failure, exercise tolerance, quality of life, lipid and carbohydrate metabolism. RESULTS: In group 1 an antianginal effect of nebivolol manifested with less frequent (by 54.7%) development of angina pectoris (p = 0.0003), a 59.8% (p = 0.0004) decrease in 24-h need in nitroglycerine. In group 2 these reductions were 63.4 and 61.6% (p < 0.01), respectively. Exercise tolerance increased by 36.2 and 25.2%, left ventricular ejection fraction significantly increased by 5.9 and 5%, respectively, quality of life improved by 25 and 23%, respectively. As a result, a functional class of chronic cardiac failure lowered. Nebivolol had no negative effect on compensation of blood lipid and carbohydrate metabolism. A trend to blood insulin fall by 18.4% was found. IR index diminished by 11.9%. CONCLUSION: Administration of nebivolol in a dose 1.25-5 mg/day raised exercise tolerance, improved quality of life, reduced IR index by 11.9%, triglycerides level by 5.3%. This lowered the risk of effects of diabetic atherogenic dyslipidemia.     

多囊卵巢综合征患者血清脂联素、瘦素水平与胰岛素抵抗相关性的研究

目的研究多囊卵巢综合征(PCOS)患者血清脂联素、瘦素水平与胰岛素抵抗的相关性。方法选58例PCOS患者和46例非PCOS患者,根据体质指数(BMI)分为肥胖组与非肥胖组,根据胰岛素抵抗诊断标准分为胰岛素抵抗组和非胰岛素抵抗组。对所有患者的血清脂联素表达水平、瘦素水平及内分泌代谢等各项指标进行检测并分析相关性。结果①多囊卵巢综合征组患者的血清脂联素表达水平明显低于对照组(P<0.05);非肥胖多囊卵巢综合征组患者的血清脂联素表达水平显著低于非肥胖对照组(P<0.05);胰岛素抵抗组患者的血清脂联素表达水平明显低于非胰岛素抵抗组(P<0.05)。多囊卵巢综合征组患者的瘦素表达水平明显高于对照组(P<0.05);胰岛素抵抗组患者的瘦素表达水平明显高于非胰岛素抵抗组(P<0.05)。②患者血清脂联素表达水平与BMI、胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、腰臀比(WHR)和三酰甘油(TG)等指标呈负相关性关系(P<0.05)。患者血清瘦素表达水平与BMI、FINS、HOMA-IR、WHR和TG)指标呈正相关性关系(P<0.05)。结论多囊卵巢综合征患者大多具有低脂联素表达水平、高瘦素血症等特征,且血清脂联素表达水平与瘦素表达水平、胰岛素抵抗严重程度之间存在着负相关性关系,脂联素和瘦素可作此疾病患者远期出现糖尿病并发症的预测指标之一。     

Adiponectin and other adipocytokines as predictors of markers of triglyceride-rich lipoprotein metabolism

BACKGROUND: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. METHODS: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22-35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. RESULTS: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-alpha were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (beta coefficient = -0.354; P = 0.048), apoC-III (beta coefficient = -0.406; P = 0.012), RLP-cholesterol (beta coefficient = -0.377; P = 0.016), and triglycerides (beta coefficient = -0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). CONCLUSIONS: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.