Influence of Lys656Asn polymorphism of the leptin receptor gene on insulin resistance in nondiabetic obese patients

BACKGROUND: Alterations of the normal leptin receptor (LEPR) gene may be involved in the development of obesity. Leptin has been shown to be able to modulate insulin secretion. Different polymorphisms in the LEPR gene have been studied, albeit with unclear results. The polymorphism on codon 656 produces a change in charge, making this change possibly functional. OBJECTIVE: The objective of this study was to investigate the influence of Lys656Asn polymorphism in the LEPR gene on serum insulin, glucose values, and insulin resistance in the fasted state among obese men and women without diabetes mellitus. DESIGN: Two hundred thirty-three (body mass index, >30 kg/m(2)) nondiabetic obese patients were analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure determination, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. Statistical analysis was performed for Lys656/Asn656 and Asn656/Asn656 jointly as a mutant allelic group and for Lys656/Lys656 as a wild allelic group. RESULTS: The subjects' (67 males and 166 females) mean age and mean body mass index were 43.6+/-16.6 years and 35.3+/-5.6 kg/m(2), respectively. One hundred forty-three patients (61.9%) had the genotype Lys656/Lys656 (wild group), whereas 88 (38.1%) had either the genotype Lys656/Asn656 (n=81; 30.7%) or the genotype Asn656/Asn656 (n=7; 7.4%) (mutant group). Age and sex distribution were similar in both groups. No difference was detected between the mutant and wild allelic groups in anthropometric parameters and dietary intakes. Homeostasis model assessment (HOMA; 2.8+/-1.7 vs. 5.6+/-4.8; P<.05) and insulin (18.1+/-10.7 vs. 32.1+/-25 mUI/ml; P<.05) levels were higher in males with the genotypes Lys656/Asn656 and Asn656/Asn656 than in males with the genotype Lys656/Lys656. Leptin levels were higher in males with a mutant genotype than in males with a wild genotype (39.3+/-23 vs. 63.5+/-28 ng/ml; P<.05). CONCLUSION: The novel findings of our study are those of the association of the Lys656/Asn656 and Asn656/Asn656 genotypes with higher levels of insulin, HOMA, and leptin in males and the lack of such an association in females.     

G109T polymorphism of SLC22A12 gene is associated with serum uric acid level, but not with metabolic syndrome

SLC22A12 gene, encoding urate transport 1, has been known to be responsible to urate metabolism. This study sought to determine the association between the novel G109T polymorphism in SLC22A12 with serum uric acid and the development of metabolic syndrome in Korean male subjects. A total of 132 healthy male subjects were enrolled in this study. Metabolic syndrome was determined using the modified guidelines for metabolic syndrome proposed by the National Cholesterol Education Program’s Third Adult Treatment Panel. Genotyping for the SLC22A12 gene was assessed using denaturing high-performance liquid chromatography analysis. Serum uric acid and fractional excretion of uric acid (FEUA) from blood and urine samples were measured. Frequencies of the 109GG, 109GT, and 109TT genotypes were 57.6, 38.6, and 3.8%, respectively. Serum uric acid levels and FEUAs were significantly different among the three genotypes of the G109T polymorphism (P?=?0.035 and P?=?0.033, respectively). In addition, subjects of genotypes with the T allele had lower uric acid levels and higher FEUAs compared to those with the 109GG genotype (P?=?0.007 and P?=?0.031, respectively). The G109T polymorphism of the SLC22A12 gene has no association with metabolic syndrome. However, a number of metabolic syndrome components were related to serum uric acid level (r?=?0.285, P?=?0.001) and also significantly different between genotype with and without T allele (P?=?0.008). The novel G109T polymorphism of the SLC22A12 gene is related to serum uric acid level, but not to the development of metabolic syndrome.     

Renal nerve stimulation causes alpha 1-adrenoceptor-mediated sodium retention but not alpha 2-adrenoceptor antagonism of vasopressin

Renal alpha 2-adrenoceptor stimulation by epinephrine infusion reverses cyclic adenosine monophosphate-mediated effects of vasopressin on sodium and water excretion. We used this response to determine whether renal nerve stimulation can activate renal alpha 2-adrenoceptors in the non-recirculating isolated perfused rat kidney (Krebs-Henseleit solution; 3.5 g/100 ml Ficoll; 1 g/100 ml albumin; 36 degrees C; propranolol 100 nM). In the presence of alpha 1-adrenoceptor blockade with prazosin (30 nM) alpha 2-adrenoceptor stimulation with epinephrine reversed the cyclic adenosine monophosphate-mediated effects of vasopressin on sodium (P less than 0.05) and water (P less than 0.05) excretion. Subthreshold (for vasoconstriction) renal nerve stimulation (10 V; 1 msec; 0.65 +/- 0.10 Hz) failed to alter the effect of vasopressin. Similarly, higher levels of renal nerve stimulation [plus prazosin (100 nM) or phenoxybenzamine (1.0 mg/kg per hr) to block alpha 1-adrenoceptors] did not activate renal alpha 2-adrenoceptors which are associated with the antagonism of the effects of vasopressin. The same level of subthreshold renal nerve stimulation (0.85 +/- 0.14 Hz) in the absence of vasopressin, and without alpha 1- or alpha 2-adrenoceptor blockade, decreased (P less than 0.05) sodium and water excretion. The reversal of this effect by alpha 1-adrenoceptor blockade (prazosin 30 nM) but not alpha 2-adrenoceptor blockade (yohimbine 300 nM) indicates that this effect of renal nerve stimulation is mediated through alpha 1-adrenoceptors. Thus, subthreshold renal nerve stimulation in the rat kidney induces sodium and water retention through activation of alpha 1-adrenoceptors, as shown by others in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy

OBJECTIVE: This study examined the frequency of the Lys198Asn polymorphism in the endothelin-1 (ET-1) gene in women with pre-eclampsia and normal pregnancy; and its contribution to levels of plasma ET-1 and blood pressure. DESIGN AND METHODS: This was a retrospective study examining the frequency of the ET-1 Lys198Asn polymorphism in 72 proteinuric pre-eclamptics and 81 normal pregnant women. Height, weight, blood pressure and plasma ET-1 were measured antenatally and at 6 weeks post-partum. Using specific mutagenic primers, the frequency of the G/G (normal), G/T heterozygote and T/T (mutant) genotypes of the Lys198Asn polymorphism were examined. RESULTS: The polymorphism was not associated with pre-eclampsia. However, in the combined pregnant groups after correction for BMI and group, a significant effect of the T-allele (T/T,G/T) on systolic blood pressure was found (121 +/- 1.5 mmHg compared with 116 +/- 1.3 mmHg in the G/G homozygotes). A significant interaction was found between the T-allele and pregnancy in determining systolic blood pressure, so that the effect was no longer seen post-partum. Pregnant women with the T/T genotype had significantly elevated plasma ET-1 levels 5.8 pg/ml [confidence interval (CI) 3.7-9.1] compared with 3.1 pg/ml (CI 2.6-3.8) in the G/T heterozygotes and 3.6 pg/ml (CI 3.0-4.1) in the normal G/G homozygotes. CONCLUSION: The Lys198Asn polymorphism does not directly contribute to the incidence of pre-eclampsia. However, the association of the T-allele with raised blood pressure and the T/T genotype with increased plasma ET-1 levels suggest that this polymorphism may interact with other genes or environmental factors to sensitize pregnant women to develop pre-eclampsia.     

Effects of alpha 1- and alpha 2-adrenoceptor stimulation and blockade on plasma insulin levels in the mouse

Stimulation of alpha-adrenoceptors is known to inhibit insulin secretion under a variety of conditions. In this study, the question of whether these alpha-adrenoceptors are of the alpha 1- or the alpha 2-subtype was investigated in the mouse. The selective alpha 2-adrenoceptor agonist clonidine (0.05-50 nmol/kg) was found to markedly inhibit the insulin secretory response to both glucose and the cholinergic agonist carbachol. This inhibition of insulin secretion was counteracted by the alpha 2-adrenoceptor antagonist yohimbine (2.6 mumol/kg), but not by the alpha 1-adrenoceptor antagonist prazosin (2.6 mumol/kg). In contrast, the alpha 1-adrenoceptor agonist phenylephrine (0.05-50 nmol/kg) did not affect the insulin secretory response to either glucose or carbachol. Moreover, both yohimbine and prazosin increased basal plasma insulin levels. It is concluded that alpha 1- and alpha 2-adrenoceptor blockade is followed by enhancement of basal plasma insulin levels in the mouse, whereas alpha 2-adrenoceptor stimulation but not alpha 1-adrenoceptor stimulation impairs the insulin secretory response to glucose and carbachol.     

Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men

To assess the effects of dehydroepiandrosterone (DHEA) on body fat mass, serum lipid levels, and tissue sensitivity to insulin, five normal men were given placebo and five normal men were given oral DHEA [1600 mg/day (554.7 mmol/day)] for 28 days in a randomized, double blind study. In the DHEA group serum DHEA-S levels rose 2.5- to 3.5-fold, and mean (+/- SEM) serum androstenedione rose from 4.3 +/- 0.6 to 8.6 +/- 1.2 nmol/L (P less than 0.004, by paired t test), but serum total testosterone, free testosterone, sex hormone-binding globulin, estradiol, and estrone levels did not change. In the DHEA group the mean percent body fat decreased by 31%, with no change in weight. This suggests that the reduction in fat mass was coupled with an increase in muscle mass. DHEA administration also resulted in a fall in mean serum total cholesterol concentration (4.82 +/- 0.21 vs. 4.48 +/- 0.29 nmol/L; P less than 0.05), which was due almost entirely to a fall of 7.5% in mean serum low density lipoprotein cholesterol (3.21 +/- 0.11 vs. 2.97 +/- 0.14 nmol/L; P less than 0.01). No changes in anthropometric parameters or serum lipid levels occurred in the placebo group. Tissue sensitivity to insulin, assessed by the hyperinsulinemic-euglycemic clamp technique, did not change in either the placebo or DHEA groups. These results suggest that in normal men DHEA administration reduces body fat, increases muscle mass, and reduces serum low density lipoprotein cholesterol levels. Tissue sensitivity to insulin was unaffected by short term DHEA administration.     

Proportion of hemoglobin G Philadelphia (alpha 268 Asn leads to Lys beta 2) in heterozygotes is determined by alpha-globin gene deletions.

In humans the alpha-globin genes are duplicated and closely linked. Whereas individuals heterozygous for most alpha-chain mutations possess approximately 25% abnormal hemoglobin, heterozygotes for the alpha-chain variant Hb G Philadelphia synthesize either 33% or 50% Hb G. Both variable gene dosage and interaction with alpha-thalassemia have been proposed to explain this observation. To differentiate between these models, we have performed restriction endonuclease mapping and hematological studies on individuals with Hb G from four families. In every case the alpha G locus was carried on an EcoRI or EcoRI + BamHI fragment approximately 4 kilobases shorter than that bearing the two linked alpha A loci of hematologically normal individuals. Bgl II digestion revealed that the alpha G gene is the only alpha locus on the affected chromosome. Erythrocyte indices and alpha/beta synthesis ratios indicated that the alpha G chromosome confers alpha-thalassemia. In addition to the alpha G gene, subjects who synthesized 33% Hb G possessed two alpha A genes on the homologous chromosome and exhibited the mild form of alpha-thalassemia trait ("silent carrier"). Subjects who synthesized 50% Hb G possessed a single alpha A gene trans to the alpha G locus and displayed the more pronounced form of alpha-thalassemia trait. One subject, who synthesized 100% alpha G chains and had Hb G-Hb H disease, was found to have a single nonfunctional alpha gene trans to the alpha G gene. Thus the proportion of Hb G synthesized by heterozygotes is determined by interaction with alpha-globin gene deletions cis and trans to the alpha G locus.     

Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study

BACKGROUND: Non-alcoholic fatty liver disease is a common reason for hepatological consultation and may herald severe hepatic and extra-hepatic disease. The aetiopathogenesis of this condition is an area of increasing interest. AIM: To evaluate anthropometric and biochemical factors associated to non-alcoholic fatty liver disease in a case-control study. Methods. Demographic and biochemical data of 60 consecutive patients with bright liver absent-to-low alcohol consumption, no evidence of viral, genetic and autoimmune diseases, were compared to those of 60 age- and gender-matched historical controls without fatty liver by univariate and multiple logistic regression analysis. RESULTS: Patients were more often hypertriglyceridaemic, obese and diabetic than controls (p<.01). Mean values of alanine transaminase, gammaglutamyltranspeptidase, triglycerides, uric acid, fasting and log insulin, transferrin percent saturation and ferritin were significantly higher in the patients, while transferrin and quantitative insulin sensitivity check index, a quantitative insulin sensitivity index, were lower. No iron storage was found in those who underwent liver biopsy At univariate analysis the relative risk for non-alcoholic fatty liver disease significantly increased (p<0. 05) with increasing body mass index, fasting insulin, alanine transaminase, uric acid, triglycerides and gammaglutamyltranspeptidase; it decreased with increasing transferrin and quantitative insulin sensitivity check index. Multiple logistic regression analysis disclosed only fasting insulin and uric acid to be independent predictors of non-alcoholic fatty liver disease (p<0.05). CONCLUSIONS: Fasting insulin and serum uric acid levels indicating insulin resistance, but not indices of iron overload, are independent predictors of non-alcoholic fatty liver disease.     

Elevated levels of leptin and insulin but not of TNF alpha are associated with hypertension in type 2 diabetic males.

Leptin and TNF alpha are thought to influence blood pressure. Therefore, the aim of our study was to investigate leptin and TNF alpha levels and their association with blood pressure, sex steroids, insulin, creatinine and lipids in type 2 diabetic patients. In 424 type 2 diabetic patients (79 hypertensive females [+Hf], 79 normotensive females [-Hf]; 133 hypertensive males [+Hm], 133 normotensive males [-Hm]) matched for sex, age and BMI serum leptin levels were measured by RIA and TNF alpha, insulin, estradiol, progesterone by ELISA as well as free testosterone by RIA. Leptin levels were comparable in +Hf and -Hf (16.5 +/- 1.0 microg/l vs 16.3 +/- 1.0 microg/l) but higher in +Hm as compared to -Hm (8.3 +/- 0.47 microg/l vs 6.5 +/- 0.34 microg/l; p<0.05). In addition, in comparison to -Hm serum levels of insulin (190 +/- 10 pmol/l vs 161 +/- 11 pmol/l; p< 0.005) and also of creatinine (118.6 +/- 3.6 micromol/l vs 101.7 +/- 2.3; p< 0.0001) were higher in +Hm. Pearson's Correlation coefficient revealed a positive correlation between levels of leptin and diastolic blood pressure (p<0.05) and also between leptin and insulin (p<0.001) in males, however, only before correction for BMI. No correlation between leptin and creatinine was found in males and females. Levels of TNF alpha were comparable in all subgroups. No correlation between levels of TNF alpha and serum leptin levels, blood pressure and insulin was found. In females TNF alpha was positively correlated with creatinine (p<0.001) and in males positively with progesterone (p<0.001). Taken together, higher serum leptin levels were found in hypertensive type 2 diabetic males as compared to normotensives, which may be related to the BMI and higher levels of insulin. These findings are accompanied by a trend to lower levels of free testosterone in hypertensive type 2 diabetic males. TNF alpha levels were comparable in female and male hypertensive and normotensive type 2 diabetic subjects.     

Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis

OBJECTIVE: To measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclass (CXC and CC) in patients with newly diagnosed chronic autoimmune thyroiditis (AT), and relate the findings to the clinical phenotype. DESIGN AND METHODS: Serum CXCL10 and CCL2 were assayed in 70 consecutive patients with newly diagnosed chronic AT, in sex- and age-matched healthy volunteers (n = 37) and in 20 patients with non-toxic multinodular goiter, extracted from a random sample of the general population from the same geographic area. RESULTS: CXCL10 serum levels were significantly higher in patients with thyroiditis than in controls or multinodular goiter patients, while comparable CCL2 levels were found between groups. CXCL10 levels were significantly increased in hypothyroid patients and in those with an hypoechoic pattern (P = 0.0004 and P = 0.0001, respectively) while serum CCL2 levels were significantly increased in patients older than 50 years and in those with hypothyroidism (P = 0.0001 and P = 0.03, respectively). No correlation between CXCL10 and CCL2 serum levels could be demonstrated. CXCL10 and CCL2 were studied separately in relation to clinical features of AT patients. Two separate multiple linear regression models for CXCL10 and CCL2 were performed, including age, thyroid volume, thyroid stimulating hormone (TSH), FT4, anti-thyroid peroxidase (AbTPO), hypoechoic pattern, and the presence of hypervascularity, demonstrating that ln of serum CXCL10 levels was associated with TSH independently of other possible confounders levels [regression coefficient (R.C.) 0.143 confidence interval (C.I.) (0.042-0.245); P = 0.0059], while serum CCL2 were significantly associated only with age [R.C. 5.412 C.I. (3.838-6.986); P < 0.0001]. CONCLUSION: Our results, obtained in a large cohort of newly diagnosed AT patients demonstrate increased CXCL10 especially in hypothyroid patients with a more aggressive disorder, and normal CCL2 serum levels in AT.     

血清维生素A、C、E水平与尿酸水平的相关性

目的 探讨血清维生素A、C、E水平与尿酸水平的关系.方法 采用高效液相法检测100例高尿酸血症患者和100例正常对照组的血清维生素A、C、E水平,利用SPSS16.0统计软件分析尿酸与血清维生素A、C、E水平的关系.结果 高尿酸血症患者血清维生素A水平高于对照组,但维生素C、E水平低于对照组.高尿酸血症患者维生素C、E缺乏高于对照组(P＜0.05).结论 高尿酸血症患者的血清维生素C、E水平降低,可能参与了高尿酸血症的的发生.     

Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with serum uric acid levels in Chinese subjects with type 2 diabetes

Nitric oxide (NO) was found to modulate uric acid production through its influence on xanthine oxidase activity, and a close circadian relationship of serum uric acid (SUA) and NO was reported. Studies also revealed that serum NO activity could be determined by endothelial constitutive nitric oxide synthase gene (ecNOS) polymorphism. This study was designed to investigate whether SUA could be influenced by a 27-bp repeat polymorphism in intron 4 of ecNOS gene. A total of 398 nondiabetic subjects and 800 patients with type 2 diabetes were studied. The ecNOS gene intron 4 polymorphism was determined by polymerase chain reaction (PCR). The mean SUA level of patients having type 2 diabetes was significantly lower than that of control subjects (6.1 +/- 1.8 mg/dL v 6.6 +/- 1.8 mg/dL, P<.001); and the mean SUA level of diabetic patients with ecNOS ab/aa genotypes was lower than that of patients with bb genotype (5.7 +/- 1.6 mg/dL v 6.2 +/- 1.8 mg/dL, P=.008). When subgrouped by gender, the SUA of female diabetic subjects was found to be significantly associated with ecNOS genotype. Using Pearson's correlation analysis and multiple linear regression analysis, ecNOS genotype was noticed to be an independent factor in contributing to SUA variability in female diabetic patients. Our results suggest that SUA levels may be associated with NO activity and can be genetically predetermined.     

Low serum uric acid concentration augments insulin effects on the prevalence of metabolic syndrome

Aim

Insulin and uric acid were shown affect the prevalence of Metabolic Syndrome (MetS), but no studies examine their interaction. Therefore, we conducted this study to determine their biological interaction in subjects from central Mexico.

STEMI患者服用替格瑞洛期间血清尿酸水平的变化及其对血小板反应性的影响初探

目的:比较行急诊经皮冠状动脉介入治疗（PCI）的ST段抬高型心肌梗死（STEMI）患者在服用替格瑞洛和氯吡格雷期间血清尿酸水平的变化,并初步探讨血清尿酸水平的变化对血小板反应性的影响。方法:选取2017年4月至2020年1月于阜外医院行急诊PCI存活出院且接受阿司匹林和替格瑞洛或氯吡格雷治疗的STEMI患者,分为替格瑞...     

2型糖尿病患者中血尿酸相关基因的基因间相互作用分析

目的 探讨T2DM患者中SUA与相关基因的关联及交互作用.方法 纳入1574例T2DM患者,采用基质辅助激光解吸电离飞行时间质谱技术对56个基因的86个SNP位点进行基因分型,运用PLINK软件进行关联分析及基因型交互作用分析.结果 在T2DM患者中ABCG2（rs2231142）、PKHD1（rs9395706）、PDGFB（rs2285094）、LPHN3 （rs6856526）及MC4R（rs17782313）基因的多态性与SUA水平相关（P＜0.05）.同时,有6组基因存在交互作用（P＜0.001）.结论 ABCG2、PKHD1、PDGFB、LPHN3及MC4R基因的多态性与T2DM患者SUA水平相关.     

Renal handling of uric acid in gout: Impaired tubular transport of urate not dependent on serum urate levels

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levels. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean +/- SD) 3,707 +/- 443 micrograms/min/1.73 m2 in controls and 2,215 +/- 738 micrograms/min/1.73 m2 in patients with gout (P less than 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 +/- 202 micrograms/min/1.73 m2) than in controls (922 +/- 136 micrograms/min/1.73 m2; P less than 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients.(ABSTRACT TRUNCATED AT 250 WORDS)