Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

Obesity-related indices are associated with albuminuria and advanced kidney disease in type 2 diabetes mellitus

Obesity is an important risk factor for the development of diseases including diabetes, hypertension, and cardiovascular disease. However, few reports have investigated the relationships between these obesity-related indices and diabetic nephropathy. The aim of this study was to evaluate associations between obesity-related markers with albuminuria and advanced kidney disease in patients with type 2 diabetes mellitus (DM). Obesity-related indices including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body roundness index (BRI), conicity index (CI), lipid accumulation product (LAP), visceral adiposity index (VAI), body adiposity index (BAI), abdominal volume index (AVI), body shape index (BSI), and triglyceride glucose (TyG) index were measured. Albuminuria was defined as a urine albumin/creatinine ratio of ≥30 mg/g. Advanced kidney disease was defined as an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m². A total of 1872 patients with type 2 DM (mean age 64.0 ± 11.3 years, 809 males and 1063 females) were enrolled. In multivariable analysis, 11 high obesity-related indices (BMI, WHR, WHtR, LAP, BRI, CI, VAI, BAI, AVI, ABSI, and TyG index) were significantly associated with albuminuria. In addition, high BMI, WHR, WHtR, LAP, BRI, CI, VAI, and AVI were significantly associated with eGFR <30 ml/min/1.73 m². The results of this study showed that various obesity-related indices were significantly associated with albuminuria and advanced kidney disease in patients with type 2 DM. Screening may be considered in public health programs to recognize and take appropriate steps to prevent subsequent complications.     

Polymorphisms in IGF-binding protein 1 are associated with impaired renal function in type 2 diabetes

The dysregulation of the IGF system has been implicated in the pathogenesis of obesity, diabetes, and diabetes complications such as nephropathy, but little is known about the genomics of the IGF system in health and disease. We genotyped 13 single nucleotide polymorphisms (SNPs) in IGFBP1 gene in 732 representative type 2 diabetic patients from the Salford Diabetes Register. Of the 13 SNPs, 8 were polymorphic and 7 of those had minor allele frequencies >0.1, one of which was in the gene promoter and one of which was nonsynonymous in exon 4. The minor alleles of these SNPs and two others were associated with a reduced prevalence of diabetic nephropathy. Haplotype analysis revealed that 97% of the genetic variation for IGFBP1 in the population sample could be accounted for using two of the "reno-protective" SNPs, with other SNPs adding little extra information. One of these two SNPs was the nonsynonymous mutation in exon 4, lying close to the integrin-binding RGD motif, which is thought to affect tissue delivery of IGF-I by IGF-binding protein 1 (IGFBP-1), possibly suggesting a "reno-protective" effect via altered IGFBP-1 binding. In conclusion, we have described the first genomic markers to be associated with diabetic microvascular complications within the human IGFBP1 gene.     

Circulating asprosin levels are increased in patients with type 2 diabetes and associated with early-stage diabetic kidney disease

International Urology and Nephrology - Asprosin was a newly identified secreted hormone which could induce hepatic glucose release. Since asprosin closely associated with the risk factors of...     

Pancreas islet transplantation in patients with type 1 diabetes mellitus after kidney transplantation

Diabetic patients with end-stage renal disease have a high mortality rate. A combined kidney-pancreas transplant is associated with greater life expectancy. Pancreas islet transplantation is an alternative involving a lower degree of morbidity. We present two patients, of 41 and 37 years of age, with a long history of diabetes mellitus (C-peptide negative), both with a previous kidney transplant, who had been treated with 22 and 28 U of insulin/d, respectively. Both patients had frequent episodes of unawareness hypoglycemia. Pancreatic islets were infused to a total of 7809 and 19,180 IE/kg, respectively. Basal posttransplant C peptide levels were 2.9 and 1.3 ng/mL. After the implant, one patient required occasional doses of insulin, and the other patient more than 50% reduced dose. After the first implant neither patient had any episodes of unawareness hypoglycemia. HbA1c at 4 months were 6.2% and 6.9%. There were no transplant-related complications.     

Polymorphisms in the estrogen receptor genes are associated with hip fractures in Chinese

IntroductionHip fractures (HF) are a major cause of public health burden with strong genetic determination. However, the true causal genes remain largely unknown.Materials and methodsBased on the important biological role of estrogens in bone homeostasis, this study aimed to investigate whether the estrogen receptor genes, ESR1 and ESR2, affect the onset of HF in 700 elderly Chinese subjects (350 with osteoporotic HF and 350 healthy controls). We genotyped 32 SNPs in total and examined their associations both by the single-SNP and haplotype tests.ResultsWe identified two novel SNPs of ESR1, rs3020314 and rs1884051, were significantly associated with HF (rs3020314: P = 0.0004, OR = 1.66, 95%CI: 1.25–2.18; rs1884051: P = 0.0004, OR = 1.46, 95%CI: 1.19–1.81). We firstly detected significant association of ESR2 with HF (rs960070: P = 0.0070, OR = 1.43, 95%CI: 1.10–1.86). Haplotype analyses corroborated our single-SNP results.ConclusionOur findings have important implications for understanding the pathology of osteoporotic fractures. Independent replication studies are needed to validate our results and explore the most possible functional variants for molecular studies.     

Interleukin-1 receptor antagonist gene polymorphisms are associated with disease severity in Black South Africans with rheumatoid arthritis

ObjectiveTo test for genetic associations between polymorphisms of the interleukin-1 (IL-1) gene cluster and disease susceptibility and severity in Black South Africans with rheumatoid arthritis (RA).MethodsAllele and genotype frequencies of IL1B (?511) and (+3954) and IL1RN variable number of tandem repeat (VNTR) and (+2018) were compared between 141 RA patients and 101 healthy controls.ResultsNo significant differences in allelic distribution at the four loci were observed between RA patients and controls. Within the RA group, the IL1RN*2 (two repeats of an 86 bp tandem repeat) at the IL1RN VNTR locus was independently associated with higher Larsen radiologic damage scores (LDS), corrected for disease duration (p = 0.04). Moreover, the inferred haplotype, consisting of IL1RN*2 and (+2018) ‘C’ allele, was associated with significantly higher LDS, on average 15 points higher, compared to the base haplotype of IL1RN*long (three or more repeats) and (+2018) ‘T’ allele (p = 0.009). The common IL1B (?511) ‘T’ allele was associated with a poorer modified health assessment questionnaire disability index (p = 0.02).ConclusionOur findings provide further evidence of a possible role of polymorphisms of the IL-1 gene cluster in disease severity in RA, and particularly IL1RN*2 as a marker of erosive joint damage in Black South Africans with RA.     

Outcome of cadaver kidney transplantation in 23 patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (DM) is a growing cause of end-stage renal failure worldwide. Yet, only a minority of type 2 diabetics are considered today for kidney transplantation (KT). The scarcity of data on the outcome of such patients after KT prompted us to review our experience. METHODS: Between 1 January 1983 and 30 June 1996, 23 patients with type 2 DM received a first cadaver KT at a mean age of 57+/-9 (41-73) years, after a dialysis period ranging from 5 to 72 (mean 25+/-18) months. Only nine patients had a history of coronary and/or peripheral vascular disease before KT. All were given cyclosporin- or tacrolimus-based immunosuppression. Post-KT follow-up ranged from 4 to 181 (mean 70+/-38) months. Outcome analysis focused on the impact of cardiovascular complications. RESULTS: Patient survival at 1, 5 and 8 years was 91, 83 and 76% respectively. Death was due to infection in three patients and to a cardiovascular event in two. The actuarial risk of coronary, cerebrovascular, peripheral vascular, and any cardiovascular event after KT was 14, 13, 9 and 30% at 1 year, 20, 13, 50 and 58% at 5 years, and 20, 46, 66 and 72% at 8 years respectively. Post-KT hospital readmissions averaged 10 days/patient-year and were mostly related to the management of peripheral vascular disease. CONCLUSION: KT is an excellent therapeutic option for selected patients with type 2 DM. Peripheral vascular disease is the leading cause of morbidity following KT. KT should be considered in type 2 diabetics with a low/medium cardiovascular risk.     

Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes

BACKGROUND: Advanced glycation end products (AGEs) are implicated in the development and progression of diabetic nephropathy. We examined the predictors of low-molecular-weight (LMW) AGEs in a cross-sectional survey of 604 patients with type 2 diabetes in a single clinic. METHODS: A clinical history and results of routine blood and urine testing were obtained for all patients over a 2-year period. Fluorescent LMW AGEs were estimated in serum samples taken concurrently, using an established flow injection method. Predictors of LMW AGEs were identified using multiple regression analysis. RESULTS: LMW AGEs were 34% higher in patients with diabetes than nondiabetic volunteers from the same community (P < 0.001). Independent predictors for LMW AGEs in patients with diabetes were glomerular filtration rate (GFR) and hemoglobin (both P < 0.001). While patients with renal impairment and anemia had the highest levels of LMW AGEs, both GFR and hemoglobin remained predictive when patients with a serum creatinine or hemoglobin within the "normal range" were analyzed separately. Patients with hyperfiltration had significantly lower LMW AGEs than those with normal renal function. Gender was also a significant independent predictor of LMW AGEs in patients without anemia. However, LMW AGEs were not associated with metabolic control or the presence of macrovascular disease. CONCLUSION: Circulating levels of LMW AGEs are elevated in patients with diabetes, especially those with impaired renal function or anemia. These findings extend the evidence for an association between AGEs and progressive renal injury in patients with type 2 diabetes. Whether LMW AGEs contribute to, or are a marker of, renal damage needs to be established by prospective studies.     

Stress,inflammatory markers and factors associated in patients with type 2 diabetes mellitus

Stress is evaluated using tumour necrosis factor‐α (TNF‐α), Heat Shock Protein 60 (Hsp60) and other markers in chronic diseases. We examined the association of Hsp60, cortisol, TNF‐α and interleukin‐6 (IL‐6) serum levels with psychological and socio‐economic factors in patients with type 2 diabetes mellitus (DM‐2). We studied 151 DM‐2 patients in groups with <1 year and >5 years since diagnosis. Clinical data, family income and questionnaires of anxiety, depression, perceived stress, social support, glucose, glycated haemoglobin, lipids, Hsp60, cortisol, IL‐6 and TNF‐α were collected. Patients with >5 years since diagnosis of DM‐2 had lower body mass index (p < 0.016), higher glucose (p < 0.005) and HbA_1c (p < 0.005) levels. The group of recent diagnosis had higher Hsp60 (p < 0.00003). Hsp60 was associated negatively with years since diagnosis (p < 0.000012), and positively with glucose (p < 0.029). Cortisol was positively associated with glucose levels (p < 0.019) and family income (p < 0.037). TNF‐α was associated with years since diagnosis (p < 0.004) and perceived stress (p < 0.018). At early stages of DM‐2, Hsp60 increases with glucose levels, cortisol is associated with glucose levels. At later stages TNF‐α increases, associated with perceived stress. Copyright © 2007 John Wiley & Sons, Ltd.     

507例2型糖尿病合并慢性肾脏病患者肾活检的临床病理特点

目的 总结和分析糖尿病肾病(diabetic kidney disease,DKD)与非糖尿病肾病(non-diabetic kidney disease,NDKD)患者临床病理特点,为临床2型糖尿病合并慢性肾脏病患者肾活检指征提供循证医学证据.方法 通过南方医科大学南方医院大数据库收集2002年2月至2018年6月在该院接受肾活检的2型糖尿病合并慢性肾脏病患者,并根据肾活检结果将其分为DKD组和NDKD组(包括DKD合并NDKD),比较两组间临床表现及病理类型特点,并采用Logistic回归模型分析DKD和NDKD患者的相关因素.结果 共纳入507例患者,DKD患者114例(22.5%),NDKD患者393例(77.5%).病理表现:NDKD的最常见病理类型为膜性肾病(30.0%)和IgA肾病(19.1%),其中有5.6%患者为DKD合并NDKD.临床表现:与NDKD组患者相比,DKD组患者有更长的糖尿病史(>1年,76.3%比36.1%,P<0.001),更易发生糖尿病视网膜病变(42.1%比4.8%,P< 0.001),24h尿蛋白量更高[3.69(1.70,6.74)g比2.21 (0.91,4.97)g,P<0.001],血肌酐更高[117.5 (85.8,194.5) μmol/L比89.0 (68.0,143.8) μmol/L,P<0.001],血红蛋白更低[(105.07±20.85) g/L比(124.41±25.02) g/L,P=0.002],胆固醇更低[(5.69±1.87) mmol/L比(6.43±2.75) mmol/L,P=0.001].Logistic回归分析显示,糖尿病史(OR=4.162,95%CI 1.717~10.098,P=0.002)、较高收缩压(每增加1 mmHg,OR=1.028,95%CI 1.011~1.045,p=0.001)、降压药服用史(OR=3.141,95%CI 1.496~6.591,P=0.002)、糖尿病视网膜病变(OR=5.561,95%CI2.361~13.100,P<0.001)、较高糖化血红蛋白(每增加1%,OR=1.680,95%CI1.333~2.118,P<0.001)是DKD的相关因素,而血尿(OR=2.781,95%CI 1.334~5.798,P=0.006)和较高血红蛋白(每增加1g/L,OR=1.022,95%CI1.008~1.037,P=0.002)则为NDKD的相关因素.结论 DKD与NDKD之间的临床表现及病理类型存在差异,糖尿病病史、眼底检查、大量蛋白尿、降压药服用史、较高的糖化血红蛋白水平对DKD的诊断有较好的预测作用,而血尿和较高的血红蛋白水平对NDKD的诊断有一定指导意义.糖尿病合并慢性肾脏病患者行肾活检的指征需根据各临床表现综合分析.     

Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2

AIMS: Hypomagnesemia has been implicated in adversely affecting diabetic complications. This is a retrospective study designed to determine whether there is any association between serum magnesium concentration [Mg2+] and the rate of renal function deterioration, as determined by the slope of serum creatinine reciprocals versus time (1/SCr-vs-t), in patients with diabetes mellitus type 2 (DM2). MATERIALS AND METHODS: DM2 patients without known kidney disease seen at Olive View-UCLA Medical Center for any reason during January-March 2001 were included. For each patient, all available data from our electronic database for [Mg2+], hemoglobin A(1C) (HbA(1C), serum creatinine (SCr), lipid profiles, routine urinary analysis, as well as history of hypertension and pharmacy profiles were retrieved. The average of all parameters obtained and linear regression analyses for the slope of 1/SCr-vs-t plot were performed for each patient. Patients were stratified by gender and divided into four groups based on increasing [Mg2+]. Correlations between each parameter including the slope of 1/SCr-vs-t and the four magnesium groups were analyzed. RESULTS: 252 males and 298 females with a mean follow-up of 62.6 +/- 22.5 months were included. Patients belonging to lower [Mg2+] groups for both genders had significantly worse slopes of 1/SCr-vs-t plot independent of the presence of hypertension and use of ACEI/ARB, diuretics, HMG-CoA enzyme inhibitors or aspirin. In a multivariate regression analysis controlling for age, HbA(1C) and various components of the lipid profile, [Mg2+] remained an independent predictor for the slope of 1/SCr-vs-t. A trend for worse proteinuria based on routine urinary analysis was observed among patients belonging to the lowest [Mg2+] group. CONCLUSIONS: Lower [Mg2+] is associated with a faster renal function deterioration rate in DM2 patients.     

Baseline anxiety disorders are associated with progression of diabetic kidney disease in type 2 diabetes

BackgroundDiabetic kidney disease (DKD) is a leading cause of kidney failure worldwide. Anxiety has been associated with disease progression in non-diabetes patients. We aimed to examine the prospective association between anxiety and progression of DKD in type 2 diabetes.MethodsWe conducted a prospective cohort study of 2040 participants with type 2 diabetes at the Diabetes Center of Shanghai General Hospital between May 2017 and June 2020. Anxiety disorders at baseline were diagnosed by a structured clinical interview based on the 10th Revision of International Classification of Disease (ICD). Progression of DKD was identified as the transition from one urinary albumin excretion rate (AER) stage to the next or the development of kidney failure during the follow-up period.ResultsAt baseline, 403 (19.8%) had a diagnosis of anxiety disorders, of whom 107 (26.6%) also received a depression diagnosis. During a median follow-up time of 3.2 years, deterioration of the kidney status occurred in 340 (16.7%) individuals. After adjustment for potential confounders including depression or an anxiety × depression interaction term, anxiety disorders were independently related to an increased risk of progression of DKD (HR 1.539, 95% CI 1.130–2.095, p = 0.006; HR 1.536, 95% CI 1.111–2.122, p = 0.009, respectively).ConclusionsAnxiety disorders at baseline, independent of possible confounders, were associated with the progression of DKD in type 2 diabetes. Whether therapeutic interventions for anxiety reduce the risk needs to be investigated.     

Interleukin-1 and interleukin-2 defects associated with murine graft-versus-host-induced immunodeficiency

In this study we investigated the mechanism, or mechanisms, involved in graft-versus-host (GVH)-induced T cell immunodeficiency. Chronic GVH reactions were induced in normal CBA X A F1 (BAF1) hybrid mice by the injection of parental A strain lymphoid cells. At various times (43-91 days) after GVH induction, the functional status of GVH T cells was assessed using interleukin-1 (IL-1) and interleukin-2 (IL-2) as probes. The response of GVH thymocytes to IL-1 was depressed when compared with normal thymocytes. Although GVH peanut-agglutinin-negative (PNA-) thymocytes did respond to IL-2 alone or IL-2 plus phytohemagglutinin (PHA), this response was significantly lower than the response of PNA- thymocytes from normal mice. In addition, GVH spleen cells failed to produce significant amounts of IL-2 when stimulated with concanavalin A. These results suggest that the long term immunosuppression associated with murine chronic GVH disease is due, at least in part, to a decrease in the responsiveness to IL-1 and IL-2, and to a marked deficiency in IL-2 production.     

Association of interleukin-1beta gene and receptor antagonist polymorphisms with calcium oxalate urolithiasis

BACKGROUND AND PURPOSE: Genetic polymorphisms of the interleukin-1beta (IL-1beta) promoter region (-511) and exon 5 +3954 and a variable number of tandem repeats in the IL receptor antagonist (IL-1RA) gene have been proposed as markers for calcium oxalate urolithiasis. Because the prevalence of these polymorphisms could be influenced by racial variation/ethnicity, we explored the association of IL-1 gene-cluster polymorphisms with stone formation in a north India population. PATIENTS AND METHODS: The case-control study involved 150 stone-free control subjects (mean age 46.5 +/- 10.5 years) and 130 patients (mean age 40.0 +/- 11.5 years) with calcium oxalate urolithiasis. Biallelic polymorphisms of two loci, IL-1beta (-511) and IL-1beta (+3954), as well as the penta-allelic variable number of tandem repeats of IL-1RA, were genotyped by polymerase chain reaction-based restriction analysis. Haplotypes were constructed for the IL-1 gene cluster using SNP Analyzer software. RESULTS: We observed a significant association between stone disease and IL-1beta -511 and IL-1RA polymorphisms (P < 0.001 and P = 0.039, respectively), whereas no association was observed for IL-1beta +3954 (P = 0.408). The frequency of the TT (-511) and I/II (410/240; IL-1RA) genotypes was higher in patients than in control subjects (50/130 v 16/150 and 55/130 v 38/150, respectively), whereas the frequencies of the haplotypes were similar (P = 0.485). Significant linkage disequilibrium showed that three genes were strongly linked (P < 0.0001). Patients with a combination of high IL-1beta (-511 and +3954) and low IL-1RA genotypes were at significantly higher risk for urolithiasis (P < 0.001; odds ratio = 5.448, 0.013, and 2.560, respectively). CONCLUSION: Our study demonstrated a strong association of IL-1RA and IL-1beta-511 and suggested that differences in the IL-1 gene cluster could be linked to the risk of urolithiasis. A combination of IL-1beta and IL-1RA associations exhibiting gene-gene interaction further substantiates the finding of risk.     

肝细胞肝癌病人血清IL-12、IL-2、sIL-2R水平的相关性

目的探讨肝细胞肝癌 (hepatocellularcarcinoma ,HCC)病人血清IL 12、IL 2、sIL 2R水平的相关关系。方法 6 0例HCC病人 ,随机分为 2组。试验组 (30例 )接受IL 2 (IL 2 10 0万U/d× 7d ,静脉点滴注射 )治疗 ;对照组 (30例 )没有接受生物治疗。两组基础治疗基本相似。采用酶联免疫吸附 (ELISA)法检测所有病人治疗前后血清IL 12、IL 2、sIL 2R水平变化。结果血清IL 12水平与血清IL 2水平正相关 ,IL 12与sIL 2R无关 ,IL 2与sIL 2R负相关。IL 2治疗后平均血清IL 12、IL 2、sIL 2R水平显著性升高。IL 2治疗后血清IL 12水平下降的HCC病人预后差。结论IL 12与IL 2之间可能存在一个反馈环路 ,sIL 2R是这个环路的负调节因素。IL 2治疗可刺激内源性IL 12释放。HCC病人的预后可能与IL 2诱生的IL 12变化有关