Identification of New Genetic Risk Variants for Type 2 Diabetes

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r²<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49×10⁻⁹ (1.15, 1.10–1.20), 1.45×10⁻⁸ (1.13, 1.08–1.18), and 7.14×10⁻⁷ (1.13, 1.08–1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.     

Joint Effect of Genetic and Lifestyle Risk Factors on Type 2 Diabetes Risk among Chinese Men and Women

More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) was 1.08 (95% CI: 1.06–1.09) for GRS1 and 1.15 (95% CI: 1.13–1.18) for GRS2. The OR for quintiles were 1.00, 1.26, 1.69, 1.95 and 2.18 (P<0.0001) for GRS1 and 1.00, 1.33, 1.60, 2.03 and 2.80 (P<0.001) for GRS2. Participants in the higher tertile of GRS1 and the higher BMI category had a higher risk of T2D compared to those on the lower tertiles of the GRS1 and of BMI (OR = 11.08; 95% CI: 7.39–16.62). We found similar results when we investigated joint effects between GRS1 and WHR terciles and exercise participation. We finally investigated the joint effect between tertiles of GRSs and a composite high risk score (no exercise participation and high BMI and WHR) on T2D risk. We found that compared to participants with low GRS1 and no high risk factors for T2D, those with high GRS1 and three high risk factors had a higher risk of T2D (OR = 13.06; 95% CI: 8.65–19.72) but the interaction factor was of marginal significance. The association was accentuated when we repeated analysis with the GRS2. In conclusion we found an association between GRS and lifestyle factors, alone and in combination, contributed to the risk of and T2D among middle age Chinese.     

Risk Factors for Hearing Impairment in Type 1 Diabetes

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment.Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment.Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia—as a modifiable risk factor—over time. In addition, the macrovascular contribution of CAC is novel and important.Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes     

2型糖尿病发生大血管并发症的危险因素分析

目的:探讨2型糖尿病患者发生大血管并发症的危险因素.方法:选取哈尔滨医科医科大学附属第四医院内分泌科2012年1月至2012年12月住院的2型糖尿病患者共计200例,根据相关辅助检查结果将其分为2型糖尿病无大血管并发症(DMl)组和2型糖尿病合并大血管并发症(DM2)组,比较2组患者血清胆红素水平及相关指标的差异.应用多因素非条件Logistic回归分析法对2型糖尿病大血管并发症危险因素建立方程.结果:2型糖尿病合并大血管并发症组患者血清胆红素水平低于2型糖尿病无大血管并发症组(P＜0.01),以糖尿病合并大血管并发症为因变量,年龄、病程、糖化血红蛋白、低密度脂蛋白胆固醇、甘油三酯、总胆红素、总胆固醇、直接胆红素、间接胆红素水平为自变量,进行Logistic逐步回归分析,结果显示病程、血清低密度脂蛋白胆固醇、年龄和总胆固醇是2型糖尿病合并大血管并发症的独立危险因素,血清胆红素水平是其保护性因素.结论:病程、年龄、血清低密度脂蛋白胆固醇和总胆固醇水平是2型糖尿病合并大血管并发症的独立危险因素,而血清胆红素水平是其保护性因素.     

2型糖尿病合并下肢动脉粥样硬化的危险因素

下肢动脉粥样硬化是2型糖尿病(T2DM)患者最常见的大血管并发症之一。作为T2DM患者严重的慢并发症之一,下肢动脉粥样硬化可引起糖尿病足的发生,严重情况下可导致足坏疽。因此,阐明T2DM合并下肢动脉粥样硬化的危险因素,早期预防和治疗糖尿病合并下肢动脉粥样硬化症,不仅提高了患者的生活质量,而且减轻了家庭和社会的经济负担,具有较大的现实意义。影响T2DM患者下肢动脉粥样硬化的因素错综复杂,分为不可调控的和可调控的因素,不可调控的危险因素包括年龄、种族、遗传等,可调控的危险因素包括吸烟、高血糖、高血脂、高血压,以及近年提出的肥胖、胰岛素抵抗、高纤维蛋白血症、炎症等。本文就T2DM合并下肢动脉粥样硬化的危险因素做一综述。     

Inclusion of Plasma Lipid Species Improves Classification of Individuals at Risk of Type 2 Diabetes

Background

A significant proportion of individuals with diabetes or impaired glucose tolerance have fasting plasma glucose less than 6.1 mmol/L and so are not identified with fasting plasma glucose measurements. In this study, we sought to evaluate the utility of plasma lipids to improve on fasting plasma glucose and other standard risk factors for the identification of type 2 diabetes or those at increased risk (impaired glucose tolerance).

Methods and Findings

Our diabetes risk classification model was trained and cross-validated on a cohort 76 individuals with undiagnosed diabetes or impaired glucose tolerance and 170 gender and body mass index matched individuals with normal glucose tolerance, all with fasting plasma glucose less than 6.1 mmol/L. The inclusion of 21 individual plasma lipid species to triglycerides and HbA1c as predictors in the diabetes risk classification model resulted in a statistically significant gain in area under the receiver operator characteristic curve of 0.049 (p<0.001) and a net reclassification improvement of 10.5% (p<0.001). The gain in area under the curve and net reclassification improvement were subsequently validated on a separate cohort of 485 subjects.

Conclusions

Plasma lipid species can improve the performance of classification models based on standard lipid and non-lipid risk factors.     

Risk Factors and Primary Prevention Trials for Type 1 Diabetes

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease resulting in the designated immune destruction of insulin producing β-cells, usually diagnosed in youth, and associated with important psychological, familial, and social disorders. Once diagnosed, patients need lifelong insulin treatment and will experience multiple disease-associated complications. There is no cure for T1DM currently. The last decade has witnessed great progress in elucidating the causes and treatment of the disease based on numerous researches both in rodent models of spontaneous diabetes and in humans. This article summarises our current understanding of the pathogenesis of T1DM, the roles of the immune system, genes, environment and other factors in the continuing and rapid increase in T1DM incidence at younger ages in humans. In addition, we discuss the strategies for primary and secondary prevention trials of T1DM. The purpose of this review is to provide an overview of this disorder''s pathogenesis, risk factors that cause the disease, as well as to bring forward an ideal approach to prevent and cure the disorder.     

2型糖尿病患者发生动脉硬化的危险因素分析

目的:观察2型糖尿病患者的大动脉硬化情况及探讨其相关危险因素.方法:选择上海普陀区人民医院内分泌科就诊的2型糖尿病者共1000人.所有对象完成常规的体检、生化检查及脉搏波传导速度等检查.结果:(1)2型糖尿病人群的平均PWV值为1668 cm/秒.(2)Pearson相关分析结果显示,与PWV显著相关的因素依次是有收缩压、年龄、舒张压、糖尿病病程、尿蛋白指数、腰围、糖化血红蛋白、体重指数、LDL及TC,相关系数分别为0.429、0.360、0.317、0.225、0.163、0.159、0.157、0.110、0.092、0.085(P＜0.05).(3)多元逐步回归分析表明影响PWV的因素有收缩压、年龄、糖化血红蛋白、糖尿病病程,β系数分别为:0.334、0.276、0.103、0.067(P＜0.05).结论:2型糖尿病人群中平均脉搏波传播速度高于基准值.血压、年龄、糖化血红蛋白、糖尿病病程均为糖尿病动脉硬化的独立危险因素.     

Genetic Variants of TPCN2 Associated with Type 2 Diabetes Risk in the Chinese Population

Objective

The aim of this study was to determine whether TPCN2 genetic variants are associated with type 2 diabetes and to elucidate which variants in TPCN2 confer diabetes susceptibility in the Chinese population.

Research Design and Methods

The sample population included 384 patients with type 2 diabetes and 1468 controls. Anthropometric parameters, glycemic and lipid profiles and insulin resistance were measured. We selected 6 TPCN2 tag single nucleotide polymorphisms (rs35264875, rs267603153, rs267603154, rs3829241, rs1551305, and rs3750965). Genotypes were determined using a Sequenom MassARRAY SNP genotyping system.

Results

Ultimately, we genotyped 3 single nucleotide polymorphisms (rs3750965, rs3829241, and rs1551305) in all individuals. There was a 5.1% higher prevalence of the rs1551305 variant allele in type 2 diabetes individuals (A) compared with wild-type homozygous individuals (G). The AA genotype of rs1551305 was associated with a higher diabetes risk (p<0.05). The distributions of rs3829241 and rs3750965 polymorphisms were not significantly different between the two groups. HOMA-%B of subjects harboring the AA genotype of rs1551305 decreased by 14.87% relative to the GG genotype.

Conclusions

TPCN2 plays a role in metabolic regulation, and the rs1551305 single nucleotide polymorphism is associated with type 2 diabetes risk. Future work will begin to unravel the underlying mechanisms.     

Reduction of Specific Circulating Lymphocyte Populations with Metabolic Risk Factors in Patients at Risk to Develop Type 2 Diabetes

Low-grade inflammation, characterized by increased pro-inflammatory cytokine levels, is present in patients with obesity-linked insulin resistance, hyperglycemia and hyperlipidemia and considered to play a leading role to progression into type 2 diabetes (T2D). In adipose tissue in obese patients and in pancreatic islets in T2D patients cellular inflammation is present. However, the systemic leukocyte compartment and the circulating endothelial/precursor compartment in patients at risk to develop T2D has so far not been analyzed in detail. To address this, peripheral blood cells from a cohort of 20 subjects at risk to develop diabetes with normal to impaired glucose tolerance were analyzed by flow cytometry using a wide range of cellular markers and correlated to known metabolic risk factors for T2D i.e. fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG), HbA1c, body mass index (BMI), homeostasis model assessment of β-cell function (HOMA-B), homeostasis model assessment of insulin sensitivity (HOMA-IS) and fasting insulin (FI). The four highest ranked cell markers for each risk factor were identified by random forest analysis. In the cohort, a significant negative correlation between the number of TLR4⁺ CD4 T cells and increased FPG was demonstrated. Similarly, with increased BMI the frequency of TLR4⁺ B cells was significantly decreased, as was the frequency of IL-21R⁺ CD4 T cells. Unlinked to metabolic risk factors, the frequency of regulatory T cells was reduced and TLR4⁺ CD4 T cells were increased with age. Taken together, in this small cohort of subjects at risk to develop T2D, a modulation of the circulating immune cell pool was demonstrated to correlate with risk factors like FPG and BMI. This may provide novel insights into the inflammatory mechanisms involved in the progression to diabetes in subjects at risk.     

2型糖尿病患者下肢血管病变的危险因素分析

目的:探讨2型糖尿病患者发生下肢血管病变的危险因素.方法:回顾性分析我院2009年12月～2011年12月收治的98例2型糖尿病患者的临床资料,通过彩色多普勒超声检查其下肢血管,按下肢血管有无病变将其分为单纯2型糖尿病租和2型糖尿病合并下肢血管病变组,通过非条件Logistic回归分析导致2型糖尿病患者发生下肢血管病变的危险因素.结果:彩色多普勒超声检查结果显示,98例2型糖尿病患者中,61例发生不同程度下肢血管病变,占62.24％.与单纯2型糖尿病组比较,下肢血管病变组患者年龄、病程、收缩压及低密度脂蛋白胆固醇的差异均有统计学意义(P＜0.05),经非条件Logistic回归分析,患者的年龄、病程、SBP及LDL-L是下肢血管病变的独立危险因素(P＜0.05).结论:2型糖尿病患者下肢血管病变的发生与患者的年龄、病程、血压及血脂情况密切相关.     

SARS-CoV-2 Seroprevalence in Individuals With Type 1 and Type 2 Diabetes Compared With Controls

ObjectiveData for the association between diabetes and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility are conflicting. We aimed to evaluate this association using an analytical cross-sectional study design.MethodsStudy participants were recruited from endocrine clinics of our hospital and belonged to 3 groups: group 1 (type 1 diabetes mellitus [T1DM]), group 2 (type 2 diabetes mellitus [T2DM]), and group 3 (controls). All participants submitted blood samples for SARS-CoV-2 S1/S2 immunoglobulin G antibody test (LIAISON; DiaSorin) and were interviewed for a history of documented infection.ResultsWe evaluated a total of 643 participants (T1DM, 149; T2DM, 160; control, 334; mean age, 37.9 ± 11.5 years). A total of 324 (50.4%) participants were seropositive for SARS-CoV-2. The seropositivity rate was significantly higher in the T1DM (55.7% vs 44.9%, P = .028) and T2DM (56.9% vs 44.9%, P = .013) groups than in the control group. The antibody levels in seropositive participants with T1DM and T2DM were not significantly different from those in seropositive controls. On multivariable analysis, low education status (odds ratio [OR], 1.41 [95% CI, 1.03-1.94]; P = .035), diabetes (OR, 1.68 [95% CI, 1.20-2.34]; P = .002), and overweight/obesity (OR, 1.52 [95% CI, 1.10-2.10]; P = .012) showed a significant association with SARS-CoV-2 seropositivity. The association between diabetes and SARS-CoV-2 seropositivity was found to further increase in participants with coexisting overweight/obesity (adjusted OR, 2.63 [95% CI, 1.54-4.47]; P < .001).ConclusionSARS-CoV-2 seropositivity, assessed before the onset of the national vaccination program, was significantly higher in participants with T1DM and T2DM than in controls. The antibody response did not differ between seropositive participants with and without diabetes. These findings point toward an increased SARS-CoV-2 susceptibility for patients with diabetes, in general, without any differential effect of the diabetes type.     

Weight Loss and Leptin Changes in Individuals with Type 2 Diabetes

WILLIAMS, KATHERINE V., MONICA MULLEN, WE1 LANG, ROBERT V. CONSIDINE, AND RENA R. WING. Weight loss and leptin changes in individuals with type 2 diabetes. Obes Res. Objective To identify variables associated with leptin change in subjects with type 2 diabetes after 3 weeks and 20 weeks of weight loss. Research Methods and Procedures Subjects with type 2 diabetes treated with diet or sulfonylureas (n = 54) were enrolled in a 20-week behavioral weight control program. Sulfonylureas were stopped ≥2 weeks before study entry. Seven subjects who restarted sulfonylureas after week 3 had their data analyzed separately after this point. Results Leptin, fasting plasma glucose, and insulin levels were measured at baseline and at 3, 10, and 20 weeks. After 3 weeks, subjects lost 2.7±2.0 kg (p<0.001), and had significant decreases in leptin (5.2±7.0 ng/mL, p<0.001), fasting plasma glucose (1.8±1.8 mmol/L, p<0.001), and insulin (23±60 pmol/L, p<0.03). Between week 3 and week 20, subjects lost an additional 6.3±4.4 kg (P<0.001), but had no further changes in leptin. The primary determinants of leptin change at all time-points were weight loss and initial leptin level. Changes in insulin were not related to changes in leptin after controlling for the effects of weight loss. At week 20, more recent weight loss (week 10 to week 20) was as strong a predictor of overall change in leptin as overall weight loss (baseline to 20 week). Subjects who restarted sulfonylureas had an increase in both leptin levels (+1.9±9.0 ng/mL, p<0.05) and insulin levels (+23±65 pmol/L, p<0.05), despite significant overall weight loss (-7.4±4.0 kg, p<0.01). Initial changes in leptin (0 weeks to 3 weeks) did not affect subsequent ability to lose weight. Discussion Both short- and long-term changes in weight had an effect on leptin changes in individuals with type 2 diabetes. Although physiological insulin changes did not independently influence changes in leptin concentration with weight loss, increases in insulin levels with sulfonyl-urea therapy were associated with increases in leptin levels despite weight loss.     

A Risk Assessment Model for Type 2 Diabetes in Chinese

Aims

To develop a risk assessment model for persons at risk from type 2 diabetes in Chinese.

Materials and Methods

The model was generated from the cross-sectional data of 16246 persons aged from 20 years old and over. C4.5 algorithm and multivariate logistic regression were used for variable selection. Relative risk value combined with expert decision constructed a comprehensive risk assessment for evaluating the individual risk category. The validity of the model was tested by cross validation and a survey performed six years later with some participants.

Results

Nine variables were selected as risk variables. A mathematical model was established to calculate the average probability of diabetes in each cluster''s group divided by sex and age. A series of criteria combined with relative RR value (2.2) and level of risk variables stratified individuals into four risk groups (non, low, medium and high risk). The overall accuracy reached 90.99% evaluated by cross-validation inside the model population. The incidence of diabetes for each risk group increased from 1.5 (non-risk group) to 28.2(high-risk group) per one thousand persons per year with six years follow-up.

Discussion

The model could determine the individual risk for type 2 diabetes by four risk degrees. This model could be used as a technique tool not only to support screening persons at different risk, but also to evaluate the result of the intervention.     

Genetic Predisposition for Development of Nephropathy in Type 2 Diabetes Mellitus

The aim of the study was to explore the association of the angiotensin-converting enzyme (ACE) gene I/D polymorphism and the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with development of diabetic nephropathy in type 2 diabetes mellitus. Three groups were recruited during 2007–2011: 232 normal controls, 185 type 2 diabetics without nephropathy, and 407 type 2 diabetics with nephropathy. The ACE I/D and MTHFR C677T polymorphisms were examined using PCR and PCR-RFLP methods. We found no significant association of the ACE I/D polymorphism with diabetic nephropathy in genotype, allele, dominant, and recessive models. We observed a significant association of MTHFR C677T with development of diabetic nephropathy in type 2 diabetics. The MTHFR C677T polymorphism plays a significant role in predisposition of renal insufficiency in diabetic patients.     

老年2型糖尿病患者发生严重低血糖相关危险因素分析

目的:研究老年2型糖尿病患者发生严重低血糖的相关危险因素。方法:选取2013年7月到2014年7月我院收治的老年2型糖尿病患者200例,根据是否发生严重低血糖将患者分为非低血糖组(138例)和低血糖组(62例),比较两组临床资料。结果:低血糖组和非低血糖组体重指数、住院时间以及糖尿病病程比较差异具有统计学意义(P0.05);低血糖组心脑血管疾病药物联用率显著高于非低血糖组,二甲双胍应用率显著低于非低血糖组,胰岛素应用率以及口服降糖药(OAD)和胰岛素的联合应用率显著高于非低血糖组,两组比较差异具有统计学意义(P0.05);低血糖组低钾血症发生率显著高于非低血糖组,肾功能有关的指标显著高于非低血糖组,低血糖组白细胞和中性粒细胞显著高于非低血糖组,两组比较差异具有统计学意义(P0.05);Logistic多因素回归分析可知,病程超过10年、胰岛素应用以及和OAD联用、果糖胺低于2.5 mmol/L、白细胞升高、肾功能受损均和严重低血糖发生具有相关关系。结论:病程超过10年、胰岛素应用以及和OAD联用、白细胞升高、果糖胺低于2.5 mmol/L、肾功能受损均和严重低血糖发生有关,在行降糖治疗时应该谨慎评估上述危险因素。     

Clinical Use of Liraglutide in Type 2 Diabetes and its Effects on Cardiovascular Risk Factors

ObjectiveTo assess whether liraglutide, a glucagonlike peptide-1 receptor agonist, has cardioprotective properties in addition to its glycemic effects.MethodsWe performed a retrospective analysis of medical records of 110 obese patients with type 2 diabetes mellitus treated with liraglutide for at least 6 months between March 2010 and April 2011 at our tertiary care referral center. The variables analyzed were body mass index, hemoglobin A_1c (A1C), systolic blood pressure (SBP), plasma C-reactive protein (CRP) concentrations, and serum lipids.ResultsIn our overall study cohort, we noted a reduction in mean weight from 120 ± 5 kg to 115 ± 3 kg and a decrease in mean A1C from 7.8% ± 0.6% to 7.2% ± 0.2%. The mean triglyceride concentration decreased from 173 ± 19 mg/dL to 151 ± 15 mg/dL, the mean SBP was reduced from 132 ± 6 mm Hg to 125 ± 4 mm Hg, and the mean CRP concentration declined from 4.7 ± 0.8 mg/L to 3.2 ± 0.4 mg/L after treatment with liraglutide for a minimal duration of 6 months and a mean duration of 7.5 months (for all the foregoing changes, P < .05).These variables decreased whether these patients were previously treated with orally administered hypoglycemic agents alone or in combination with insulin or exenatide.ConclusionOur findings in a clinical practice show that liraglutide is a potent antidiabetes drug, whether given in combination with orally administered agents or insulin or as a substitution for exenatide. It lowers body weight, A1C levels, SBP, and CRP and triglyceride concentrations. (Endocr Pract. 2012;18:140-145)