Short Sleep Duration Is Associated with Risk of Future Diabetes but Not Cardiovascular Disease: a Prospective Study and Meta-Analysis

Epidemiologic studies have observed association between short sleep duration and both cardiovascular disease (CVD) and type 2 diabetes, although these results may reflect confounding by pre-existing illness. This study aimed to determine whether short sleep duration predicts future CVD or type 2 diabetes after accounting for baseline health. Baseline data for 241,949 adults were collected through the 45 and Up Study, an Australian prospective cohort study, with health outcomes identified via electronic database linkage. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals. Compared to 7h sleep, <6h sleep was associated with incident CVD in participants reporting ill-health at baseline (HR=1·38 [95% CI: 1·12-1·70]), but not after excluding those with baseline illness and adjusting for baseline health status (1·03 [0·88-1·21]). In contrast, the risk of incident type 2 diabetes was significantly increased in those with <6h versus 7h sleep, even after excluding those with baseline illness and adjusting for baseline health (HR=1·29 [1·08-1·53], P=0.004). This suggests the association is valid and does not simply reflect confounding or reverse causation. Meta-analysis of ten prospective studies including 447,124 participants also confirmed an association between short sleep and incident diabetes (1·33 [1·20-1·48]). Obtaining less than 6 hours of sleep each night (compared to 7 hours) may increase type 2 diabetes risk by approximately 30%.     

HbA1c Alone Is a Poor Indicator of Cardiometabolic Risk in Middle-Aged Subjects with Pre-Diabetes but Is Suitable for Type 2 Diabetes Diagnosis: A Cross-Sectional Study

Objectives

Glycated haemoglobin A_1c (HbA_1c) measurement is recommended as an alternative to fasting plasma glucose (FPG) for the diagnosis of pre-diabetes and type 2 diabetes. However, evidence suggests discordance between HbA_1c and FPG. In this study we examine a range of metabolic risk features, pro-inflammatory cytokines, acute-phase response proteins, coagulation factors and white blood cell counts to determine which assay more accurately identifies individuals at increased cardiometabolic risk.

Materials and Methods

This was a cross-sectional study involving a random sample of 2,047 men and women aged 46-73 years. Binary and multinomial logistic regression were employed to examine risk feature associations with pre-diabetes [either HbA_1c levels 5.7-6.4% (39-46 mmol/mol) or impaired FPG levels 5.6-6.9 mmol/l] and type 2 diabetes [either HbA_1c levels >6.5% (>48 mmol/mol) or FPG levels >7.0 mmol/l]. Receiver operating characteristic curve analysis was used to evaluate the ability of HbA_1c to discriminate pre-diabetes and diabetes defined by FPG.

Results

Stronger associations with diabetes-related phenotypes were observed in pre-diabetic subjects diagnosed by FPG compared to those detected by HbA_1c. Individuals with type 2 diabetes exhibited cardiometabolic profiles that were broadly similar according to diagnosis by either assay. Pre-diabetic participants classified by both assays displayed a more pro-inflammatory, pro-atherogenic, hypertensive and insulin resistant profile. Odds ratios of having three or more metabolic syndrome features were also noticeably increased (OR: 4.0, 95% CI: 2.8-5.8) when compared to subjects diagnosed by either HbA_1c (OR: 1.4, 95% CI: 1.2-1.8) or FPG (OR: 3.0, 95% CI: 1.7-5.1) separately.

Conclusions

In middle-aged Caucasian-Europeans, HbA_1c alone is a poor indicator of cardiometabolic risk but is suitable for diagnosing diabetes. Combined use of HbA_1c and FPG may be of additional benefit for detecting individuals at highest odds of type 2 diabetes development.     

Osteocalcin Is Not Associated with the Risk of Type 2 Diabetes: Findings from the EPIC-NL Study

Objective

To investigate whether total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC) and percentage of uncarboxylated osteocalcin (%ucOC) are associated with the risk of type 2 diabetes.

Methods

This nested case control study included 1,635 participants, 833 incident diabetes cases and 802 non-diabetic control participants, aged 21–70 years from the EPIC-NL cohort. Baseline concentrations of tOC, ucOC and %ucOC were assessed. During 10 years of follow-up, diabetes cases were self-reported and verified against information from general practitioners or pharmacists. The association between the different forms of osteocalcin and diabetes risk was assessed with logistic regression adjusted for diabetes risk factors (waist circumference, age, sex, cohort, smoking status, family history of diabetes, hypertension, alcohol intake, physical activity and education) and dietary factors (total energy intake and energy adjusted intake of fat, fiber, protein and calcium).

Results

TOC concentration was not associated with diabetes risk, with an odds ratio (OR) of 0.97 (0.91–1.03) for each ng/ml increment after adjustment for diabetes risk factors and dietary factors. No association between ucOC and %ucOC and the risk of diabetes was observed either. In sex stratified analyses (P interaction = 0.07), higher %ucOC tended to be associated with an increased risk of type 2 diabetes in a multivariable model in women (OR 1.05 for each increment of 5% ucOC (1.00–1.11), P_trend = 0.08), but not in men (OR 0.96 for each increment of 5% ucOC (0.88–1.04)). When waist circumference was replaced by body mass index, none of the osteocalcin forms were associated with the risk of type 2 diabetes in the final model among both women and men.

Conclusions

Available evidence suggests that tOC, ucOC and %ucOC are each not associated with the risk of type 2 diabetes. However, more large-scale cohort studies are needed to clarify the presence of any association between the different forms of osteocalcin and the risk of type 2 diabetes.     

Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes

Accumulating evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with left ventricular diastolic dysfunction (LVDD) in nondiabetic individuals. To date, there are very limited data on this topic in patients with type 2 diabetes and it remains uncertain whether NAFLD is independently associated with the presence of LVDD in this patient population. We performed a liver ultrasonography and trans-thoracic echocardiography (with speckle-tracking strain analysis) in 222 (156 men and 66 women) consecutive type 2 diabetic outpatients with no previous history of ischemic heart disease, chronic heart failure, valvular diseases and known hepatic diseases. Binary logistic regression analysis was used to examine the association between NAFLD and the presence/severity of LVDD graded according to the current criteria of the American Society of Echocardiography, and to identify the variables that were independently associated with LVDD, which was included as the dependent variable. Patients with ultrasound-diagnosed NAFLD (n = 158; 71.2% of total) were more likely to be female, overweight/obese, and had longer diabetes duration, higher hemoglobin A1c and lower estimated glomerular filtration rate (eGFR) than those without NAFLD. Notably, they also had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without NAFLD (71% vs. 33%; P<0.001). Age, hypertension, smoking, medication use, E/A ratio, LV volumes and mass were comparable between the two groups of patients. NAFLD was associated with a three-fold increased odds of mild and/or moderate LVDD after adjusting for age, sex, body mass index, hypertension, diabetes duration, hemoglobin A1c, eGFR, LV mass index and ejection fraction (adjusted-odds ratio 3.08, 95%CI 1.5–6.4, P = 0.003). In conclusion, NAFLD is independently associated with early LVDD in type 2 diabetic patients with preserved systolic function.     

Lifestyle Factors Associated with Type 2 Diabetes and Use of Different Glucose-Lowering Drugs: Cross-Sectional Study

Aims

To examine the lifestyle profile among persons with and without Type 2 diabetes mellitus (DM) and among users of different glucose-lowering drugs.

Methods

We used questionnaire data from a Danish health survey and identified presence of Type 2 DM and use of medications through medical databases. We calculated age- and gender-standardized prevalence ratios (PRs) of lifestyle factors according to Type 2 DM and different glucose-lowering drugs.

Results

Of 21,637 survey participants aged 25–79 years, 680 (3%) had Type 2 DM (median age 63 years) with a median diabetes duration of 5 years. Participants with Type 2 DM had a substantially higher prevalence of obesity (36% vs. 13%, PR: 3.1, 95% confidence interval (CI): 2.8–3.6), yet more reported to eat a very healthy diet (25% vs. 21%, PR: 1.2, 95% CI: 1.0–1.4) and to exercise regularly (67% vs. 53%, PR: 1.3, 95% CI: 1.2–1.4). Also, fewer were current smokers or had high alcohol intake. When compared with metformin users, obesity was substantially less prevalent in users of sulfonylurea (PR: 0.5, 95% CI: 0.4–0-8), and insulin and analogues (PR: 0.4, 95% CI: 0.3–0.7). Tobacco smoking was more prevalent in sulfonylurea users (PR: 1.4, 95% CI: 0.9–2.1) compared with metformin users. We found no material differences in physical exercise, diet or alcohol intake according to type of glucose-lowering drug.

Conclusions

Type 2 DM patients are substantially more obese than other individuals, but otherwise report to have a healthier lifestyle. Metformin use is strongly associated with obesity, whereas sulfonylurea use tends to be associated with tobacco smoking.     

2型糖尿病患者血脂水平与心脑血管并发症的相关性分析

目的：探讨2型糖尿病患者血脂水平与其心脑血管并发症的相关性。方法：选择中国医科大学附属盛京医院2011年3月～2012年5月就诊的2型糖尿病患者236例和同期200例健康体检者为研究对象,检测和比较其空腹血糖（FBG）、胆固醇（CH）、甘油三酯（11G）、高密度脂蛋白（HDL）和低密度脂蛋白（LDL）水平。结果：2型糖尿病组患者FBG、血清CH、TG、LDL的含量与对照组比较均显著升高（P〈0．01）,而HDL的含量较对照组显著降低（P〈0．01）;在2型糖尿病组中,有心脑血管并发症的患者血清CH、TG、LDL的含量显著高于无并发症者（P〈0．01）;而血清HDL含量显著低于无并发症者（P〈0．01）。相关性分析结果显示,2型糖尿病患者CH、TG和LDL的含量与其合并心脑血管并发症均存在正相关（r=0．337,P〈0．05;r==0．514,P〈0．05;r=0．438,P〈0．05）,而HDL的含量与其合并心脑血管并发症存在显著负相关（r=-0．237,P〈0．05）。结论：2型糖尿病患者存在显著的糖脂代谢紊乱,且血脂水平与心脑血管并发症的发生密切相关,检测并控制2型糖尿病患者的血脂水平有助于预防其心脑血管病变的发生。     

Target Values of Cardiovascular Risk Factors Are Not Associated with All-Cause Mortality in Patients with Type 2 Diabetes Mellitus

Background

To investigate prospectively the relationship between target values of glycated hemoglobin, blood pressure and LDL-cholesterol, as considered in a combined fashion, and all-cause mortality in patients with type 2 diabetes mellitus.

Methods

Two cohorts of patients with type 2 diabetes mellitus, the Gargano Mortality Study (n=810) and the Foggia Mortality Study (n=929), were investigated. A weighted target risk score was built as a weight linear combination of the recommended targets reached by each patient.

Results

In the Gargano Mortality Study and in the Foggia Mortality Study (mean follow up=7.4 and 5.5 years, respectively), 161 (19.9%) and 220 (23.7%) patients died, with an age and sex adjusted annual incidence rate of 2.1 and 2.8 per 100 person-years, respectively. In both study samples the weighted target risk score tended to be linearly associated with all-cause mortality (HR for one point increment=1.30, 95% CI: 1.11-1.53, p=0.001, and HR=1.08, 95% CI: 0.95-1.24, p=0.243, respectively). When the two cohorts were pooled and analyzed together, a clear association between weighted target risk score and all-cause mortality was observed (HR for one point increment=1.17, 95% CI:1.05-1.30, p=0.004). This counterintuitive association was no longer observable in a model including age, sex, body mass index, smoking habit, estimated glomerular filtration rate, albuminuria and anti-diabetic, anti-hypertensive and anti-dyslipidemic treatment as covariates (HR for one point increment=0.99, 95% CI: 0.87-1.12, p=0.852).

Conclusions

In a real life clinical set of patients with type 2 diabetes mellitus, the combination of recommended target values of established cardiovascular risk factors is not associated with all-cause mortality.     

Plasma HMGB-1 Levels in Subjects with Obesity and Type 2 Diabetes: A Cross-Sectional Study in China

Object

To detect the levels of plasma High-Mobility Group Box-1(HMGB1) in Chinese subject with obesity and type 2 diabetes mellitus (T2DM), and to investigate the correlations between plasma HMGB1 concentration and parameters of body fat, insulin resistance (IR) metabolism and inflammation.

Methods

This study recruited 79 normal glucose tolerance (NGT) subjects and 76 newly diagnosed T2DM patients. NGT and T2DM groups were divided into normal weight (NW) and obese (OB)subgroups respectively. Anthropometric parameters such as height, weight, waist circumference, hip circumference and blood pressure were measured. Plasma concentrations of HMGB1, IL-6, fasting plasma glucose (FPG), 2 hours post challenge plasma glucose (2hPG), serum lipid, glycated hemoglobin (HbA_1C) and fasting insulin (FINS) were examined. The homeostasis model assessment (HOMA) was performed to assess IR status.

Results

Plasma HMGB1 levels were higher in T2DM group than that in NGT group. The concentrations of serum HMGB1 were also higher in subjects with OB than those in subjects with NW both in NGT and T2DM groups. Plasma levels of HMGB1 were positively correlated with waist hip ratio (WHR), blood pressure, FPG, FINS, HOMA-IR, TG, IL-6 and negatively correlated with HOMA-βand high-density lipoprotein-cholesterol (HDL-c) independent of age, gender and BMI. Plasma levels of HMGB1 were significantly correlated with diabetes in fully adjusted models.

Conclusion

Plasma HMGB1 levels were increased in Chinese subjects with pure T2DM, which might be caused by IR. Serum HMGB1 participated in the pathological process of obesity and T2DM via its proinflammatory effect.     

Rs4074134 Near BDNF Gene Is Associated with Type 2 Diabetes Mellitus in Chinese Han Population Independently of Body Mass Index

Obesity and family history are the most important predictors for type 2 diabetes mellitus(T2DM) in the Chinese Han population. However, it is not known whether the genetic loci related to obesity are associated with the risk of developing T2DM in this population. The present case-control study evaluated the associations between five genetic loci for obesity and the pathogenesis of T2DM. The study included 1117 Chinese Han patients with T2DM, 1629 patients with pre-diabetes (impaired fasting glucose and impaired glucose tolerance, IFG/IGT) and 1113 control subjects residing in Beijing. Five genetic loci including rs2815752 near NEGR1, rs10938397 near GNPDA2, rs4074134 near BDNF, rs17782313 near MC4R and rs1084753 near KCTD15 were genotyped. The results showed an association between rs4074134-BDNF minor allele and T2DM irrespective of age, gender and body mass index (BMI) (OR = 0.87; 95%CI: 0.77–0.99, P = 0.04). This SNP was also associated with pre-diabetes (OR = 0.87; 95%CI: 0.77–0.97, P = 0.01) independently of age, gender and BMI. No associations were found between diabetes or pre-diabetes and any of the other SNP loci studied. Genotype–phenotype association analysis (adjusting for age and gender) showed rs4074134-BDNF to be associated with BMI, waist circumference, fasting and postprandial plasma glucose, fasting serum insulin, and HOMA-IR in subjects without T2DM. However, fasting and postprandial plasma glucose were the only significant factors after adjusting for BMI. These results suggest that the common variation of BDNF (rs4074134) is associated with T2DM independently of obesity in Chinese Han population. This variant also has an effect on plasma glucose concentration, BMI and insulin sensitivity.     

The 9p21 Locus Is Associated with Coronary Artery Disease and Cardiovascular Events in the Presence (but Not in the Absence) of Coronary Calcification

Variants at the 9p21 locus have been associated with coronary artery disease (CAD); coronary artery calcification (CAC) is related to CAD and other cardiovascular events. To determine the association of the 9p21 locus with CAD in the presence and absence of CAC, 4 groups were enrolled in a case-control study, including 527 CAD patients without CAC, 692 CAD patients with CAC, 585 individuals with simple CAC but no CAD, and 725 healthy controls. The rs1333049 representing the locus was associated with CAD in the presence of CAC (odds ratio = 1.38 in allelic analysis, 95%CI, 1.19–1.60, P<0.001), but not in the absence of CAC. Additionally, rs1333049 was not associated with simple CAC or CAC severity/extent in CAD patients with CAC. 849 CAD patients undergoing revascularization (660 with CAC and 189 without CAC) were enrolled in a cohort study to test its association with cardiovascular events in CAD patients with and without CAC in a 3-year follow-up. rs1333049 was significantly associated with the incidence of cardiovascular events in non-target vessels in patients with CAC (hazard ratio = 1.44, 95%CI, 1.08–1.91, P = 0.012), but not in those without CAC. The variants at the 9p21 locus were related to CAD and post-revascularization events only in the presence of CAC, suggesting that they may confer risk of calcification-related coronary atherosclerosis.     

Proximal Tubule Dysfunction Is Associated with Podocyte Damage Biomarkers Nephrin and Vascular Endothelial Growth Factor in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study

Background

There is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor.

Materials and Methods

Two groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried.

Results

Urinary alpha₁-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R² = 0.269; p<0.001; R² = 0.125; p<0.001), nephrinuria (R² = 0.529; p<0.001; R² = 0.203; p<0.001), urinary vascular endothelial growth factor (R² = 0.709; p<0.001; R² = 0.360; p<0.001), urinary advanced glycation end-products (R² = 0.578; p<0.001; R² = 0.405; p<0.001), serum cystatin C (R² = 0.130; p<0.001; R² = 0.128; p<0.001), and glomerular filtration rate (R² = 0.167; p<0.001; R² = 0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R² = 0.498; p<0.001; R² = 0.227; p<0.001), urinary advanced glycation end-products (R² = 0.251; p<0.001; R² = 0.308; p<0.001), serum cystatin C (R² = 0.157; p<0.001; R² = 0.226; p<0.001), and glomerular filtration rate (R² = 0.087; p = 0.007; R² = 0.218; p<0.001).

Conclusions

In Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.     

Variant rs2237892 of KCNQ1 Is Potentially Associated with Hypertension and Macrovascular Complications in Type 2 Diabetes Mellitus in A Chinese Han Population

KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus(T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2 DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism(SNP) rs2237892 within KCNQ1 and TD2 M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM(odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75). Genotypes CT(OR, 1.97; 95% CI,1.24–3.15) and CC(OR, 2.49; 95% CI, 1.57–3.95) were associated with an increased risk of T2 DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure(P = 0.015), prevalence of hypertension(P = 0.037), and risk of macrovascular disease(OR, 2.10; CI, 1.00–4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or     

Manganese Superoxide Dismutase (SOD2) Polymorphisms,Plasma Advanced Oxidation Protein Products (AOPP) Concentration and Risk of Kidney Complications in Subjects with Type 1 Diabetes

Aims

Oxidative stress is involved in the pathophysiology of diabetic nephropathy. Manganese superoxide dismutase (SOD2) catalyses the dismutation of superoxide, regulates the metabolism of reactive oxygen species in the mitochondria and is highly expressed in the kidney. Plasma concentration of advanced oxidation protein products (AOPP), a marker of oxidative stress, was found to be increased in patients with kidney disease. We investigated associations of SOD2 allelic variations, plasma SOD activity and AOPP concentration with diabetic nephropathy in type 1 diabetic subjects.

Methods

Eight SNPs in the SOD2 region were analysed in 1285 Caucasian subjects with type 1 diabetes from the SURGENE prospective study (n = 340; 10-year follow-up), GENESIS (n = 501) and GENEDIAB (n = 444) cross-sectional studies. Baseline plasma concentration of AOPP and SOD activity were measured in GENEDIAB participants. Hazard ratio (HR) and odds ratio (OR) were determined for incidence and prevalence of nephropathy. Analyses were adjusted or stratified by retinopathy stages.

Results

In the SURGENE cohort, the T-allele of rs4880 (V16A) was associated with the incidence of renal events (new cases, or the progression to a more severe stage of nephropathy; HR 1.99, 95% CI 1.24–3.12, p = 0.004) and with the decline in estimated glomerular filtration rate (eGFR) during follow-up. Similar associations were observed for rs2758329 and rs8031. Associations were replicated in GENESIS/GENEDIAB cohorts, in the subset of participants without proliferative retinopathy, and were confirmed by haplotype analyses. Risk allele and haplotype were also associated with higher plasma AOPP concentration and lower SOD activity.

Conclusions

SOD2 allelic variations were associated with the incidence and the progression of diabetic nephropathy, with a faster decline in eGFR and with plasma AOPP concentration and SOD activity in subjects with type 1 diabetes. These results are consistent with a role for SOD2 in the protection against oxidative stress and kidney disease in type 1 diabetes.     

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

Background

While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes.

Objective

To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors.

Design

Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006).

Setting

Twenty-two outpatient diabetes clinics across Italy.

Patients

Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303).

Interventions

Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume.

Main Outcome Measure(s)

Hemoglobin (Hb) A_1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores.

Results

Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA_1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects.

Conclusions

Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors.

Trial Registration

www.ISRCTN.org ISRCTN-04252749.     

Associations of Circulating Lymphocyte Subpopulations with Type 2 Diabetes: Cross-Sectional Results from the Multi-Ethnic Study of Atherosclerosis (MESA)

ObjectiveDistinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies.MethodsCirculating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4⁺ naive, CD4⁺ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models.ResultsEach standard deviation (SD) higher CD4⁺ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1–47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4–36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4⁺ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin.ConclusionsA higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4⁺ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.     

Relationship of Dickkopf1 (DKK1) with Cardiovascular Disease and Bone Metabolism in Caucasian Type 2 Diabetes Mellitus

ObjectivesDickkopf-1 (DKK1) is a potent inhibitor of Wnt signalling, which exerts anabolic effects on bone and also takes part in the regulation of vascular cells. Our aims were to evaluate serum DKK1 in type 2 diabetes (T2DM) patients and to analyze its relationships with cardiovascular disease (CVD). We also evaluated the relationship between DKK1 and bone metabolism.DesignWe conducted a cross-sectional study in which we measured serum DKK1 (ELISA, Biomedica) in 126 subjects: 72 patients with T2DM and 54 non-diabetic subjects. We analysed its relationship with clinical CVD, preclinical CVD expressed as carotid intima media thickness (IMT), and bone metabolism.ResultsT2DM patients with CVD (P = 0,026) and abnormal carotid IMT (P = 0,038) had higher DKK1 concentrations. DKK1 was related to the presence of CVD in T2DM, independently of the presence of risk factors for atherosclerosis. Therefore, for each increase of 28 pg/ml of serum DKK1 there was a 6,2% increase in the risk of CVD in T2DM patients. The ROC curve analysis to evaluate the usefulness of DKK1 as a marker for high risk of CVD showed an area under the curve of 0,667 (95% CI: 0,538–0,795; P = 0,016). In addition, there was a positive correlation between serum DKK1 and spine bone mineral density in the total sample (r = 0,183; P = 0,048).ConclusionIn summary, circulating DKK1 levels are higher in T2DM with CVD and are associated with an abnormal carotid IMT in this cross-sectional study. DKK1 may be involved in vascular disease of T2DM patients.     

Effects of Clopidogrel and Proton Pump Inhibitors on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus after Drug-Eluting Stent Implantation: A Nationwide Cohort Study

Objective

To investigate whether there is an increased risk of cardiac events in diabetic patients with a combined therapy of clopidogrel (CLO) and proton pump inhibitors (PPIs) after drug-eluting stent (DES) deployment.

Methods

By using National Health Insurance Research Database, all patients who received CLO with or without PPI therapy within 90 days after undergoing DES (limus-eluting or paclitaxel-eluting stents) deployment were enrolled. Endpoints were acute coronary syndrome (ACS) and readmission for revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) after 3, 6, and 12 months.

Results

A total of 6,603 diabetic patients received LESs (5,933 in the CLO subgroup and 670 in the CLO plus PPIs subgroup), and 3,202 patients received PESs (2,923 in the CLO subgroup and 279 in the CLO plus PPIs subgroup). The patients who received CLO plus PPIs were at higher risk of ACS than those receiving CLO within 1 year after DES deployment (LESs: 6-month hazard ratio [HR] = 1.63, and 1-year HR = 1.37; PESs: 3-month HR = 1.72). Patients with a history of ACS who received CLO plus PPIs were at higher risk of ACS after LES implantation (HR = 1.55) than those in the CLO group.

Conclusion

In “real-world” diabetic patients with LES deployment, the combination of PPIs and CLO is associated with higher rates of ACS after 6 months and 1 year. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of cardiac events, emphasizing the clinical importance of this drug—drug interaction.     

Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response,but Not Immune Measures,Commonly Associated with Asthma

Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta) and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean = 1.25 years, n = 24 behaviorally inhibited animals), we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ) in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+). Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p = 0.031), confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within lung tissue that is not specifically associated with behavioral inhibition) may trigger the airways response.     

Regular Breakfast Consumption and Type 2 Diabetes Risk Markers in 9- to 10-Year-Old Children in the Child Heart and Health Study in England (CHASE): A Cross-Sectional Analysis

Background

Regular breakfast consumption may protect against type 2 diabetes risk in adults but little is known about its influence on type 2 diabetes risk markers in children. We investigated the associations between breakfast consumption (frequency and content) and risk markers for type 2 diabetes (particularly insulin resistance and glycaemia) and cardiovascular disease in children.

Methods and Findings

We conducted a cross-sectional study of 4,116 UK primary school children aged 9–10 years. Participants provided information on breakfast frequency, had measurements of body composition, and gave fasting blood samples for measurements of blood lipids, insulin, glucose, and glycated haemoglobin (HbA1c). A subgroup of 2,004 children also completed a 24-hour dietary recall. Among 4,116 children studied, 3,056 (74%) ate breakfast daily, 450 (11%) most days, 372 (9%) some days, and 238 (6%) not usually. Graded associations between breakfast frequency and risk markers were observed; children who reported not usually having breakfast had higher fasting insulin (percent difference 26.4%, 95% CI 16.6%–37.0%), insulin resistance (percent difference 26.7%, 95% CI 17.0%–37.2%), HbA1c (percent difference 1.2%, 95% CI 0.4%–2.0%), glucose (percent difference 1.0%, 95% CI 0.0%–2.0%), and urate (percent difference 6%, 95% CI 3%–10%) than those who reported having breakfast daily; these differences were little affected by adjustment for adiposity, socioeconomic status, and physical activity levels. When the higher levels of triglyceride, systolic blood pressure, and C-reactive protein for those who usually did not eat breakfast relative to those who ate breakfast daily were adjusted for adiposity, the differences were no longer significant. Children eating a high fibre cereal breakfast had lower insulin resistance than those eating other breakfast types (p for heterogeneity <0.01). Differences in nutrient intakes between breakfast frequency groups did not account for the differences in type 2 diabetes markers.

Conclusions

Children who ate breakfast daily, particularly a high fibre cereal breakfast, had a more favourable type 2 diabetes risk profile. Trials are needed to quantify the protective effect of breakfast on emerging type 2 diabetes risk. Please see later in the article for the Editors'' Summary