Correction: Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

[This corrects the article DOI: 10.1371/journal.pgen.1006379.].

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or ß-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes.

AIMS/HYPOTHESIS: Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. METHODS: In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. RESULTS: Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. CONCLUSIONS/INTERPRETATION: We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. ACCESS TO RESEARCH MATERIALS: Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).

Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multicohort Nontargeted Metabolomics Observational and Mendelian Randomization Study.

Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity and circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data were generated with nontargeted ultraperformance liquid chromatography coupled to time-of-flight mass spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N = 1,135), PIVUS (N = 970), and TwinGene (N = 2,059). We assessed associations of general adiposity measured as BMI and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We used MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N = 7,373), the CHARGE Consortium (N = 8,631), the Framingham Heart Study (N = 2,076), and the DIRECT Consortium (N = 3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (P value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid, and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The results of the replication effort provided support for a causal association of adiposity with reduced levels of arachidonic acid (P value = 0.03). Adiposity is associated with variation of large parts of the circulating metabolome; however, further investigation of causality is required in well-powered cohorts.

Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation.

We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.

Efficacy of screening for high blood pressure in dental health care.

BACKGROUND: There is consensus on the importance of early detection and treatment of high blood pressure. Dental care is one of few medical services to which a considerable proportion of the general population comes for regular check-ups. We tested the effects of blood pressure screening in dental care centres with subsequent work-up of subjects screening positive in primary health care (PHCC). METHODS: Altogether 1,149 subjects 40-65 years old or 20-39 years old with body mass index >25, and with no previously known hypertension, who came for a dental examination had their blood pressure measured with an Omron M4® automatic blood pressure reading device. Subjects with systolic blood pressure readings above 160 mmHg or diastolic above 90 mmHg were referred to their PHCC for a check up. Outcome data were obtained by scrutiny of PHCC and hospital patient records for hypertension diagnoses during the three years following screening. RESULTS: 237 (20.6%) subjects screened positive. Of these, 230 (97.1%) came to their PHCC within the 3-year follow-up period, as compared with 695 (76.2%) of those who screened negative (p < 0.0001). Of those who screened positive, 76 (32.1%) received a diagnosis of hypertension, as compared with 26 (2.9%) of those who screened negative. Sensitivity was 79.1%, specificity 84.8% and positive predictive value 30.1%. The number of subjects needed to screen to find one case of hypertension was 18. CONCLUSIONS: Co-operation between dental and primary care for blood pressure screening and work-up appears to be an effective way of detecting previously unknown hypertension.

Associations between short sleep duration and central obesity in women.

STUDY OBJECTIVES: The aim was to assess associations between sleep duration, sleep stages, and central obesity in women. DESIGN: Cross-sectional study. SETTING: City of Uppsala, Sweden. PARTICIPANTS: Population-based sample of 400 women (range 20-70 years). INTERVENTIONS: Full-night polysomnography and measurement of anthropometric variables. MEASUREMENTS AND RESULTS: Sleep duration was inversely related to both waist circumference and sagittal abdominal diameter. Sleep duration remained inversely related to waist circumference (adj. beta = -1.22 cm/h; P = 0.016) and sagittal abdominal diameter (adj. beta = -0.46 cm/h; P = 0.001) after adjusting for potential confounders. Duration of slow wave sleep (SWS, adj. beta = -0.058 cm/min; P = 0.025) and REM sleep (adj. beta = -0.062 cm/min; P = 0.002) were both inversely related to waist circumference afteradjustments. Moreover,duration of REM sleep was inversely related to sagittal abdominal diameter (adj. beta = -0.021 cm/min; P < 0.0001). These associations were stronger in young women (age < 50 years). CONCLUSION: An inverse relationship between short sleep duration and central obesity was found in women after adjusting for confounders. Loss of SWS and REM sleep may be important factors in the association between sleep loss and central obesity.

Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated metabolites were associated with prevalent T2D, notably lower urine levels of 3-hydroxyundecanoyl-carnitine. In participants without diabetes at baseline, LASSO regression in the training set selected six metabolites that improved prediction of T2D beyond established risk factors risk over up to 12 years' follow-up in the test sample, from C-statistic 0.866 to 0.892. Our results in one of the largest non-targeted urinary metabolomics study to date demonstrate the role of the urine metabolome in identifying at-risk persons for T2D and suggest urine 3-hydroxyundecanoyl-carnitine as a biomarker candidate.

Physical activity and quality of life in subjects with chronic disease: chronic obstructive pulmonary disease compared with rheumatoid arthritis and diabetes mellitus.

OBJECTIVE: Chronic diseases interfere with the life situation of the affected person in different ways. The aim was to compare the burden of disease in three chronic diseases - chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), diabetes mellitus (DM) - and in healthy subjects, with a particular interest in physical activity, quality of life, and psychological health. DESIGN: Cross-sectional, observational study. SETTING AND SUBJECTS: Postal survey questionnaire to a stratified, random population of 68 460 subjects aged 18-84 years in Sweden. The subjects included were 40-84 years old (n = 43 589) and data were analysed for COPD (n = 526), RA (n = 1120), DM (n = 2149) and healthy subjects (n = 6960). RESULT: Some 84% of subjects with COPD, 74% (RA), 72% (DM), and 60% in healthy subjects (p < 0.001, COPD versus RA, DM, and healthy subjects) had a physical activity level considered too low to maintain good health according to guidelines. Quality of life (EuroQol five-dimension questionnaire, EQ-5D) was lower in COPD and RA than in DM. Anxiety/depression was more common in subjects with COPD (53%) than in those with RA (48%) and DM (35%) (p < 0.001, COPD versus RA and DM), whereas mobility problems were more common in RA (55%) than COPD (48%) and DM (36%) (p < 0.001, RA versus COPD and DM). All differences between groups remained significant after adjusting for age, sex, and socioeconomic background factors. CONCLUSION: Subjects with chronic diseases had a low level of physical activity, most evident in subjects with COPD. COPD and RA had a higher negative impact on quality of life than DM. Our results indicate that increased attention regarding physical inactivity in subjects with chronic diseases is needed to minimize the burden of disease.

Health related quality of life and sense of coherence in Sudanese diabetic subjects with lower limb amputation.

Quality of life is an important outcome measure in diabetic patients with lower limb amputation (LLA). The aim of this study was to investigate the influence of lower limb amputation on health-related quality of life (HRQOL) in Sudanese diabetic subjects. Additionally the Sense of Coherence scale (SOC-13) and a symptom check list was used in subjects with LLA. A total of 60 (M/F; 40/20) diabetic subjects with LLA and 60 (M/F; 23/37) diabetic reference subjects without LLA, were studied. For both groups HRQOL was measured using The Medical Outcomes Study questionnaire (MOS). Subjects with LLA had significantly poorer HRQOL compared to the reference group in most HRQOL domains (p < 0.0001). Duration of diabetes had the greatest negative impact on HRQOL in both groups, those with LLA (p < 0.0001), and in those without LLA (p < 0.0001), although subjects who were amputated earlier had poorer HRQOL than recently amputated (p < 0.0001). Higher SOC scores were recorded in LLA patients who have greater ratings of positive feelings, family satisfaction and sleep in the HRQOL examination (p < 0.0001). In conclusion, Sudanese diabetic subjects with LLA have a poor quality of life. The triad of diabetes duration, symptoms and amputations, has turned to be important risk factor for poorer HRQOL. Functional and mobility status were suggested to be an important determinant of HRQOL among this population. As the Sudanese population has coherent social relationships, this poor performance of the diabetic subjects will certainly increase the burden on the whole family, in both integrity and economical status. Nevertheless, these deep-rooted social interrelations together with increasing diabetes awareness have substantially improved the family satisfaction among our patients.

Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation.

BACKGROUND: When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. METHODS: The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. RESULTS: Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 ± 5 days after the first transplant) between the 2 arms (1.33 ± 1.10 versus 1.56 ± 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. CONCLUSIONS: Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.

Serum adiponectin in elderly men does not correlate with fracture risk.

CONTEXT: Recent evidence suggests that adiponectin may play a role in bone metabolism, but studies of the correlation between serum adiponectin and bone mineral density (BMD) have given conflicting results, and the impact on fracture risk is unknown. OBJECTIVE: Our objective was to investigate the association between serum adiponectin levels and BMD and fracture risk. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURES: We used regression analyses to estimate the relationship between adiponectin and BMD in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort of 441 men and 457 women aged 70 yr. The association was thereafter analyzed in the Uppsala Longitudinal Study of Adult Men (ULSAM), in which adiponectin was analyzed at age 70 yr and BMD at 82 yr in 507 men. Fractures in the ULSAM were documented in 314 men during 15 yr follow-up. Cox regression analysis was used to determine the risk of fracture according to serum adiponectin levels. RESULTS: In multivariable analysis a negative association between adiponectin and BMD was found in both cohorts. When individuals in the highest quintile of adiponectin were compared with those in the lowest quintile, adjusted BMD was 9.7% lower at the lumbar spine, 7.1% lower at the proximal femur, and 5.2% lower for total body in the Prospective Investigation of the Vasculature in Uppsala Seniors (P < 0.001 for all three), and 8.1, 5.1, and 4.1% (P < 0.003 for all three), respectively, in the ULSAM. However, the hazard ratio for fracture per 1 sd of serum adiponectin was 0.99 (95% confidence interval 0.89-1.11). CONCLUSION: Although adiponectin was a negative determinant of BMD in two independent cohorts, it was not associated with fracture risk in men.

Plasma proteome changes in subjects with Type 2 diabetes mellitus with a low or high early insulin response.

Circulating proteins contribute to the pathogenesis of T2DM (Type 2 diabetes mellitus) in various ways. The aim of the present study was to investigate variations in plasma protein levels in subjects with T2DM and differences in beta-cell function, characterized by the EIR (early insulin response), and to compare these protein levels with those observed in individuals with NGT (normal glucose tolerance). Ten subjects with NGT+high EIR, ten with T2DM+high EIR, and ten with T2DM+low EIR were selected from the community-based ULSAM (Uppsala Longitudinal Study of Adult Men) cohort. Plasma protein profiling was performed using SELDI-TOF (surface-enhanced laser-desorption ionization-time-of-flight) MS. In total, nine plasma proteins differed between the three study groups (P<0.05, as determined by ANOVA). The levels of two forms of transthyretin, haemoglobin alpha-chain and haemoglobin beta-chain were decreased in plasma from subjects with T2DM compared with subjects with NGT, irrespective of the EIR of the subjects. Apolipoprotein H was decreased in plasma from individuals with T2DM+high EIR compared with subjects with NGT. Four additional unidentified plasma proteins also varied in different ways between the experimental groups. In conclusion, the proteins detected in the present study may be related to the development of beta-cell dysfunction.

C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy.

OBJECTIVE: C-peptide replacement in animals results in amelioration of diabetes-induced functional and structural abnormalities in peripheral nerves. The present study was undertaken to examine whether C-peptide administration to patients with type 1 diabetes and peripheral neuropathy improves sensory nerve function. RESEARCH DESIGN AND METHODS: This was an exploratory, double-blinded, randomized, and placebo-controlled study with three study groups that was carried out at five centers in Sweden. C-peptide was given as a replacement dose (1.5 mg/day, divided into four subcutaneous doses) or a dose three times higher (4.5 mg/day) during 6 months. Neurological examination and neurophysiological measurements were performed before and after 6 months of treatment with C-peptide or placebo. RESULTS: The age of the 139 patients who completed the protocol was 44.2 +/- 0.6 (mean +/- SE) years and their duration of diabetes was 30.6 +/- 0.8 years. Clinical neurological impairment (NIA) (score >7 points) of the lower extremities was present in 86% of the patients at baseline. Sensory nerve conduction velocity (SCV) was 2.6 +/- 0.08 SD below body height-corrected normal values at baseline and improved similarly within the two C-peptide groups (P < 0.007). The number of patients responding with a SCV peak potential improvement >1.0 m/s was greater in C-peptide-treated patients than in those receiving placebo (P < 0.03). In the least severely affected patients (SCV < 2.5 SD below normal at baseline, n = 70) SCV improved by 1.0 m/s (P < 0.014 vs. placebo). NIA score and vibration perception both improved within the C-peptide-treated groups (P < 0.011 and P < 0.002). A1C levels (7.6 +/- 0.1% at baseline) decreased slightly but similarly in C-peptide-and placebo-treated patients during the study. CONCLUSIONS: C-peptide treatment for 6 months improves sensory nerve function in early-stage type 1 diabetic neuropathy.

The Impact of Continuous Positive Airway Pressure on Circulating IGF-1 in Patients With Obstructive Sleep Apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a disease with metabolic and cardiovascular consequences and is associated with decreased serum concentrations of insulin-like growth factor-1 (IGF-1). The aim of this study was to investigate whether continuous positive airway pressure (CPAP) will increase serum IGF-1 concentration in patients with OSA. METHODS: Patients with moderate to severe OSA were recruited from a sleep clinic and serum IGF-1 was measured before initiation of CPAP and at follow-up after 4.8 ± 2.5 months. Patients adherent to CPAP treatment (usage ≥ 4 h/night) were compared with those considered to be nonadherent (usage < 4 h/night). RESULTS: Complete data were obtained from 69 patients (86% male, age 56 ± 12 years, respiratory event index 43 ± 21 events/h, Epworth Sleepiness Scale score 12 ± 5). In those adherent to CPAP (n = 42), there was an increase in serum IGF-1 concentration with 21.1 (95% confidence interval [CI]: 13.1 to 29.2) µg/L compared to 4.7 (95% CI: -4.1 to 13.5) µg/L in the nonadherent group (n = 27) (P = .0083). In a linear multivariate model adjusting for sex, age, body mass index, respiratory event index, and mean oxygen saturation during the night recording, the change in serum IGF-1 concentration was significantly associated with adherence to CPAP treatment (adjusted ß coefficient: 21.8, 95% CI: 10.2 to 33.4) and inversely associated with change in body mass index (adjusted ß coefficient: -7.1, 95% CI: -11.3 to -3.0) and change in hemoglobin A1c (adjusted ß coefficient: -1.8, 95% CI: -33 to -0.3). CONCLUSIONS: CPAP usage ≥ 4 h/night is associated with increased serum IGF-1 concentration in male patients with OSA.

Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance.

Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 ± 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10- and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10- or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.

Serum adiponectin is a predictor of coronary heart disease: a population-based 10-year follow-up study in elderly men.

CONTEXT: Cross-sectional and nested case-control studies indicate a relationship between adiponectin, obesity, and coronary heart disease (CHD). OBJECTIVE: Our objective was to investigate whether adiponectin could predict CHD in a population-based cohort of elderly men. DESIGN AND SETTING: From 1991-1995 a baseline investigation was carried out in 832 healthy men aged 70 yr in the Uppsala Longitudinal Study of Adult Men (ULSAM study). They were followed up to 10.4 yr using Swedish national registry data. The baseline investigation included anthropometry, blood pressure, smoking, serum lipids, a euglycemic insulin clamp, and fasting serum adiponectin. MAIN OUTCOME MEASURES: Main outcome measures were defined as death or first-time hospitalization for CHD (n = 116), recorded in the Cause of Death Registry or in the Hospital-Discharge Registry of the National Board of Health and Welfare, Sweden. Associations were analyzed using Cox's proportional hazards regression, presented as hazard ratios (HR) with 95% confidence intervals (CI) for 1 sd increase in the predictor variable. RESULTS: In a multivariable analysis including total cholesterol (HR, 1.24; CI, 1.02-1.50), high-density lipoprotein cholesterol (HR, 0.72; CI, 0.58-0.89), smoking (HR, 1.39; CI, 0.91-2.14), and systolic blood pressure (HR, 1.26; CI, 1.05-1.52), serum adiponectin was associated with lower risk for CHD (HR, 0.81; CI, 0.66-0.99). The association was independent of BMI and remained significant after adjustment for insulin sensitivity index. CONCLUSIONS: In this population-based cohort of healthy men, elevated serum levels of adiponectin were associated with a lower risk for CHD. Importantly, the association between adiponectin and CHD was independent of other well-known risk factors.

Snoring and daytime sleepiness as risk factors for hypertension and diabetes in women--a population-based study.

The aim of this study was to analyze whether snoring and excessive daytime sleepiness (EDS), the main symptoms of obstructive sleep apnea syndrome (OSAS), are associated with hypertension and diabetes in women. A random sample of 6779 women aged 20-99 years answered questionnaires on sleep disturbances, daytime symptoms and somatic diseases. The women were categorized into four groups: "no EDS or snoring" (reference group), "snoring but no EDS", "EDS but no snoring" and "snoring and EDS". Prevalences of hypertension and diabetes were lowest in the reference group (8.7% and 1.6%, respectively) and highest among women with both snoring and EDS (hypertension: 26.3%, diabetes: 5.8%). In a multivariate model adjusting for age, body mass index, smoking, physical activity and alcohol dependency, "snoring and EDS" was a risk factor for hypertension (adjusted OR 1.82 (95% CI 1.30-2.55)) while isolated snoring or EDS was not. "Snoring and EDS" was more closely related to hypertension among women aged <50 years (adj. OR 3.41 (1.78-6.54) vs. 1.50 (1.02-2.19), P=0.01). For diabetes, both "EDS but no snoring" and "snoring and EDS" were risk factors and the associations were most pronounced in women aged >50 years (adj. OR 2.33 (1.28-4.26) for "EDS but no snoring" and 2.00 (1.05-3.84) for "snoring and EDS"). We conclude that the combination of snoring and EDS is a risk factor for hypertension and diabetes in women. For hypertension, the risk is partly age dependent and, for diabetes, EDS without snoring is a risk factor of similar magnitude. These differences might indicate differences in pathophysiologic mechanisms underlying the association between sleep-disordered breathing and hypertension and diabetes respectively.