IGFBP1 increases ß-cell regeneration by promoting α- to ß-cell transdifferentiation.

There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of ß cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during ß-cell regeneration. We then tested the proteins' ability to potentiate ß-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted ß-cell regeneration by potentiating α- to ß-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of ß-cell regeneration and highlight its clinical importance in diabetes.

Effects of acute fructose loading on levels of serum uric acid-a pilot study.

BACKGROUND: Fructose intake may lead to hyperuricaemia, which is associated with increased risk and progression of kidney disease. We aimed to explore the acute effects of fructose loading from different sources, with and without a pizza, on levels of serum uric acid in patients with chronic kidney disease (CKD), type 2 diabetes (T2D) without CKD, and in healthy subjects (HS). METHODS: The study included six HS, and three CKD stage 4-5 and seven T2D patients. Drinks consumed were blueberry drink (17.5 g fructose), Coca-Cola (18 g fructose) and fructose drink (35 g fructose). The drinks were also combined with pizza, in total six interventions. Serum samples were collected fasting and 30, 60, 90 and 120 minutes after intake and also 240 minutes after drink + pizza, and analysed for fructose, uric acid and triglycerides. Postprandial responses were explored using repeated-measure ANOVA. RESULTS: Baseline serum uric acid levels were increased in CKD (P = 0.037). There were significant differences in serum fructose and serum uric levels over time between drinks and drinks + pizza for all groups (P < 0.001 and P < 0.05, respectively). The highest peak in serum fructose followed the fructose drink interventions and the lowest the blueberry drink. The fructose drink interventions gave the highest responses in serum uric acid and the lowest responses followed the blueberry drink. Triglycerides increased following pizza interventions (P < 0.001). CONCLUSIONS: Intake of fructose increases serum uric acid. The fructose intake via a blueberry drink induced lowest increase and thus may be protective.

Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE).

Aims: We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results: We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion: Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.

Exposure to traffic noise and markers of obesity.

OBJECTIVES: Limited evidence suggests adverse effects of traffic noise exposure on the metabolic system. This study investigates the association between road traffic noise and obesity markers as well as the role of combined exposure to multiple sources of traffic noise. METHODS: In a cross-sectional study performed in 2002-2006, we assessed exposure to noise from road traffic, railways and aircraft at the residences of 5075 Swedish men and women, primarily from suburban and semirural areas of Stockholm County. A detailed questionnaire and medical examination provided information on markers of obesity and potential confounders. Multiple linear and logistic regression models were used to assess associations between traffic noise and body mass index (BMI), waist circumference and waist-hip ratio using WHO definitions of obesity. RESULTS: Road traffic noise was significantly related to waist circumference with a 0.21 cm (95% CI 0.01 to 0.41) increase per 5 dB(A) rise in L(den). The OR for central obesity among those exposed to road traffic noise ≥ 45 dB(A) was 1.18 (95% CI 1.03 to 1.34) in comparison to those exposed below this level. Similar results were seen for waist-hip ratio (OR 1.29; 95% CI 1.14 to 1.45) but not for BMI (OR 0.89; 95% CI 0.76 to 1.04). Central obesity was also associated with exposure to railway and aircraft noise, and a particularly high risk was seen for combined exposure to all three sources of traffic noise (OR 1.95; 95% CI 1.24 to 3.05). CONCLUSIONS: Our results suggest that traffic noise exposure can increase the risk of central obesity. Combined exposure to different sources of traffic noise may convey a particularly high risk.

Psychotic disorder is an independent risk factor for increased fasting glucose and waist circumference.

BACKGROUND: Psychosis is associated with excess cardiovascular morbidity and mortality. AIMS: To determine the prevalence of cardiovascular risk factors in patients with psychotic disorders compared with the population. METHODS: 731 consecutive patients with psychosis recruited from psychiatric outpatient clinics in Stockholm County, Sweden, were compared with 5580 individuals from a population study performed in the same area. The main outcome measures were waist circumference, body mass index (BMI) and fasting glucose. RESULTS: Mean waist circumference in patients vs. controls was for males 106 and 94 cm, respectively, and for females 97 and 85 cm, respectively (P < 0.001); mean fasting glucose in patients vs. controls was for males 5.8 and 5.2 mmol/l, respectively, and for females 5.6 and 4.8 mmol/l, respectively (P < 0.001). Comparisons were controlled for differences in age and family history of diabetes. Increased waist circumference was more common in psychotic patients compared with controls (OR = 3.99; 95% CI 3.09-5.15), controlling for fasting insulin, differences in gender, blood pressure, fasting glucose, family history of diabetes, age and tobacco use. Increased fasting blood glucose was also more common in psychotic patients (OR = 2.41; 95% CI 1.84-3.14) controlling for the same factors with the exception of fasting glucose and with the addition of increased waist circumference. CONCLUSION: Our study shows that the psychosis illness per se can be considered as a cardiovascular risk factor, independent of the traditional risk factors such as age and smoking.

The influence of non-response in a population-based cohort study on type 2 diabetes evaluated by the Swedish Prescribed Drug Register.

Bias due to non-response in observational studies may lead to false risk estimates. We evaluated potential selective non-response in Stockholm Diabetes Prevention Program (SDPP) using a population-based drug register. A cohort of 12,952 men and 19,416 women, aged 35-56 years, was screened for diabetes and family history of diabetes (FHD). Response rate: 79% in men and 85% in women. Of the 4,209 men and 6,916 women that were invited, 70 and 68% participated in a baseline health examination including oral glucose tolerance test. A follow-up was performed in 79% of male and 70% of female baseline participants. We used data from the prescription register to estimate absolute risks and ORs for drug-treated diabetes in the non-response/non-participation groups. At both screening and baseline steps absolute risks of drug-treated diabetes were equal in non-participants and participants. Adjusted ORs were 0.9-1.0. At follow-up, absolute risks were higher among non-participants than participants, men 6.2/4.4% and women 2.6/1.6%, adjusted ORs 1.4 (0.9-2.3) and 1.5 (0.9-2.4), suggesting selective non-participation. Further analyses of FHD, smoking, physical activity, socioeconomic position and psychological distress demonstrated no previous false risk estimates for type 2 diabetes. However, for body mass index, there were indications of overestimation in women. We conclude that bias from non-response was not present at screening or baseline steps, suggesting that diabetes prevalence and risks may be estimated from a population-based cohort study with high attendance rate such as the SDPP. However, follow-up data should be treated with some caution, since the sample may have become biased.

High consumption of smokeless tobacco ("snus") predicts increased risk of type 2 diabetes in a 10-year prospective study of middle-aged Swedish men.

AIMS: Cigarette smoking increases the risk of type 2 diabetes (T2D). In Sweden and the US, people shift from smoking cigarettes to smokeless tobacco, i.e. oral moist snuff, "snus", to attain harm-reduction. There are limited and conflicting data as to whether snus increases the risk of T2D. The present study investigated if snus use predicts the risk of T2D incidence. METHODS: This is a prospective population-based study where middle-aged Swedish men (n=2,383), without previously diagnosed T2D, were investigated with oral glucose tolerance test (OGTT) at baseline in 1992-94 and at follow-up 10 years later. Odds ratios (ORs) for newly diagnosed T2D at follow-up were assessed among those using snus, or cigarettes, at both baseline and follow-up, adjusted for major confounders. RESULTS: The OR for T2D was not significantly increased in the whole group of snus users. However, the risk of diabetes increased with increasing weekly snus consumption; ORs (CIs) for >four boxes of snus/week were 2.1 (CI 0.9-4.9), and for >five boxes/week 3.3 (CI 1.4-8.1). For comparison, men smoking at baseline and still smoking at follow-up had an increased risk of diabetes compared with never smokers, OR 1.5 (CI 0.8-3.0), most evident for those smoking >15 cigarettes per day, OR 2.4 (CI 1.0-5.8). Tobacco use was associated with estimations of low insulin response (OGTT), but not low insulin sensitivity (HOMA). CONCLUSIONS: High consumption of snus, like smoking, predicts risk of developing T2D. This should be considered when seeking harm-reduction by changing from use of cigarettes to snus. T2D risk from tobacco use may be mediated by effects on beta-cell function.

Adiponectin, IGFBP-1 and -2 are independent predictors in forecasting prediabetes and type 2 diabetes.

Objective: Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT). Design: Subjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men). Methods: The evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test. Results: After adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone. Conclusion: Differences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.

Aircraft noise and incidence of hypertension--gender specific effects.

Recent studies show associations between aircraft noise and cardiovascular outcomes such as hypertension. However, these studies were mostly cross-sectional and there are uncertainties regarding potential gender differences as well as sensitive subgroups. In this study, we investigated the cumulative incidence of hypertension in relation to aircraft noise exposure among Swedish men and women living in Stockholm County. A total of 4721 subjects, aged 35-56 at baseline, were followed for 8-10 years. The population was selected according to family history of diabetes, which was present for half of the subjects. The exposure assessment was performed by geographical information systems and based on residential history during the period of follow-up. Blood pressure was measured at baseline and at the end of follow-up. Additional information regarding diagnosis and treatment of hypertension as well as various lifestyle factors was provided by questionnaires. In the overall population, no increased risk for hypertension was found among subjects exposed to aircraft noise ≥ 50 dB(A) L(den); relative risk (RR) 1.02 (95% CI 0.90-1.15). When restricting the cohort to those not using tobacco at the blood pressure measurements, a significant risk increase per 5 dB(A) of aircraft noise exposure was found in men; RR 1.21 (1.05-1.39), but not in women; RR 0.97 (0.83-1.13). In both sexes combined, an increased risk of hypertension related to aircraft noise exposure was indicated primarily among those reporting annoyance to aircraft noise; RR 1.42 (1.11-1.82). No consistent effect modification was detected for any of the cardiovascular risk factors under investigation although a family history of diabetes appeared to modify the risk in women. In conclusion, the results suggest an increased risk of hypertension following long-term aircraft noise exposure in men, and that subjects annoyed by aircraft noise may be particularly sensitive to noise related hypertension.

A cost-effectiveness analysis of a community-based diabetes prevention program in Sweden.

OBJECTIVES: Lifestyle changes to prevent type 2 diabetes among high-risk persons have been shown to be cost-effective. This study investigates the cost-effectiveness of a community-based program promoting general population lifestyle changes to prevent diabetes. METHODS: The 10-year program was implemented in three municipalities in Sweden. Effectiveness was measured with a quasiexperimental cohort design, that is, risk factor levels in a population group aged 36-56 years at baseline and 8-10 years later (2,149 men; 3,092 women) in the program municipalities and a control area were compared. The incremental cost-utility analysis included future diabetes and cardiovascular disease-related health effects and societal costs (discounted 3 percent), estimated by a Markov model. RESULTS: In all areas, risk factor levels increased during follow-up, leading to increased societal costs of between SEK40,000 and 90,000 (1 Euro 2004 = SEK9.13; 1 US$ = SEK 7.35) and quality-adjusted life-year (QALY) losses between 0.12 and 0.48 per individual. Compared with the control area, the cost increases and QALY losses for women were more favorable in two program areas but less favorable in one, and less favorable for men in both areas (data unavailable for one municipality). The findings indicate that the program was cost-effective in only two female study groups. CONCLUSIONS: Conflicting results on the cost-effectiveness of the program were obtained. As several potentially valuable aspects of the program are not included in the cost-effectiveness analysis, the societal value of the program might not be adequately reflected.

Genetic variants of increased waist circumference in psychosis.

OBJECTIVE: We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference. PATIENTS AND METHODS: We analyzed the association in (i) a case-case model in which patients with schizophrenia spectrum disorder with increased waist circumference (≥80 cm for women and ≥94 cm for men) (n=534) were compared with patients with normal waist circumference (<80 cm for women; <94 cm for men) (n=124), and in (ii) a case-control model in which schizophrenia spectrum disorder patients with increased waist circumference or irrespective of waist circumference were compared with population-derived controls (n=494) adjusted for age, sex, fasting glucose, smoking, and family history of diabetes. RESULTS: Genetic variants in five genes (MIA3, MRAS, P2RX7, CAMKK2, and SMAD3) were associated with increased waist circumference in patients with schizophrenia spectrum disorder (P<0.046). Genetic variants in three other genes (PPARD, MNTR1B, and NOTCH2) were associated with increased waist circumference in patients when compared with control individuals (P<0.037). Genetic variants in the PPARD, MNTR1B, NOTCH2, and HNF1B were nominally associated with schizophrenia spectrum disorder irrespective of waist circumference (P<0.027). No differences in waist circumference between specific psychosis diagnoses were detected. CONCLUSION: Increased waist circumference in patients with schizophrenia spectrum disorder may be explained, in part, by increased metabolic risk gene burden, and it indicates a shared genetic susceptibility to metabolic disorder and psychosis per se. Along these lines, common metabolic risk genetic variants confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders.

Melatonin receptor 1B gene associated with hyperglycemia in bipolar disorder.

Bipolar patients are at a higher risk of developing metabolic disorders. Cardiovascular morbidity and mortality is twice the rate reported in the population. Antipsychotic medication increases the risk of metabolic abnormalities. However, bipolar disorder and schizophrenia have a similarly increased mortality from cardiovascular causes of death, although bipolar patients medicate with antipsychotic drugs to a much smaller extent than schizophrenic patients. Bipolar disorder and schizophrenia share substantial genetic risk components; thus, increased metabolic abnormalities is hypothesized to be an effect of specific sets of metabolic risk genes, which might overlap with the metabolic risk genes in schizophrenia. This study reports that a functional genetic variant of MTNR1B, previously implicated in the impairment of glucose-stimulated insulin release also in schizophrenia, was associated with elevated fasting glucose levels in bipolar patients and controls. This finding suggests that the MTNR1B-dependent vulnerability for elevated fasting plasma glucose levels is shared between bipolar disorder and schizophrenia.

Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness.

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

Growth hormone induced lipolysis during short- and long-term administration in adult Prader-Willi patients.

Prader-Willi syndrome (PWS) is a complex genetic disease, clinically characterised by short stature, abnormal body composition, with more body fat than lean body mass, hyperphagia and obesity. Partial growth hormone (GH) deficiency is common, and GH treatment to PWS children and adults has shown beneficial effects on body composition. In this study, we have evaluated indices of GH's lipolytic effect in 6 PWS adults analysing glycerol, lactate and glucose in dialysate from microdialysis in subcutaneous abdominal adipose tissue. The patients were four men and two women, 19-37 years old; all hypogonadal. BMI was 24.2-49.1, mean 35.9 kg/m(2). All had normal serum insulin levels. They received GH therapy (Genotropin Pfizer) during 12 months and doses were individually titrated to normal serum IGF-I for age. Immediately before treatment start and at 12 months, 30-36 h after the last GH injection, sampling of dialysate was carried out at night (11 p.m. to 7 a.m.), as well as after intravenously injection of a standardised GH dose (0.8 mg). At baseline individual mean night time glycerol and lactate were similar to levels in adults without PWS (160.7-278.1 micromol/L and 0.80-3.99 mmol/L, respectively), and did not change with 12 months GH treatment. Glucose levels were normal, except in a patient with diabetes, and did not change during the study. Compared to baseline the immediate effect of GH injection resulted in a significant increase in glycerol levels after 12 months. In conclusion, night time lipolytic response in this small group of PWS adults seemed normal and did not change after 12 months GH treatment. On the other hand short-term GH induced lipolysis increased, indicating normal lipolytic response in PWS.

Social network and development of prediabetes and type 2 diabetes in middle-aged Swedish women and men.

AIM: Explore if social network affects development of prediabetes and type 2 diabetes. METHODS: Individuals with normal glucose tolerance at baseline, 2924 women and 2039 men, aged 35-56 years, were followed-up 8-10 years later by an oral glucose tolerance test. Prediabetes and type 2 diabetes was then evident in 168 and 50 women and in 236 and 93 men, respectively. Measures of social network (AVSI-index (availability of social integration), civil status and participation in social activities), recorded by questionnaire at baseline, were evaluated by logistic regression. RESULTS: Having AVSI scores in the highest tertile was associated with a decreased risk to develop type 2 diabetes in women (age-adjusted odds ratio 0.41 [95% CI: 0.19-0.88]) less significant after full adjustment (0.50 [0.22-1.16]). Contrary, in men AVSI was associated with an increased risk to develop type 2 diabetes (1.93 [1.03-3.60]) after full adjustment. Participation in social activities decreased the risk to develop prediabetes and type 2 diabetes in women, (age-adjusted 0.65 [0.46-0.91] and 0.43 [0.24-0.77], respectively), less significant when adjusted for confounders (0.78 [0.54-1.12] and 0.59 [0.31-1.13]). In men a decreased risk was observed for prediabetes (0.59 [0.43-0.82] multi-adjusted model). Being married or living with a partner decreased type 2 diabetes risk only in men (0.57 [0.33-0.97] and 0.61 [0.34-1.08] age- and multi-adjusted models, respectively). CONCLUSIONS: Individuals having a social network seemed less likely to develop abnormal glucose regulation. Contradictory to an overall protective pattern of having a social network, high AVSI-index in men increased the risk to develop type 2 diabetes.

Diabetes and glucose disturbances in patients with psychosis in Sweden.

OBJECTIVE: The objectives of this study were to (1) analyze the prevalence of diabetes, prediabetes, and antidiabetic medication in patients with psychosis compared with control subjects and (2) determine what factors in patients with psychosis were associated with antidiabetic medication. METHOD: We studied 977 patients with psychosis recruited from outpatient clinics in Stockholm County, Sweden, and they were compared with 3908 non-psychotic control subjects for fasting plasma glucose levels; prevalence of diabetes, prediabetes, antidiabetic treatment, and tobacco use; and blood pressure, weight, height, and waist circumference. Group differences were evaluated with analysis of variance and χ(2) test, and factors associated with antidiabetic treatment were evaluated with logistic regression. RESULTS: Diabetes was observed in 94 (10%) patients with psychosis, 2.7 times the prevalence observed in control subjects. Among patients with psychosis, 87 (10%) had prediabetes (fasting glucose, 6.1-6.9 mmol/L) compared with 149 (3.8%) control subjects. Most patients with psychosis (77%) who had prediabetes fulfilled criteria for metabolic syndrome. In patients with psychosis, both lipid-lowering medication and fasting glucose were significantly associated with antidiabetic treatment. There was no significant relation between antidiabetic treatment and lifestyle factors such as smoking or degree of psychiatric illness. CONCLUSIONS: The high prevalence of impaired fasting glucose and metabolic syndrome in patients with psychosis warrants further clinical research in preventing or delaying the onset of diabetes in these patients by pharmacotherapy and/or lifestyle intervention.

Traffic-related air pollution exposure and incidence of stroke in four cohorts from Stockholm.

We investigated the risk of stroke related to long-term ambient air pollution exposure, in particular the role of various exposure time windows, using four cohorts from Stockholm County, Sweden. In total, 22,587 individuals were recruited from 1992 to 2004 and followed until 2011. Yearly air pollution levels resulting from local road traffic emissions were assessed at participant residences using dispersion models for particulate matter (PM10) and nitrogen oxides (NOX). Cohort-specific hazard ratios were estimated for time-weighted air pollution exposure during different time windows and the incidence of stroke, adjusted for common risk factors, and then meta-analysed. Overall, 868 subjects suffered a non-fatal or fatal stroke during 238,731 person-years of follow-up. An increment of 20 µg/m(3) in estimated annual mean of road-traffic related NOX exposure at recruitment was associated with a hazard ratio of 1.16 (95% CI 0.83-1.61), with evidence of heterogeneity between the cohorts. For PM10, an increment of 10 µg/m(3) corresponded to a hazard ratio of 1.14 (95% CI 0.68-1.90). Time-window analyses did not reveal any clear induction-latency pattern. In conclusion, we found suggestive evidence of an association between long-term exposure to NOX and PM10 from local traffic and stroke at comparatively low levels of air pollution.

Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity.

Previous investigations of adults with the Prader-Willi syndrome (PWS) are few and have demonstrated severe obesity with increased morbidity and mortality in cardiovascular disease. It is, thus, important to identify risk factors and, if possible, start prevention. We studied the clinical, genetic, endocrinological, and metabolic findings in 19 adult PWS patients (10 men; mean age, 25 yr). The PWS karyotype was demonstrated in 13 patients. The mean body mass index was 35.6 kg/m(2), and total body fat was increased. Two thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency (GHD). Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9 patients, and modest dyslipidemia in 7. IGF-binding protein-1 correlated negatively with insulin levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, body mass index, waist/hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a), which was significantly higher in the group with the negative karyotype. IGF-I and lumbar spine bone mineral density were significantly lower in patients with genetic alteration, indicating a more severe GHD. The risk factors found in this study predicting cardiovascular disease are interpreted as secondary to GHD. These findings point to the importance of evaluating treatment of GHD in adults with PWS.

Glucagon and GLP-1 stimulate IGFBP-1 secretion in Hep G2 cells without effect on IGFBP-1 mRNA.

Glucagon has previously been reported to increase serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) in humans. The in vitro effect of glucagon and glucagon-like peptide-1 (7-36) amide (GLP-1) was investigated in Hep G2 human hepatoma cells. The expression of IGFBP-1 mRNA was determined by solution hybridization assay and IGFBP-1 secretion was measured by radioimmunoassay. In contrast to forskolin the peptides glucagon and GLP-1 had no effect on IGFBP-1 mRNA at 3, 6 and 24 h incubation or any detectable effect on the apparent half-life of IGFBP-1 mRNA. However, the exposure to glucagon (10 microg/mL, 2.87 microM) and GLP-1 (1 microM) caused a two-fold stimulation in protein levels of IGFBP-1 after 6 h incubation, declining to control levels after 24 h. This transient effect was dose dependent, remained when transcription was inhibited and required protein synthesis. The regulation of IGFBP-1 secretion by glucagon and GLP-1 appeared to be cAMP independent. In conclusion, glucagon and GPL-1 were shown to have a post-transcriptional stimulatory effect on IGFBP-1 release.

Long-term aircraft noise exposure and body mass index, waist circumference, and type 2 diabetes: a prospective study.

BACKGROUND: Long-term aircraft noise exposure may increase the risk of cardiovascular disease, but no study has investigated chronic effects on the metabolic system. OBJECTIVES: The aim of this study was to investigate effects of long-term aircraft noise exposure on body mass index (BMI), waist circumference, and type 2 diabetes. Furthermore, we explored the modifying effects of sleep disturbance. METHODS: This prospective cohort study of residents of Stockholm County, Sweden, followed 5,156 participants with normal baseline oral glucose tolerance tests (OGTT) for up to 10 years. Exposure to aircraft noise was estimated based on residential history. Information on outcomes and confounders was obtained from baseline and follow-up surveys and examinations, and participants who developed prediabetes or type 2 diabetes were identified by self-reported physician diagnosis or OGTT at follow-up. Adjusted associations were assessed by linear, logistic, and random-effects models. RESULTS: The mean (± SD) increases in BMI and waist circumference during follow-up were 1.09 ± 1.97 kg/m2 and 4.39 ± 6.39 cm, respectively. The cumulative incidence of prediabetes and type 2 diabetes was 8% and 3%, respectively. Based on an ordinal noise variable, a 5-dB(A) increase in aircraft noise was associated with a greater increase in waist circumference of 1.51 cm (95% CI: 1.13, 1.89), fully adjusted. This association appeared particularly strong among those who did not change their home address during the study period, which may be a result of lower exposure misclassification. However, no clear associations were found for BMI or type 2 diabetes. Furthermore, sleep disturbances did not appear to modify the associations with aircraft noise. CONCLUSIONS: Long-term aircraft noise exposure may be linked to metabolic outcomes, in particular increased waist circumference.