A Swedish primary healthcare prevention programme focusing on promotion of physical activity and a healthy lifestyle reduced cardiovascular events and mortality: 22-year follow-up of 5761 study participants and a reference group.

OBJECTIVE: To evaluate long-term risk of first cardiovascular (CV) events, CV deaths and all-cause deaths in community-dwelling participants of a cardiovascular disease (CVD) prevention programme delivered in a primary care setting. METHODS: Individuals who visited a primary healthcare service in Sollentuna (Sweden) and agreed to participate in the programme between 1988 and 1993 were followed. They had at least one CV risk factor but no prior myocardial infarction and received support to increase physical activity using the programme Physical Activity on Prescription and to adopt health-promoting behaviours including cooking classes, weight reduction, smoking cessation and stress management. Participants (n=5761) were compared with a randomly selected, propensity score-matched reference group from the general population in Stockholm County (n=34 556). All individuals were followed in Swedish registers until December 2011. RESULTS: In the intervention group and the reference group there were 698 (12.1%) and 4647 (13.4%) first CV events, 308 (5.3%) and 2261 (6.5%) CV deaths, and 919 (16.5%) and 6405 (18.5%) all-cause deaths, respectively, during a mean follow-up of 22 years. The HR (95% CI) in the intervention group compared with the reference group was 0.88 (0.81 to 0.95) for first CV events, 0.79 (0.70 to 0.89) for CV deaths and 0.83 (0.78 to 0.89) for all-cause deaths. CONCLUSIONS: Participation in a CVD prevention programme in primary healthcare focusing on promotion of physical activity and healthy lifestyle was associated with lower risk of CV events (12%), CV deaths (21%) and all-cause deaths (17%) after two decades. Promoting physical activity and healthy living in the primary healthcare setting may prevent CVD.

Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men.

Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.

Long-term effects of a Swedish lifestyle intervention programme on lifestyle habits and quality of life in people with increased cardiovascular risk.

AIMS: The aim of this study was to evaluate the effects of a structured intervention programme on lifestyle habits and quality of life after six months and one year in participants with increased cardiovascular risk. METHODS: Participants aged ≥18 years with increased cardiovascular risk were referred from primary health care and hospitals. The programme was launched at an outpatient clinic in a department of cardiology at a university hospital. It consisted of individual visits to a nurse for a health check-up and lifestyle counselling at baseline, after six months and at one year. In addition, five group sessions - focusing on nicotine, alcohol, physical activity, eating habits, stress, sleep and behavioural change - were offered to the participants and their relatives or friends. Lifestyle habits and quality of life were assessed with questionnaires at baseline, after six months and at one year. RESULTS: One hundred participants (64 women, 36 men, age 58±11 years) were included in the programme. Compared with the baseline, significant and favourable changes in reported lifestyle habits were noted. Exercise levels were higher after one year and sedentary time decreased from 7.4 to 6.3 h/day. Dietary habits improved and the number of participants with a high consumption of alcohol decreased. Quality of life improved after one year. CONCLUSIONS: Participating in a structured lifestyle programme resulted in improved lifestyle habits and quality of life over one year in people with increased cardiovascular risk. Components such as an inter-professional teamwork, a focus on lifestyle rather than the disease, and combining individual visits and group sessions, might be central to the positive outcome of the programme.

Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60-Year-Olds.

BACKGROUND: Malondialdehyde (MDA) is generated during lipid peroxidation as in oxidized low-density lipoprotein, but antibodies against oxidized low-density lipoprotein show variable results in clinical studies. We therefore studied the risk of cardiovascular disease (CVD) associated with IgM antibodies against MDA conjugated with human albumin (anti-MDA). METHODS AND RESULTS: In a 5- to 7-year follow-up of 60-year-old men and women from Stockholm County previously screened for cardiovascular risk factors (2039 men, 2193 women), 209 incident CVD cases (defined as new events of coronary heart disease, fatal and nonfatal myocardial infarction, ischemic stroke, and hospitalization for angina pectoris) and 620 age- and sex-matched controls were tested for IgM anti-MDA by ELISA. Antibody peptide/protein characterization was done using a proteomics de novo sequencing approach. After adjustment for smoking, body-mass index, type 2 diabetes mellitus, hyperlipidemia, and hypertension, an increased CVD risk was observed in the low IgM anti-MDA percentiles (below 10th and 25th) (odds ratio and 95% CI: 2.0; 1.19-3.36 and 1.67; 1.16-2.41, respectively). Anti-MDA above the 66th percentile was associated with a decreased CVD risk (odds ratio 0.68; CI: 0.48-0.98). After stratification by sex, associations were only present among men. IgM anti-MDA levels were lower among cases (median [interquartile range]: 141.0 [112.7-164.3] versus 147.4 [123.5-169.6]; P=0.0177), even more so among men (130.6 [107.7-155.3] versus 143.0 [120.1-165.2]; P=0.001). The IgM anti-MDA variable region profiles are distinctly different and also more homologous in their content (correlates strongly with fewer peptides) than control antibodies (not binding MDA). CONCLUSIONS: IgM anti-MDA is a protection marker for CVD. This finding could have diagnostic and therapeutic implications.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors.

BACKGROUND: The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment. METHODS AND RESULTS: Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30-2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12-1.95). CONCLUSIONS: Serum PCSK9 concentration is associated with future risk of CVD even after adjustments for established CVD risk factors. Further studies are needed to confirm this observation.

Time Trends in Incidence and Mortality of Acute Myocardial Infarction, and All-Cause Mortality following a Cardiovascular Prevention Program in Sweden.

BACKGROUND: In 1988, a cardiovascular prevention program which combined an individual and a population-based strategy was launched within primary health-care in Sollentuna, a municipality in Stockholm County. The aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program. MATERIALS AND METHODS: The average population in Sollentuna was 56,589 (49% men) and in Stockholm County (Sollentuna included) 1,795,504 (49% men) during the study period of 1987-2010. Cases of hospitalized acute myocardial infarction and death were obtained for the population of Sollentuna and the rest of Stockholm County using national registries of hospital discharges and deaths. Acute myocardial infarction incidence and mortality were estimated using the average population of Sollentuna and Stockholm in 1987-2010. RESULTS: During the observation period, the incidence of acute myocardial infarction decreased more in Sollentuna compared with the rest of Stockholm County in women (-22% vs. -7%; for difference in slope <0.05). There was a trend towards a greater decline in Sollentuna compared to the rest of Stockholm County in the incidence of acute myocardial infarction (in men), acute myocardial mortality, and all-cause mortality but the differences were not significant. CONCLUSION: During a period of steep decline in acute myocardial infarction incidence and mortality in Stockholm County the municipality of Sollentuna showed a stronger trend in women possibly compatible with favorable influence of a cardiovascular prevention program. TRIAL REGISTRATION: ClinicalTrials.gov NCT02212145.

The metabolic syndrome and ECG detected left ventricular hypertrophy--influences from IGF-1 and IGF-binding protein-1.

BACKGROUND AND AIMS: The metabolic syndrome (MetS) is associated with an increased risk for left ventricular hypertrophy (LVH) and cardiovascular mortality. The aim of this study was to investigate potential influences from insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) on the relationship between the MetS and LVH, also taking into account the role of physical activity (PA), use of oestrogen and gender. METHODS AND RESULTS: In a population-based cross-sectional study of 60-year-old men (n = 1822) and women (n = 2049) participants underwent physical examination and laboratory tests, including electrocardiography (ECG), and completed an extensive questionnaire. Women showed higher levels of IGFBP-1 than men (37.0 vs. 28.0 µg/l, p < 0.001), and women with LVH had lower levels of IGFBP-1 than women without LVH (31.0 µg/l vs. 37.0 µg/l, p < 0.001). Furthermore, women with low levels of IGFBP-1 had a significantly increased risk of having LVH (crude OR ≈ 2.5). When stratifying for PA and oestrogen, respectively, a weaker association between IGFBP-1 and LVH was demonstrated in physically active men and women, compared to inactive individuals, as well as in women using oestrogen, compared to non-users. CONCLUSION: In a representative sample of 60-year-old Swedish men and women, the main findings were higher levels of IGFBP-1 in women than in men; lower levels of IGFBP-1 in women with LVH, compared to women without LVH; and an increased risk of having LVH in women with low levels of IGFBP-1. The association between IGFBP-1 and LVH was diminished in physically active men and women, as well as in women using oestrogen.

Differences in anthropometric measures in immigrants and Swedish-born individuals: results from two community-based cohort studies.

AIM: To study differences in body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), waist-hip-height ratio (WHHR) and percent body fat in immigrants and Swedish-born men and women in two large population-based samples. METHODS: A cross-sectional analysis of 60-year-old individuals, n=4 232. To replicate the results, we also assessed another large independent cohort cross-sectionally, the Malmö Diet and Cancer Study (MDC, n=26 777). The data from both cohorts were collected in the 1990s in Sweden. RESULTS: Significant differences between Finnish-born, Middle Eastern and women from the rest of the world were seen for all anthropometric measures, using Swedish-born women as referent. However, WHHR was the only anthropometric measure that identified all these three groups of immigrant women as different from Swedish-born women with high statistical certainty (p<0.001). Apart from WHHR that identified differences in anthropometry in all immigrant groups of men using Swedish-born men as referent, few significant differences were seen in anthropometry among groups of immigrant men. These finding were observed in both cohorts, and remained after adjustments for smoking, physical activity and educational level. CONCLUSION: The present study confirms previous findings of more obesity among immigrants and is the first to report that WHHR measurements may detect anthropometric differences between different ethnic groups better than other anthropometrical measures.

The risk of type 2 diabetes in men is synergistically affected by parental history of diabetes and overweight.

Interactions between genetic- and lifestyle factors may be of specific importance for the development of type 2 diabetes. Only a few earlier studies have evaluated interaction effects for the combination of family history of diabetes and presence of risk factors related to lifestyle. We explored whether 60-year-old men and women from Stockholm with a parental history of diabetes are more susceptible than their counterparts without a parental history of diabetes to the negative influence from physical inactivity, overweight or smoking regarding risk of developing type 2 diabetes. The study comprised 4232 participants of which 205 men and 113 women had diabetes (the vast majority type 2 diabetes considering the age of study participants) and 224 men and 115 women had prediabetes (fasting glucose 6.1-6.9 mmol/l). Prevalence odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using logistic regression. Biologic interaction was analyzed using a Synergy index (S) score. The crude OR for type 2 diabetes associated with a parental history of diabetes was 2.4 (95% CI 1.7-3.5) in men and 1.4 (95% CI 0.9-2.3) in women. Adjustments for overweight, physical inactivity and current smoking had minimal effects on the association observed in men whereas in women it attenuated results. In men, but not in women, a significant interaction effect that synergistically increases the risk of developing type 2 diabetes was observed for the combination of BMI>30 and a parental history of diabetes, S 2.4 (95% CI 1.1-5.1). No signs of interactions were noted for a parental history of diabetes combined with physical inactivity and smoking, respectively. In conclusion, obesity in combination with presence of a parental history of diabetes may be particularly hazardous in men as these two factors were observed to synergistically increase the risk of developing type 2 diabetes in men.

Low levels of IgM antibodies to oxidized cardiolipin increase and high levels decrease risk of cardiovascular disease among 60-year olds: a prospective study.

BACKGROUND: Antibodies against cardiolipin (aCL) are associated with increased risk of cardiovascular disease (CVD). We here determine the role of antibodies against oxidized CL (aOxCL). METHODS: One third of sixty-year olds from the Stockholm County were screened (2039 men, 2193 women), where 211 incident CVD-cases and 633 age- and sex-matched controls were identified (5-7 year follow-up). Antibodies were determined by ELISA and uptake of oxLDL in macrophages by FACScan. RESULTS: IgM aOxCL was lower among CVD cases than controls (p=0.024). aOxCL-levels were divided in quartiles with the highest quartile set as the reference group. After adjustment for smoking, BMI, type II diabetes, hypercholesterolaemia and hypertension, an increased risk was determined in the lowest quartile of IgM aOxCL (OR: 1.80, CI: 1.12-2.91, p=0.0159); OR for men in the lowest quartile was 2.46 (CI 1.34-4.53, p=0.0037) for CVD and for stroke: 12.28 (CI: 1.48-101.77, p=0.02). IgG aOxCL levels did not differ between quartiles in CVD-risk. High levels of IgM aOxCL (reaching significance above 86th) and IgG aOxCL (above 95th percentile) were associated with decreased risk of CVD (OR: 0.485, CI: 0.283-0.829; p=0.0082 and OR: 0.23, CI: 0.07-0.69; p=0.0091). aCL were not associated with CVD. oxCL but not CL competed out uptake of OxLDL in macrophages, and aOxLDL recognized oxCL but not CL. In contrast to aCL, aOxCL was not dependent on co-factor Beta2-glycoprotein-I. CONCLUSIONS: aOxCL is a novel risk/protection marker for CVD, with therapeutic implications. OxCL competes with oxLDL for uptake in macrophages and the possibility that aOxCL inhibits such uptake by interfering with same or similar epitopes in oxCL and oxLDL should be further studied.

Seven modifiable lifestyle factors predict reduced risk for ischemic cardiovascular disease and all-cause mortality regardless of body mass index: a cohort study.

OBJECTIVES: A healthy lifestyle has an impact on cardiovascular health. Yet, the importance of body mass index (BMI) and gender remains less clear. The aim of this study was to investigate whether healthy lifestyle factors can predict incident cardiovascular disease (CVD) and all-cause mortality. METHODS: Representative population-based prospective cohort study of 60-year-old women (n=2193) and men (n=2039). The following factors related to a healthy lifestyle were assessed using a questionnaire: non-smoking, alcohol intake of 0.6-30 g/day, moderate physical activity at least once a week, low intake of processed meats, weekly intake of fish, daily intake of fruit, and daily intake of vegetables. These factors were combined to produce a total score of healthy lifestyle factors (0-7) and classified into four groups: unhealthy (0-2 lifestyle factors), intermediate (3), healthy (4-5), and very healthy (6-7). National registers enabled identification of incident CVD (n=375) and all-cause mortality (n=427) over a follow-up of 11 years. RESULTS: Very healthy women and men exhibited a decreased risk for incident CVD compared with unhealthy individuals, with hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for educational level and BMI of 0.44 (0.26-0.75) and 0.39 (0.25-0.61), respectively. The corresponding HRs (95% CIs) for all-cause mortality for very healthy women and men were 0.25 (0.15-0.44) and 0.35 (0.23-0.54), respectively. CONCLUSION: With seven healthy lifestyle factors, it was possible to identify men and women with substantially lower relative risks of incident CVD and death, regardless of BMI and educational level.

Low levels of IgM antibodies to phosphorylcholine predict cardiovascular disease in 60-year old men: effects on uptake of oxidized LDL in macrophages as a potential mechanism.

OBJECTIVE: We here determine the role of IgM antibodies against phosphorylcholine (anti-PC) in prediction of cardiovascular disease (CVD) and on macrophage uptake of Oxidized LDL (OxLDL). METHODS: From a screening of 4232 subjects, 60-year-old (2039 men and 2193 women), 211 incident cases of CVD (myocardial infarction, ischemic stroke, or hospitalized angina pectoris) and 633 age- and sex-matched controls were identified through a 5-7 year follow-up. Serum levels of IgM anti-PC was determined by ELISA. Anti-PC was extracted from pooled human IgM and the effect of anti-PC on the uptake of OxLDL was studied by FACScan. RESULTS: Relative risks (RR) with 95% confidence intervals (CI) by quartiles of anti-PC levels with quartile 4 set as the reference value (RR = 1.0) and adjusted for smoking, BMI, type II diabetes, hypercholesterolaemia, and high blood pressure yielded an excess risk for CVD only for those within the lowest quartile of anti-PC values with an RR of 1.37 (CI 0.87-2.16). However, for men stronger associations were noted with increasing multivariately adjusted RRs from quartile 4 to quartile 1. Subjects within quartile 1 (values below 29.7 U/ml) had a significantly increased RR of 1.96 (CI 1.09-3.55). Further adjustments for hsCRP gave essentially the same results. No excess risk was noted for women. Specific anti-PC could be extracted from IgM and these antibodies inhibited macrophage uptake of OxLDL. CONCLUSIONS: Low IgM anti-PC could be a novel risk marker for CVD among men. One possible mechanism could be inhibition of uptake of oxLDL in macrophages.

Is a unified definition of metabolic syndrome needed? Comparison of three definitions of metabolic syndrome in 60-year-old men and women.

BACKGROUND: There are three commonly used definitions of the metabolic syndrome, making scientific studies hard to compare. The aim of this study was to investigate agreement in the prevalence of the metabolic syndrome defined by three different definitions and to analyze definition and gender differences. METHODS: A population-based, cross-sectional study of a total of 4232 participants--2039 men and 2193 women, aged 60 years--was employed. Three different metabolic syndrome definitions were compared: European Group for the Study of Insulin Resistance (EGIR), International Diabetes Federation (IDF), and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). Medical history, socioeconomic information, and lifestyle data were collected by a questionnaire. A medical examination including laboratory tests was performed. Significant factors for the metabolic syndrome were calculated by multivariate logistic regression. RESULTS: Forty five percent of men and 30% of women met the criteria for the metabolic syndrome by any definition, but only 17% of men and 9% of women met the criteria of all three definitions. The highest agreement was found between IDF and NCEP ATP III definition. Two significant associations were identified in both men and women by the three metabolic syndrome definitions; former smokers were highly associated with the metabolic syndrome (odds ratio [OR] congruent with 1.5), and regular physical activity (OR congruent with 0.6) was inversely associated with the metabolic syndrome. CONCLUSIONS: Depending on the definition used, different individuals were identified as having the metabolic syndrome, which affects the reliability of interpretations to be made from scientific studies of the metabolic syndrome. Unified criteria are warranted. Physicians facing a physically inactive former smoker may consider diagnosing metabolic syndrome.

Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population.

AIMS: Prospective studies indicate that apolipoprotein measurements predict coronary heart disease (CHD) risk; however, evidence is conflicting, especially in the US. Our aim was to assess whether measurements of apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) can improve the ability to predict CHD death beyond what is possible based on traditional cardiovascular (CV) risk factors and clinical routine lipid measurements. METHODS AND RESULTS: We analysed prospectively associations of apolipoprotein measurements, traditional CV risk factors, and clinical routine lipid measurements with CHD mortality in a multi-ethnic representative subset of 7594 US adults (mean age 45 years; 3881 men and 3713 women, median follow-up 124 person-months) from the Third National Health and Nutrition Examination Survey mortality study. Multiple Cox-proportional hazards regression was applied. There were 673 CV deaths of which 432 were from CHD. Concentrations of apoB [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.09-3.61], apoA-I (HR 0.48, 95% CI 0.27-0.85) and total cholesterol (TC) (HR 1.17, 95% CI 1.02-1.34) were significantly related to CHD death, whereas high density lipoprotein cholesterol (HDL-C) (HR 0.68, 95% CI 0.45-1.05) was borderline significant. Both the apoB/apoA-I ratio (HR 2.14, 95% CI 1.11-4.10) and the TC/HDL-C ratio (HR 1.10, 95% CI 1.04-1.16) were related to CHD death. Only apoB (HR 2.01, 95% CI 1.05-3.86) and the apoB/apoA-I ratio (HR 2.09, 95% CI 1.04-4.19) remained significantly associated with CHD death after adjusting for CV risk factors. CONCLUSION: In the US population, apolipoprotein measurements significantly predict CHD death, independently of conventional lipids and other CV risk factors (smoking, dyslipidaemia, hypertension, obesity, diabetes and C-reactive protein). Furthermore, the predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements. Inclusion of apolipoprotein measurements in future clinical guidelines should not be discarded.

Sex differences in risk factor control of treated hypertensives: a national primary healthcare-based study in Sweden.

BACKGROUND: To evaluate potential sex differences, this study aimed to investigate blood pressure and lipid control and other risk factors for cardiovascular disease in treated hypertensive (tHT) patients from primary healthcare. DESIGN AND METHODS: This cross-sectional survey of tHT patients was carried out between 2002 and 2005 by 264 primary care physicians from Sweden who consecutively recruited 6537 tHT patients (48% men and 52% women) from medical records. RESULTS: tHT men more often reached the treatment goal for systolic/diastolic blood pressure, less than 140/90 mmHg, than tHT women (30 vs. 26%, P<0.01). Men had lower systolic blood pressure than women, however, women had lower diastolic blood pressure and higher pulse pressure. More tHT women had total cholesterol>or=5.0 mmol/l than corresponding men (75 vs. 64% P<0.001). Men more often had diabetes (25 vs. 20% P<0.001), left ventricular hypertrophy (20 vs. 16% P<0.001), and microalbuminuria (24 vs. 16% P<0.001). Women were more often treated with diuretics (64 vs. 48%) and beta-receptor blockers (54 vs. 51%), and men more often treated with angiotensin-converting enzyme inhibitors (27 vs. 18%), calcium channel blockers (34 vs. 26%), and lipid-lowering drugs (34 vs. 29%). CONCLUSION: A need still exists for more intensified treatment of elevated blood pressure and hypercholesterolemia, especially in women. In hypertensives of both sexes, smoking and other risk factors also need to be addressed to reduce the risk of cardiovascular disease.

Association between metabolic effects and tobacco use in 60-year-old Swedish men.

There is a controversy whether use of smokeless tobacco is associated with an increased risk of diabetes. A population-based cross-sectional study was undertaken of 1,859 men, aged 60 years, in Stockholm County. No significant association was found between risk of diabetes and any use of tobacco, even if an association between snuff and risk of diabetes could not be excluded.

Insulin-induced gene 2 involvement in human adipocyte metabolism and body weight regulation.

BACKGROUND: Insulin-induced genes (INSIGs) encode proteins that block proteolytic activation of sterol regulatory element-binding proteins, transcription factors that regulate lipogenic enzymes, and adipocyte differentiation. OBJECTIVE: Here, we analyzed the relative significance of INSIG1 and INSIG2 in human liver and adipocyte metabolism, and defined a novel, functional polymorphism in the promoter of INSIG2 associated with body mass index. RESEARCH METHODS: Variations in gene expression of different human tissues, of hepatoma cells exposed to INSIG1 and INSIG2 gene silencing probes, and of differentiating 3T3-L1 adipocytes were determined by real-time quantitative PCR. The functional significance of a novel polymorphism in the promoter of INSIG2 was analyzed using in vitro methods and gene expression analysis of human adipose tissue, whereas the phenotype associated with this polymorphism was studied in two cohorts of middle-aged men. RESULTS: Gene expression analysis of 17 human tissues demonstrated that INSIG1 is highly expressed in the liver, whereas INSIG2 is ubiquitously expressed. Gene silencing experiments confirmed that INSIG1, but not INSIG2, regulates the expression of sterol regulatory element-binding proteins target genes in human hepatoma cells. In contrast, adipocyte differentiation of 3T3-L1 cells was associated with a 13-fold increase in expression of INSIG2. Significant relationships between the INSIG2-102G/A polymorphism and body mass index were observed in two cohorts of middle-aged men (ANOVA P = 0.017 and 0.044, respectively). In vitro studies and analysis of allele-specific expression in human adipose tissue substantiated the functional significance of the INSIG2-102G/A polymorphism. CONCLUSION: INSIG2 is involved in adipocyte metabolism and body weight regulation.