Leena Moilanen

Lifestyle Intervention for Prevention of Type 2 Diabetes in Primary Health Care One-year follow-up of the Finnish National Diabetes Prevention Program (FIN-D2D)

OBJECTIVE To investigate 1-year outcomes of a national diabetes prevention program in Finland. RESEARCH DESIGN AND METHODS Altogether 10,149 individuals at high risk for diabetes were identified with the Finnish Diabetes Risk Score (FINDRISC; scoring ≥15 points), by a history of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), cardiovascular disease, or gestational diabetes mellitus in 400 primary health care centers. One-year follow-up data were available for 2,798 participants who were nondiabetic at baseline (919 men and 1,879 women, aged 56.0 ± 9.9 and 54.0 ± 10.7 years [mean ± SD] with BMI 30.9 ± 4.6 and 31.6 ± 5.4 kg/m2). RESULTS The incidence of diabetes was 2.0 and 1.2% in men and women with normal glucose tolerance at baseline, 13.5 and 7.4% in those with IFG, and 16.1 and 11.3% in those with IGT, respectively. Altogether 17.5% of the subjects lost ≥5% weight with no sex difference. The relative risk of diabetes was 0.31 (95% CI 0.16–0.59) in the group who lost ≥5% weight, 0.72 (0.46–1.13) in the group who lost 2.5–4.9% weight, and 1.10 (0.77–1.58) in the group who gained ≥2.5% compared with the group who maintained weight. CONCLUSIONS The FIN-D2D was the first national effort to implement the prevention of diabetes in a primary health care setting. Methods for recruiting high-risk subjects were simple and easy to use. Moderate weight loss in this very high-risk group was especially effective in reducing risk of diabetes among those participating in the program.

Coronary Artery Disease–Associated Locus on Chromosome 9p21 and Early Markers of Atherosclerosis

Background—Genome-wide association studies have recently identified a locus on chromosome 9p21 that influences risk of coronary artery disease (CAD). The effect of the locus on early markers of atherosclerosis is unknown. We examined its association with carotid intima-media thickness (CIMT) and brachial flow-mediated dilatation (FMD). Methods and Results—We genotyped 2277 individuals, age 24 to 39 years, from the Cardiovascular Risk in Young Finns Study with CIMT and FMD measurements and 1295 individuals, age 46 to 76 years, from the Health 2000 Survey with CIMT for rs1333049, the chromosome 9p21 variant showing the strongest association with CAD. Both mean and maximum CIMT were significantly higher (P<0.001) in the older subjects of the Health 2000 Survey compared with the Young Finns Study. However, there was no association of the rs1333049 genotype with either mean or maximum CIMT at either age (P=0.959 and 0.977 for the 2 phenotypes in the Young Finns Study and P=0.714 and 0.725 in the Health 2000 Survey). Similarly, there was no association of the locus with variation in FMD in the Young Finns cohort (P=0.521). Conclusions—The chromosome 9p21 locus does not influence CAD risk through a mechanism that also affects CIMT or induces early changes in FMD.

The Metabolic Syndrome Predicts Incident Stroke A 14-Year Follow-Up Study in Elderly People in Finland

Background and Purpose— Limited information is available on the role of the metabolic syndrome (MetS) to predict stroke. We investigated the relationship of the MetS and its single components, defined by 6 different criteria, with stroke in a prospective population-based study. Methods— The MetS was defined according to the World Health Organization, the European Group for the Study of Insulin Resistance, the National Cholesterol Education Program (NCEP), the American College of Endocrinology, the International Diabetes Federation, and the American Heart Association (updated NCEP) criteria. We investigated the relationship of the MetS with stroke using Cox regression analyses in 991 Finnish subjects without diabetes, aged 65 to 74 years at baseline, and followed-up for 14 years. Results— The MetS defined by the World Health Organization, European Group for the Study of Insulin Resistance, NCEP, International Diabetes Federation, and updated NCEP criteria was significantly associated with incident stroke (fatal and nonfatal) when adjusted for confounding variables (HR, 1.52 to 1.72). After exclusion of subjects with myocardial infarction, these 5 definitions still predicted stroke (HR, 1.49 to 1.80). Of the single components of the MetS, the following predicted stroke in multivariable models when subjects with myocardial infarction were excluded: impaired glucose tolerance (2-hour glucose in an oral glucose tolerance test, 7.8 to 11.0 mmol/L) by the World Health Organization and American College of Endocrinology criteria (HR, 1.66); insulin resistance (HR, 1.60) by the European Group for the Study of Insulin Resistance criteria; and central obesity (HR, 1.52) by the NCEP criteria. Conclusions— The MetS defined by the 6 criteria except for the American College of Endocrinology definition predicts stroke in elderly subjects. However, impaired glucose tolerance alone is as strong a predictor of stroke as is the MetS defined by the World Health Organization, NCEP and updated NCEP criteria.

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

Arterial pulse wave velocity in relation to carotid intima-media thickness, brachial flow-mediated dilation and carotid artery distensibility: The Cardiovascular Risk in Young Finns Study and the Health 2000 Survey

OBJECTIVE Increased arterial pulse wave velocity (PWV) is a strong predictor of cardiovascular events and mortality. The data regarding the relationships between PWV and other indices of vascular damage is limited and partly controversial. We conducted the present study to examine PWV in relation to non-invasive measures of early atherosclerosis (brachial flow-mediated dilation [FMD], carotid intima-media thickness [IMT]) and local arterial stiffness (carotid artery distensibility [Cdist]). METHODS The study population consisted of 1754 young adults (aged 30-45 years, 45.5% males) participating in the Cardiovascular Risk in Young Finns Study (YFS), and of 336 older adults (aged 46-76 years, 43.2% males) participating in the Health 2000 Survey. FMD was measured only in the YFS cohort. FMD, IMT and Cdist were assessed by ultrasound, and PWV was measured using the whole-body impedance cardiography device. RESULTS In young adults, FMD and IMT were not associated with PWV independently of cardiovascular risk factors. Moreover, FMD status was not found to modulate the association between cardiovascular risk factors and PWV. In older adults, PWV and IMT were directly and independently associated (β=1.233, p=0.019). In both cohorts, PWV was inversely related with Cdist, and this relation remained significant (p<0.04) in models adjusted for cardiovascular risk factors. CONCLUSIONS The current findings suggest that PWV reflects a different aspect of vascular damage than FMD or IMT in young adults, whereas in older adults the information provided by PWV and IMT may be, to some extent, similar as regards subclinical vascular damage. The present observations also suggest that PWV and Cdist represent, at least in part, a similar adverse vascular wall process.

The metabolic syndrome predicts incident congestive heart failure: a 20-year follow-up study of elderly Finns.

OBJECTIVE We investigated whether the metabolic syndrome (MetS) and its components defined by four different criteria including subjects with prevalent diabetes in their definitions were associated with congestive heart failure (CHF) independent of interim myocardial infarction (MI) and prevalent diabetes during a 20-year follow-up in an elderly population-based study. METHODS AND RESULTS The MetS was defined according to the World Health Organization (WHO), the National Cholesterol Education Program (NCEP), the International Diabetes Federation (IDF), and the American Heart Association and the National Heart, Lung, and Blood Institute (AHA) criteria. The association of the MetS with incident CHF (303 cases) was investigated with Cox regression analyses in a 20-year follow-up study of 1032 Finns, aged 65-74 years at baseline. Among all subjects the MetS by all four criteria was significantly associated with a 1.45-1.74-fold risk for incident CHF after the adjustment for confounding factors. When subjects with interim MI during the follow-up and with prevalent diabetes were excluded, the MetS was significantly associated with a 1.37-1.87-fold risk for incident CHF after the adjustment for confounding factors. Of the single components of the MetS, the following were associated with incident CHF: impaired fasting glucose (IFG) [fasting plasma glucose (FPG)> or = 6.1 mmol/l, Hazards ratio (HR) 1.46 or FPG > or = 5.6 mmol/l, HR 1.62)]; raised blood pressure (BP) [(BP > or = 140/90 mmHg or antihypertensive medications, HR 1.89); central obesity (waist circumference > or = 94 cm in men or > or = 80 cm in women, HR 1.49); (waist circumference > or = 102 cm in men or > or = 88 cm in women, HR 1.48); obesity (body mass index > or = 30 kg/m(2), HR 1.79); and low high-density lipoprotein cholesterol (<1.03 mmol/l in men or <1.29 mmol/l in women, HR 1.55). CONCLUSIONS The MetS defined by four different criteria predicted CHF independent of interim MI and prevalent diabetes in elderly Finns, but not above and beyond the risk associated with one component of the MetS, hypertension.

Indoleamine 2,3‐dioxygenase activity associates with cardiovascular risk factors: The Health 2000 study

Indoleamine 2,3‐dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39‐year‐old females. Now we repeat this analysis in an older population (n = 921, age range 46–76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis – or the inflammatory response associated with it – but does not have an independent role in the pathogenesis of this disease.

Cholesterol absorption decreases after Roux-en-Y gastric bypass but not after gastric banding.

The differences in cholesterol metabolism after the 2 most common forms of obesity surgery, Roux-en-Y gastric bypass (RYGB) and gastric banding (GB), have not been well characterized. In this study, effects of RYGB and GB on cholesterol absorption and synthesis were investigated. To this aim, 1-year follow-up of cholesterol metabolism in 2 nonrandomized cohorts undergoing either RYGB (n = 29; age, 45.2 +/- 7.7 years; body mass index [BMI], 46.0 +/- 6.1 kg/m(2)) or GB (n = 26; age, 45.9 +/- 8.6 years; BMI, 50.1 +/- 7.7 kg/m(2)) was performed in a university hospital center specializing in the treatment of morbid obesity. Serum markers of cholesterol synthesis (cholestenol, desmosterol, and lathosterol) and cholesterol absorption (campesterol, sitosterol, avenasterol, and cholestanol) were measured preoperatively and at follow-up and expressed as ratios to cholesterol. As expected based on observed weight loss (25% after RYGB and 17% after GB, P < .001 between groups), both operations decreased serum levels of cholesterol synthesis markers by 12% to 28% (all Ps < .001). A decrease in cholesterol absorption markers was only observed after RYGB (-26% for sitosterol) and not after GB (+16%, P = 2 x 10(-6) for difference between the groups). The difference in sitosterol ratio between the groups remained significant after adjustment for age, BMI, fasting insulin levels, and nutritional status (P = 2 x 10(-4)), indicating a specific effect related to RYGB. We conclude that decrease in cholesterol absorption is a novel beneficial effect of RYGB. Together with an improved control of blood glucose, this may contribute to a better cardiovascular risk profile after RYGB.

Metabolic syndrome and carotid intima media thickness in the Health 2000 Survey

BACKGROUND AND PURPOSE Metabolic syndrome has been associated with increased carotid intima-media thickness (CIMT) and cardiovascular disease (CVD). The objective of this study was to examine metabolic syndrome as a determinant of CIMT in men and women and to compare the Framingham risk score (FRS) and metabolic syndrome as risk factors for increased carotid atherosclerosis. METHODS The study population consisted of 1353 Finnish men and women aged 45 years and above who participated in Finnish population-based Health 2000 Survey. CIMT was used as a marker of subclinical atherosclerosis. The National Cholesterol Education Program Adult Treatment Panel III criterion was used to define the presence of metabolic syndrome. RESULTS In multivariable models, metabolic syndrome was an independent determinant of CIMT in both sexes (p</=0.001 for both). When metabolic syndrome was included in the regression models along with its components, it was an independent determinant of CIMT in women but not in men. After dividing the population into risk categories according to FRS and the presence of metabolic syndrome, FRS predominantly determined CIMT regardless of the presence of metabolic syndrome in men. In women, however, CIMT was significantly higher in subjects with metabolic syndrome than in those without it, independently of the FRS. CONCLUSIONS Metabolic syndrome is an independent determinant of CIMT in both sexes. In women but not in men, metabolic syndrome is associated with CIMT independently of its components. Metabolic syndrome provides additional information on a persons risk for early atherosclerosis beyond FRS in women but not in men.

Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes.

Abstract.  Luotola K, Pietilä A, Zeller T, Moilanen L, Kähönen M, Nieminen MS, Kesäniemi YA, Blankenberg S, Jula A, Perola M, Salomaa V (Helsinki University Hospital, Helsinki; National Institute for Health and Welfare, Helsinki, Finland; University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany; University Hospital of Kuopio, Kuopio; Tampere University Hospital and Medical School, University of Tampere, Tampere; University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu; National Institute for Health and Welfare, Turku; and Institute for Molecular Medicine Finland, Helsinki, Finland). Associations between interleukin‐1 (IL‐1) gene variations or IL‐1 receptor antagonist levels and the development of type 2 diabetes. J Intern Med 2010; 269: 322–332.