Women with a history of gestational diabetes mellitus present an accumulation of cardiovascular risk factors at age 46-A birth cohort study.

INTRODUCTION: The incidence of gestational diabetes mellitus (GDM) is globally increasing, and it has been associated with later type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, long-term population-based studies investigating common CVD risk factors years after pregnancy are lacking. To evaluate the future mortality and morbidity in cardiovascular and metabolic diseases, we conducted a thorough investigation of midlife risk factors in women with and without previous GDM. MATERIAL AND METHODS: A prospective population-based cohort study was conducted of 3173 parous women from the Northern Finland Birth Cohort, 1966. Study participants were obtained from the national register or patient records. Those with a GDM diagnosis formed the GDM cohort (n = 271), and those without a previous GDM diagnosis formed the control cohort (n = 2902). Clinical examinations were performed on participants at the age of 46 and included anthropometric measurements, oral glucose tolerance test (OGTT), biochemical measurements, and cardiovascular assessment. RESULTS: At the age of 46, women in the GDM cohort had a higher body mass index (BMI, 29.0 kg/m2 vs 26.3 kg/m2, p < 0.001) and greater waist circumference (94.1 cm vs 86.5 cm, p < 0.001) than the control cohort. In the GDM cohort, a higher incidence of impaired glucose tolerance (12.6% vs 7.3%, p = 0.002), more previously diagnosed and OGTT-detected type 2 diabetes (23.3% vs 3.9%, p < 0.001), lower high-density lipoprotein (1.53 mmol/L vs 1.67 mmol/L, p = 0.011), higher triglycerides (1.26 mmol/L vs 1.05 mmol/L, p = 0.002) and a higher fatty liver index (6.82 vs 2.47, p < 0.001), were observed even after adjusting for BMI, polycystic ovary syndrome, parity, level of education, physical activity, smoking, and alcohol consumption. The women in the GDM cohort also had more MetS (42.6% vs 21.9%, p < 0.001) and higher risk scores for CVD and fatal events (Framingham 4.95 vs 3.60, p < 0.001; FINRISK 1.71 vs 1.08, p < 0.001). CONCLUSIONS: Women with a previous diagnosis of GDM exhibit more risk factors for CVD in midlife and are at a higher risk for cardiovascular events later in life.

Association between childhood family structure and longitudinal health behaviour changes in adulthood -Northern Finland birth cohort 1966 study.

BACKGROUND: Childhood family structure is considered to play a role in person's health and welfare. This study investigated the relationships between the longitudinal changes of adult health behaviours and childhood family structure. METHODS: From Northern Finland Birth Cohort 1966 questionnaires, we collected data on childhood family structure at the age of 14 ('two-parent family', 'one parent not living at home/no information on father', and 'father or mother deceased'), and on health behaviours (smoking, alcohol consumption and physical activity status) at the ages of 31 and 46. We used the multinomial logistic regression model to estimate the unadjusted and adjusted associations between childhood family structures and the longitudinal changes between 31 and 46 years of health behaviours (four-category variables). RESULTS: Of the study sample (n = 5431; 55.5% females), 7.1% of the offspring were represented in the 'One parent not living at home/no information on father' subgroup, 6.3% in the 'Father or mother deceased' subgroup and 86.6% in the 'Two-parent family'. 'One parent not living at home/no information on father' offspring were approximately twice as likely to smoke (adjusted OR 2.19, 95% CI 1.70-2.81) and heavily consume alcohol (adjusted OR 1.99, 95% CI 1.25-3.16) at both times in adulthood, relative to not smoking or not heavily consume alcohol, and compared with 'two-parent family' offspring. We found no statistically significant associations between childhood family structure and physical activity status changes in adulthood. CONCLUSIONS: Our findings suggest that the offspring of single-parent families in particular should be supported in early life to diminish their risk of unhealthy behaviours in adulthood.

Cross-sectional analysis of depressive symptom profiles and serum C-reactive protein levels: data from the Northern Finland 1966 birth cohort.

PURPOSE: Individuals with depression exhibit significantly higher levels of systemic inflammation than those without depression, particularly among those with atypical depression. However, this association has been less convincing at the population level among individuals without a formal depression diagnosis but with suggestive symptoms. Our aim was to clarify this association. MATERIALS AND METHODS: In a large birth cohort sample of the Finnish general population, we examined the cross-sectional association between high-sensitivity C-reactive protein (hsCRP) levels in venous blood samples and atypical/non-atypical depressive symptoms using the Beck Depression Inventory-II to screen 5443 middle-aged participants. RESULTS: As expected, depressive symptoms associated to elevated hsCRP-levels compared to non-depressed. Participants with the atypical subtype of depressive symptoms (n = 84) had an odds ratio (OR) of 2.59 (95% CI 1.40-4.81) for elevated hsCRP levels compared to the non-depressed group. Similarly, our findings indicate that participants with non-atypical symptoms (n = 440) also showed an OR of 1.42 (95% CI 1.05-1.92) when compared to the non-depressed group (n = 4919). CONCLUSIONS: These results provide additional support for previous research linking depression and inflammation and add to the field with a unique and sizeable study population. Furthermore, the current results support the notion that different types of depressive symptoms may be associated with inflammatory markers in slightly different ways.

Long-term effects on weight loss and maintenance by intensive start with diet and exercise.

This 36-month study aimed to determine whether exercise intervention added to weight loss treatment in the beginning or at 6 months is effective for weight loss and long-term weight maintenance. A total of 120 obese adults (body mass index >30) were randomly assigned to intensified behavioral modification (iBM), iBM+ additional exercise from 0 to 3 months (CWT1), iBM+ additional exercise from 6 to 9 months (CWT2), and a control group (CON). Questionnaires and measurements were collected at baseline, 3, 9, 24, and 36 months. The intervention consisted of an 12 months intensified weight-loss period followed by a 24 months weight-maintenance period. Eighty (67%) subjects (mean age 46.0 years, BMI 36.2) completed the trial. Compared with the control group, all three intervention groups had significant weight loss during the 36-month intervention period (p < 0.001). The achieved weight loss remained significant at 36 months in the iBM (-6.8%, p < 0.001), the CWT1 (-5.8%, p < 0.001), and the CWT2 group (-3.9%, p < 0.001). The CWT1 group showed significant reduction in waist circumference at 9 months (-11.3 cm, p < 0.001), at 24 months (-8.8 cm, p < 0.001), and at 36 months (-8.7 cm, p < 0.001). Intensified behavioral modification alone and with exercise resulted in clinically significant weight loss and long-term weight maintenance. The addition of exercise at the onset promoted greater reductions in waist circumference. In the treatment of obesity, including severe obesity, more intensive lifestyle interventions with exercise should be incorporated.

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis.

BACKGROUND: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. METHODS: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). RESULTS: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. CONCLUSIONS: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Skin cancers and their risk factors in older persons: a population-based study.

BACKGROUND: The number of skin cancer is increasing rapidly. However, little is known about the risk factors of skin cancer in older persons. Our objectives were to determine the risk factors for skin cancer or its precursors in an older population. More specifically, to study the association of new skin cancers with previous skin cancer, sex, age, Fitzpatrick's skin type, history of outdoor work and socioeconomic status (SES). METHODS: In this retrospective cross-sectional study of a large, well documented historical cohort data set a total body skin examination (TBSE) was performed for 552 participants aged between 70 and 93 years by dermatologists. The information gathered was augmented with health register data and self-reported data. The associations between skin cancer and its risk factors were studied by using the logistic regression analyses. RESULTS: According to the TBSE skin cancer/precursor was present in 25.5% of participants and was more common in males than in females (34.5% vs 20.2%, p < 0.001). Previous skin cancer increased the risk of subsequent skin cancer 2.6-fold (OR 2.56, 95% CI 1.43-4.55) and male sex nearly 2-fold (1.97, 95% CI 1.26-3.08). Specific risk factors for the first occurrence of skin cancer were male sex and outdoor work. There was also association between skin cancer and age and socioeconomic status. CONCLUSIONS: TBSE is recommend for physicians treating older persons to allow early recognition of skin cancers or their precursors. Older males need particularly close attention.

Cardiovascular disease risk and all-cause mortality associated with accelerometer-measured physical activity and sedentary time ‒ a prospective population-based study in older adults.

BACKGROUND: Low levels of physical activity (PA) and high sedentary time (ST) are common in older adults and lack of PA is a risk factor for cardiovascular disease (CVD). Knowledge about associations with accelerometer-measured PA, ST and CVD risk in older adults is insufficient. This study examines the associations of accelerometer-measured PA and ST with cardiovascular risk measured using the Framingham risk score (FRS) and all-cause mortality in older adults. METHODS: A population-based sample of 660 (277 men, 383 women) older people (mean age 68.9) participated in the Oulu45 cohort study from 2013‒2015. PA and ST were measured with wrist-worn accelerometers at baseline for two weeks. Ten-year CVD risk (%) was estimated with FRS. The data for all-cause mortality were identified from the Digital and Population Data Services Agency, Finland after an average of 6.2 years follow-up. The associations between moderate to vigorous physical activity (MVPA), light physical activity (LPA), ST and FRS were analyzed using the multivariable linear regression analysis. Associations between LPA, ST and mortality were analyzed using the Cox proportional-hazard regression models. RESULTS: Each 10 min increase in MVPA (ß = -0.779, 95% CI -1.186 to -0.371, p < 0.001) and LPA (ß = -0.293, 95% CI -0.448 to -0.138, p < 0.001) was negatively associated with FRS while a 10 min increase in ST (ß = 0.290, 95% CI 0.158 to 0.421, p < 0.001) was positively associated with FRS. After adjustment for waist circumference, only ST was significantly associated with FRS. Each 10 min increase in LPA was associated with 6.5% lower all-cause mortality risk (HR = 0.935, 95% CI 0.884 to 0.990, p = 0.020) and each 10 min increase in ST with 5.6% increased mortality risk (HR = 1.056, 95% CI 1.007 to 1.108, p = 0.025). CONCLUSION: A higher amount of daily physical activity, at any intensity level, and avoidance of sedentary time are associated with reduced cardiovascular disease risk in older people. Higher time spent in light physical activity and lower sedentary time are associated with lower all-cause mortality.

Parental separation and offspring morbidity in adulthood: a descriptive study of the Northern Finland Birth Cohort 1966.

Aims: Rates of parental separation have increased dramatically in recent decades. We evaluated the association of individuals' childhood family structure with their somatic health over 46 years of follow-up. Methods: Data were drawn from the Northern Finland Birth Cohort, an ongoing project in which 12,058 participants born in 1966 have been followed from their 24th gestational week. Based on information supplied at age 14 years, family structure was categorised as 'single-parent family' and 'two-parent family'. The anthropometric information, data from blood samples and medical history were collected from postal questionnaires and clinical examinations routinely performed at the ages of 31 and 46 years. Results: The study population comprised a total of 10,895 individuals; 85% (n=9253) were offspring of two-parent families and 15% (n=1642) of single-parent families. Type 2 diabetes (P=0.032) or prediabetes (P=0.007), psychoactive drug problems (P<0.001) and sexually transmitted diseases (P<0.001) were more common in the single-parent family group than in the participants from two-parent families. In addition, among men back diseases (P=0.002), and among women hypertension (P=0.003) and ovary infection (P=0.024) were more frequent in individuals affected by parental death than in those from two-parent families. Conclusions: Our results indicate the association of childhood family structure with offspring morbidity during 46 years' follow-up. The lifetime morbidity was observed to be higher among offspring from a single-parent family compared to two-parent family offspring. Public and scientific concern about the consequences of parental separation on the offspring' health exist, therefore support from healthcare professionals and society is warranted.

Association of mitochondrial DNA haplogroups J and K with low response in exercise training among Finnish military conscripts.

BACKGROUND: We have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts. RESULTS: Following a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001). CONCLUSIONS: These results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.

Evaluation of High Cholesterol and Risk of Dementia and Cognitive Decline in Older Adults Using Individual Patient Meta-Analysis.

INTRODUCTION: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially relevant in older adults where individual studies report non-linear relationships between cholesterol and cognition and, in some cases, find higher cholesterol associated with a lower risk of subsequent cognitive decline or dementia. Prior evidence synthesis based on published results has not allowed us to focus on older adults or to standardize analyses across studies. Given our ageing population, an increased risk of dementia in older adults, and the need for proportionate treatment in this age group, an individual participant data (IPD) meta-analysis is timely. METHOD: We combined data from 8 studies and over 21,000 participants aged 60 years and over in a 2-stage IPD to examine the relationship between total, high-density, and low-density lipoprotein (HDL and LDL) cholesterol and subsequent incident dementia or cognitive decline, with the latter categorized using a reliable change index method. RESULTS: Meta-analyses found no relationship between total, HDL, or LDL cholesterol (per millimoles per litre increase) and risk of cognitive decline in this older adult group averaging 76 years of age. For total cholesterol and cognitive decline: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.86: 1.01) and for incident dementia: OR 1.01 [95% CI 0.89: 1.13]. This was not altered by rerunning the analyses separately for statin users and non-users or by the presence of an APOE e4 allele. CONCLUSION: There were no clear consistent relationships between cholesterol and cognitive decline or dementia in this older adult group, nor was there evidence of effect modification by statin use. Further work is needed in younger populations to understand the role of cholesterol across the life-course and to identify any relevant intervention points. This is especially important if modification of cholesterol is to be further evaluated for its potential influence on risk of cognitive decline or dementia.

Inflammation, hippocampal volume, and cognition in schizophrenia: results from the Northern Finland Birth Cohort 1966.

Increased blood interleukin-6 (IL-6) levels are a replicated abnormality in schizophrenia, and may be associated with smaller hippocampal volumes and greater cognitive impairment. These findings have not been investigated in a population-based birth cohort. The general population Northern Finland Birth Cohort 1966 was followed until age 43. Subjects with schizophrenia were identified through the national Finnish Care Register. Blood IL-6 levels were measured in n = 82 subjects with schizophrenia and n = 5373 controls at age 31. Additionally, 31 patients with schizophrenia and 63 healthy controls underwent brain structural MRI at age 34, and cognitive testing at ages 34 and 43. Patients with schizophrenia had significantly higher median (interquartile range) blood IL-6 levels than controls (5.31, 0.85-17.20, versus 2.42, 0.54-9.36, p = 0.02) after controlling for potential confounding factors. In both schizophrenia and controls, higher blood IL-6 levels were predictors of smaller hippocampal volumes, but not cognitive performance at age 34. We found evidence for increased IL-6 levels in patients with midlife schizophrenia from a population-based birth cohort, and replicated associations between IL-6 levels and hippocampal volumes. Our results complement and extend the previous findings, providing additional evidence that IL-6 may play a role in the pathophysiology of schizophrenia and associated brain alterations.

Association of hyperglycaemia with periodontal status: Results of the Northern Finland Birth Cohort 1966 study.

AIM: To investigate the association of hyperglycaemia and changes in glycaemic control with periodontal status in non-diabetic individuals. MATERIALS AND METHODS: A sub-population (n = 647) of the Northern Finland Birth Cohort 1966 was studied. We categorized long-term glucose balance based on fasting plasma glucose (FPG) at ages 31 and 46: FPG <5.0 mmol/l (strict normoglycaemia), FPG 5.0-5.59 mmol/l (slightly elevated FPG) and FPG 5.6-6.9 mmol/l (prediabetes). Probing pocket depth (PPD) and alveolar bone level (BL) data were collected at age 46. Relative risks (RR, 95% CI) were estimated using Poisson regression models. RESULTS: Periodontal status was poorer in individuals whose glucose balance worsened from age 31 to 46 years than in those with a stable glucose balance. In the case of strict normoglycaemia at age 31 and slightly elevated FPG or prediabetes at age 46, the RRs for PPD ≥4 mm were 1.8 (95% CI 1.4-2.2) and 2.8 (95% CI 2.0-3.8) and for BL ≥5 mm 1.1 (95% CI 0.8-1.4) and 1.8 (95% CI 1.2-2.8), respectively. CONCLUSION: The results of this population-based cohort study suggest that impairment in glucose control in non-diabetic individuals is associated with periodontal pocketing and alveolar bone loss.

The association between chronic venous disease and measures of physical performance in older people: a population-based study.

BACKGROUND: Muscle pump dysfunction is an essential component of chronic venous disease (CVD) pathology. Aging reduces muscle strength which further weakens the venous return. However, the epidemiology of CVD and its relationship with the physical performance in older persons is poorly studied. We studied the prevalence of CVD in subjects aged over 70 years and its association primarily with the Short Physical Performance Battery (SPPB) and 10 m walk test. METHODS: An accurate clinical leg examination was performed and the Clinical-Etiological-Anatomical-Pathophysiological-classification (CEAP, clinical classification of chronic venous disorders, C1-C6) determined by dermatologists in 552 subjects aged between 70 and 93 years belonging to the Northern Finland Birth Cohort 1966 - Parents' Study (NFBC-PS). Linear regression analyses were used to examine the association between CVD and functional tests and anthropometric measurements. RESULTS: The prevalence of CVD (C1-C6) was 54.3%. C1 was diagnosed in 22.1% (n=84), C2 in 15.2% (n=45), C3 in 8.2% (n=45), C4 in 7.8% (43), C5 in 0.4% (n=2) and C6 in 0.5% (n=3). The prevalence and severity of CVD increased with increasing age (p<0.05). Males presented more with severe stages of CVD (C4-C6) (p<0.001). Subjects with CVD had significantly lower total SPPB scores and longer times in the 10 m walk test (p<0.001). The association between CVD severity and SPPB remained statistically significant in females after adjusting for age, body mass index (BMI) and number of children. The 10 m walk test times were associated with CVD when adjusted for sex and age but not after adjusting for BMI. CONCLUSIONS: It is recommended that detailed skin examination of legs should be performed by physicians treating older subjects in order to improve early diagnosis of CVD. We highlight the importance of physical activity in older persons - lower limb activation of older persons with CVD may improve venous return and therefore prevent progression of CVD. We found an association between CVD and gait speed, however, there may exist bidirectional relationship.

Mitochondrial DNA variation in sudden cardiac death: a population-based study.

Cardiomyopathy and cardiac conduction defects are common manifestations of mitochondrial disease. Previous studies suggest that clinically asymptomatic individuals harbouring pathogenic mitochondrial DNA (mtDNA) mutations in the cardiac muscle may have sudden cardiac death (SCD) as the first manifestation of mitochondrial disease. We investigated the contribution of pathogenic mtDNA point mutations and mtDNA haplogroups in cardiac muscle in a cohort of 280 Finnish subjects that had died from non-ischaemic SCD with the median age of death at 59 years and in 537 population controls. We did not find any common or novel pathogenic mutations, but the frequency of haplogroup H1 was higher in the SCD subjects than that in 537 population controls (odds ratio: 1.76, confidence interval 95%: 1.02-3.04). We conclude that, at the population level, pathogenic point mutations in mtDNA do not contribute to non-ischaemic SCD, but natural variation may modify the risk.

Glucose metabolism in midlife predicts participation in working life: a Northern Finland Birth Cohort 1966 study.

OBJECTIVE: To evaluate how clinically measured glucose metabolism categories predict registered participation in working life. METHODS: In the 46-year follow-up of Northern Finland Birth Cohort 1966 (n=5328, 2342 men and 2986 women), we used oral glucose tolerance tests, surveys and glycated haemoglobin to determine glucose metabolism categorised as normal, pre-diabetes, screen-detected and previous type 2 diabetes (T2D). Consequent participation in working life during the 2-year follow-up period was measured as registered disability, unemployment and employment days, for which incidence rate ratios (IRRs) with 95% CIs were calculated using Poisson regression, adjusted for baseline employment and socioeconomic, health-related and behavioural factors. RESULTS: In comparison to normal glucose, all categories of impaired glucose metabolism were associated with poorer participation in working life in the unadjusted models. After adjustments, the risks (IRR (95% CI)) of disability days remained heightened by both screen-detected and previous T2D among men (1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.5), respectively), whereas among women the risks were lowered (0.9 (0.8 to 0.9) and 0.9 (0.9 to 1.0), respectively). The risks of unemployment were consistently higher in all categories of impaired glucose metabolism, and were the highest among women with previous T2D (1.6 (1.5 to 1.6)). Correspondingly, the rates of total employment days were lower in relation to screen-detected T2D among men and women (5% and 6%, respectively), and previous T2D (6% and 3%). CONCLUSIONS: Overall, impaired glucose metabolism associated with deteriorated working life participation already in middle age. The high prevalence of impaired glucose metabolism emphasises the need for actions to support sustainable working careers.

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns.

BACKGROUND: Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. OBJECTIVE: To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. METHODS: Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. RESULTS: We identified seven novel and six previously reported genetic associations (p<3.1×10-9). Three loci were associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) level, one of which was the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Our findings suggest that the blood type B associates primarily with sVCAM-1 level, while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. The genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower circulating cholesterol levels and lower cardiovascular disease risk. CONCLUSION: The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.

The association between diabetes and cognitive changes during aging.

BACKGROUND: Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age. METHODS: to address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles. RESULTS: 11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results. CONCLUSION: Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings.

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts.

AIMS/HYPOTHESIS: Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. METHODS: NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. RESULTS: Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). CONCLUSIONS/INTERPRETATION: Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.

Associations of increased physical performance and change in body composition with molecular pathways of heart disease and diabetes risk.

Higher physical activity is associated with a reduced hazard for a plethora of diseases. It has remained unknown how the two primary physical activity-associated health effects, improved physical performance and change in body composition, independently modulate metabolic profiles toward a reduced risk for adverse outcomes. Here, we utilized a prospective cohort of 664 young men undergoing military service. We studied the metabolic associations of changes in muscle performance and body composition during military service (range 6-12 mo). We subsequently replicated our results for body composition change in 234 population-based samples with a 7-yr follow-up. We found that increased physical performance was associated with reduced very-low-density lipoprotein (VLDL)-related measures [change in VLDL cholesterol: beta = -0.135; 95% confidence interval (CI) = -0.217, -0.054, P = 1.2 × 10-3] and lower inflammation (change in glycoprotein acetyls: beta = -0.138, 95% CI = -0.217, -0.059, P = 6.5 × 10-4), independent of change in body composition. Lower body fat percentage, independent of change in muscle performance, was associated with metabolic changes including lower low-density lipoprotein (LDL) cholesterol measures (change in LDL cholesterol: beta = -0.193, 95% CI = -0.295, -0.090; P = 2.5 × 10-4), increased high-density lipoprotein (HDL) cholesterol measures (change in large HDL cholesterol: beta = 0.316, 95% CI = 0.205, 0.427; P = 3.7 × 10-8), and decreased concentrations of amino acids (change in leucine concentration: beta = -0.236, 95% CI = -0.341, -0.132; P = 1.0 × 10-5) that are type 2 diabetes biomarkers. Importantly, all body fat percentage associations were replicated in a general population-based cohort. Our findings indicate that improved muscle performance showed weaker associations on the metabolic profiles than change in body composition and reduction in body fat percentage reduces cardiometabolic risk mediated by atherogenic lipoprotein particles and branched-chain and aromatic amino acid concentrations.

Insulin resistance and systemic metabolic changes in oral glucose tolerance test in 5340 individuals: an interventional study.

BACKGROUND: Insulin resistance (IR) is predictive for type 2 diabetes and associated with various metabolic abnormalities in fasting conditions. However, limited data are available on how IR affects metabolic responses in a non-fasting setting, yet this is the state people are mostly exposed to during waking hours in the modern society. Here, we aim to comprehensively characterise the metabolic changes in response to an oral glucose test (OGTT) and assess the associations of these changes with IR. METHODS: Blood samples were obtained at 0 (fasting baseline, right before glucose ingestion), 30, 60, and 120 min during the OGTT. Seventy-eight metabolic measures were analysed at each time point for a discovery cohort of 4745 middle-aged Finnish individuals and a replication cohort of 595 senior Finnish participants. We assessed the metabolic changes in response to glucose ingestion (percentage change in relative to fasting baseline) across the four time points and further compared the response profile between five groups with different levels of IR and glucose intolerance. Further, the differences were tested for covariate adjustment, including gender, body mass index, systolic blood pressure, fasting, and 2-h glucose levels. The groups were defined as insulin sensitive with normal glucose (IS-NGT), insulin resistant with normal glucose (IR-NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and new diabetes (NDM). IS-NGT and IR-NGT were defined as the first and fourth quartile of fasting insulin in NGT individuals. RESULTS: Glucose ingestion induced multiple metabolic responses, including increased glycolysis intermediates and decreased branched-chain amino acids, ketone bodies, glycerol, and triglycerides. The IR-NGT subgroup showed smaller responses for these measures (mean + 23%, interquartile 9-34% at 120 min) compared to IS-NGT (34%, 23-44%, P < 0.0006 for difference, corrected for multiple testing). Notably, the three groups with glucose abnormality (IFG, IGT, and NDM) showed similar metabolic dysregulations as those of IR-NGT. The difference between the IS-NGT and the other subgroups was largely explained by fasting insulin, but not fasting or 2 h glucose. The findings were consistent after covariate adjustment and between the discovery and replication cohort. CONCLUSIONS: Insulin-resistant non-diabetic individuals are exposed to a similar adverse postprandial metabolic milieu, and analogous cardiometabolic risk, as those with type 2 diabetes. The wide range of metabolic abnormalities associated with IR highlights the necessity of diabetes diagnostics and clinical care beyond glucose management.