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.

Climacteric status is associated with sexual dysfunction at the age of 46 years: a population-based study.

OBJECTIVE: Increasing age and menopausal transition increase the risk of sexual dysfunction. Sexual dysfunction is common in women experiencing menopause before the age of 40 years, whereas evidence on sexual function in women experiencing menopause in their mid-40s is scarce. We aimed to investigate sexual function in 46-year-old women in relation to their menopausal status. METHODS: This study cross-sectionally evaluated sexual function of women in a prospective population-based Northern Finland Birth Cohort 1966 (NFBC1966). A 46-year follow-up study of NFBC1966 included a broad questionnaire evaluating health, lifestyle, and life situation, as well as menstrual history and sexual function, and blood sampling analysis including follicle stimulating hormone and free androgen index (FAI). The participants were divided into two groups by their menopause status, defined by follicle-stimulating hormone and menstrual history. We performed logistic regression models in which parameters of sexual function were dependent factors and climacteric status, self-reported health, FAI, relationship status, smoking, and education level were independent variables. RESULTS: The study population included 2,661 women. In regression models, more advanced climacteric status was associated with higher frequency and difficulty level of low sexual desire and vaginal dryness (odds ratios with 95% confidence intervals: 2.80 [2.12-3.71], 3.22 [2.43-4.27], 3.83 [2.82-5.20], 3.75 [2.75-5.12], respectively), lower frequency of sexual thoughts (1.34 [1.02-1.75]), and higher frequency of problems with intercourse (2.35 [1.51-3.66]). Lower FAI and poorer health were associated with impaired sexual function. CONCLUSIONS: The current study suggests that women experiencing menopausal transition in their mid-40s are at risk of impaired sexual function.

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.

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

Hyperandrogenemia in Early Adulthood Is an Independent Risk Factor for Abnormal Glucose Metabolism in Middle Age.

CONTEXT: The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. OBJECTIVE: To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 years is associated with insulin resistance, insulin secretion and AGM by age 46. DESIGN: Prospective study including 5889 females followed at ages 31 and 46 years. SETTING: General community. PARTICIPANTS: Women with HA were compared with normoandrogenic women at ages 31 and 46 years. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic ß-cell function (HOMA-B). RESULTS: At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 highest FAI quartiles at ages 31 (Q4: OR = 3.76; 95% CI, 2.24-6.32) and 46 (Q4: OR = 2.79; 95% CI, 1.74-4.46) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: Q4: OR = 0.28; 95% CI, 0.17-0.44). CONCLUSION: Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.

Is climacterium by the mid-40s associated with thyroid dysfunction or autoimmunity? A population-based study.

OBJECTIVE: We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction. METHODS: This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status. RESULTS: At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1-2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6-6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction. CONCLUSIONS: More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity.

Video Summary:http://links.lww.com/MENO/A771 .

Early-onset climacterium is not associated with impaired vitamin D status: a population-based study.

OBJECTIVE: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes. METHODS: A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH <25 IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status. RESULTS: Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ±â€Š19.8 nmol/L vs 65.2 ±â€Š19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval -1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3-10.5, P = 0.013). CONCLUSIONS: The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium.

Accumulation patterns of sedentary time and breaks and their association with cardiometabolic health markers in adults.

Breaking up sedentary time with physical activity (PA) could modify the detrimental cardiometabolic health effects of sedentary time. Our aim was to identify profiles according to distinct accumulation patterns of sedentary time and breaks in adults, and to investigate how these profiles are associated with cardiometabolic outcomes. Participants (n = 4439) of the Northern Finland Birth Cohort 1966 at age 46 years wore a hip-worn accelerometer for 7 consecutive days during waking hours. Uninterrupted ≥1-min sedentary bouts were identified, and non-sedentary bouts in between two consecutive sedentary bouts were considered as sedentary breaks. K-means clustering was performed with 65 variables characterizing how sedentary time was accumulated and interrupted. Linear regression was used to determine the association of accumulation patterns with cardiometabolic health markers. Four distinct groups were formed as follows: "Couch potatoes" (n = 1222), "Prolonged sitters" (n = 1179), "Shortened sitters" (n = 1529), and "Breakers" (n = 509). Couch potatoes had the highest level of sedentariness and the shortest sedentary breaks. Prolonged sitters, accumulating sedentary time in bouts of ≥15-30 min, had no differences in cardiometabolic outcomes compared with Couch potatoes. Shortened sitters accumulated sedentary time in bouts lasting <15 min and performed more light-intensity PA in their sedentary breaks, and Breakers performed more light-intensity and moderate-to-vigorous PA. These latter two profiles had lower levels of adiposity, blood lipids, and insulin sensitivity, compared with Couch potatoes (1.1-25.0% lower values depending on the cardiometabolic health outcome, group, and adjustments for potential confounders). Avoiding uninterrupted sedentary time with any active behavior from light-intensity upwards could be beneficial for cardiometabolic health in adults.

Association of Self-Reported Polycystic Ovary Syndrome, Obesity, and Weight Gain From Adolescence to Adulthood With Hypertensive Disorders of Pregnancy: A Community-Based Approach.

The purpose of this prospective, population-based cohort study was to evaluate the roles of polycystic ovary syndrome (PCOS), obesity, weight gain, and hyperandrogenemia in the development of hypertensive disorders of pregnancy (HDP) through fertile age both in PCOS and in non-PCOS women. The study population-NFBC1966 (Northern Finland Birth Cohort 1966)-allowed a long-term follow-up of women from age 14 until 46 years who developed HDP (n=408) or did not (n=3373). HDP diagnosis was confirmed by combining hospital discharge records, data from Finnish Medical Birth Registers, and the questionnaire data at age 46. Women with self-reported PCOS (srPCOS; n=279), defined by both oligo-amenorrhea and hirsutism at age 31 or with PCOS diagnosis by age 46, were compared with women without reported PCOS (n=1577). Women with srPCOS had an increased HDP risk (odds ratio, 1.56 [95% CI, 1.03-2.37]), but the association disappeared after adjustment for body mass index. In women with srPCOS and HDP, body mass index increased from age 14 to 46 significantly more than in srPCOS women without HDP (median [interquartile range], 9.82 [6.23-14.6] and 7.21 [4.16-10.5] kg/m2, respectively; P<0.001). Also, in non-PCOS women, the increase was higher in women with (7.54 [5.32-11.62] kg/m2; P<0.001) than without HDP (6.33 [3.90-9.33] kg/m2; P<0.001). Increase in waist circumference between ages 31 and 46 years was associated with HDP but not with PCOS. Hyperandrogenemia at 31 or 46 years did not associate with HDP (1.44 [0.98-2.11]). In conclusion, obesity, especially abdominal obesity, and weight gain from adolescence to age 46, but not srPCOS or hyperandrogenemia, were associated with an increased risk of HDP.

Compositional Associations of Sleep and Activities within the 24-h Cycle with Cardiometabolic Health Markers in Adults.

PURPOSE: This study aimed to examine how compositions of 24-h time use and time reallocations between movement behaviors are associated with cardiometabolic health in a population-based sample of middle-age Finnish adults. METHODS: Participants were 3443 adults 46 yr of age from the Northern Finland Birth Cohort 1966 study. Participants wore a hip-worn accelerometer for 14 d from which time spent in sedentary behavior (SB), light-intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) were determined. These data were combined with self-reported sleep to obtain the 24-h time-use composition. Cardiometabolic outcomes included adiposity markers, blood lipid levels, and markers of glucose control and insulin sensitivity. Multivariable-adjusted regression analysis, using a compositional data analysis approach based on isometric log-ratio transformation, was used to examine associations between movement behaviors with cardiometabolic outcomes. RESULTS: More daily time in MVPA and LPA, relative to other movement behaviors, was consistently favorably associated with all cardiometabolic outcomes. For example, relative to time spent in other behaviors, 30 min·d-1 more MVPA and LPA were both associated with lower 2-h post-glucose load insulin level (-11.8% and -2.7%, respectively). Relative to other movement behaviors, more daily time in SB was adversely associated with adiposity measures, lipid levels, and markers of insulin sensitivity, and more daily time asleep was adversely associated with adiposity measures, blood lipid, fasting plasma glucose, and 2-h insulin. For example, 60 min·d-1 more SB and sleep relative to the remaining behaviors were both associated with higher 2-h insulin (3.5% and 5.7%, respectively). CONCLUSIONS: Altering daily movement behavior compositions to incorporate more MVPA at the expense of any other movement behavior, or more LPA at the expense of SB or sleep, could help to improve cardiometabolic health in midadulthood.

Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women.

OBJECTIVE: The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. DESIGN: The study is a prospective longitudinal population-based cohort study. METHODS: The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). RESULTS: In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. CONCLUSIONS: CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Onset of the climacteric phase by the mid-forties associated with impaired insulin sensitivity: a birth cohort study.

OBJECTIVE: To investigate whether the early-onset menopausal transition is associated with deteriorated glucose tolerance in women in their mid-forties. METHODS: A cross-sectional analysis of a cohort study including 2,632 women of the Northern Finland Birth Cohort 1966. The participants were divided into two groups by their menstrual history and follicle-stimulating hormone values at age 46: climacteric and preclimacteric women. Glucose and insulin parameters, as well as mathematical indices derived from them to evaluate insulin sensitivity, were compared between the groups. The results were adjusted for measured body mass index and smoking. The possible effect of hormone therapy was investigated in subanalyses excluding hormone therapy users. RESULTS: Climacteric women (n = 379) were more often current smokers at age 46 (P = 0.008), and their body mass indices increased more from 31 to 46 years (P = 0.013), compared to preclimacteric women (n = 2,253). In a multivariable generalized linear model, being climacteric at age 46 was associated with several findings suggesting decreased insulin sensitivity: increased glycated hemoglobin (P < 0.001), 2-hour oral glucose tolerance test 30- and 60-minute insulin (P = 0.040 and 0.006, respectively), and area under the insulin curve (P = 0.005). Being climacteric also was associated with a decreased the McAuley (P = 0.024) and Belfiore indices (P = 0.027) and glucose tolerance test 60-minute glucose (P = 0.015). In subanalyses excluding hormone therapy users (n = 94), the results did not change significantly. CONCLUSIONS: Earlier onset of climacteric transition is associated with impaired insulin sensitivity in middle-aged women.

Video Summary:http://links.lww.com/MENO/A648.

Overweight, obesity and hyperandrogenemia are associated with gestational diabetes mellitus: A follow-up cohort study.

INTRODUCTION: The aim of the study was to determine the association of body mass index (BMI), self-reported symptoms or diagnosis of polycystic ovary syndrome (PCOS), and hyperandrogenemia with the occurrence of gestational diabetes mellitus (GDM) through reproductive life. MATERIAL AND METHODS: A cohort of women born in 1966 were investigated at ages 14, 31 and 46. Women with self-reported PCOS symptoms (presence of both oligo-amenorrhea and hirsutism) at age 31 or with formally diagnosed polycystic ovaries (PCO)/PCOS by age 46 formed the group of self-reported PCOS (srPCOS, n = 222) and were compared with women without self-reported PCOS symptoms or diagnosis (n = 1357). We investigated also the association of hyperandrogenism (hirsutism or biochemical hyperandrogenism) at age 31 with the occurrence of GDM throughout reproductive life. RESULTS: Self-reported PCOS alone was not a risk factor for GDM, but combined with overweight at age 31 (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.22-4.86) or 46 (OR 3.04, 95% CI 1.58-5.83) srPCOS was associated with GDM when compared with normal weight controls. The association disappeared when comparing overweight srPCOS women with overweight controls. However, hyperandrogenemia at age 31, but not hirsutism, was associated with GDM even after adjustment for BMI. CONCLUSIONS: The increased risk of GDM in women with srPCOS was mostly attributed to overweight or obesity. Importantly, normal weight women with srPCOS did not seem to be at increased risk for developing GDM. However, hyperandrogenemia was associated with GDM even after adjustment for BMI. These findings strengthen the importance of weight management in reproductive-age women and suggest a noteworthy role of hyperandrogenemia in the pathophysiology of GDM.

Effect of polycystic ovary syndrome on cardiac autonomic function at a late fertile age: a prospective Northern Finland Birth Cohort 1966 study.

OBJECTIVES: Previous studies of women in their 20s and 30s have reported impaired autonomic function in women with polycystic ovary syndrome (PCOS). We aimed to study, for the first time, whether PCOS is associated with impaired cardiac autonomic function independent of metabolic and hormonal status in their late reproductive years. DESIGN: A prospective Northern Finland Birth Cohort 1966 (NFBC1966) study including 5889 women born in 1966 and followed through the age of 46. At that age, n=3706/5123 women (72%) answered the postal questionnaires and n=3280/5123 women (64%) participated in the clinical examination. SETTING: General community. PARTICIPANTS: The sample included women presenting both irregular menses (oligomenorrhoea or amenorrhoea) and hirsutism at age 31 (n=125) or with formally diagnosed PCOS by age 46 (n=181) and women without PCOS symptoms or diagnosis (n=1577). PRIMARY AND SECONDARY OUTCOME MEASURES: Heart rate variability parameters: the root mean square of successive R-R differences (rMSSD), spectral power densities (LF: low frequency and HF: high frequency) and baroreflex sensitivity (BRS). RESULTS: We found that parasympathetic activity (assessed by rMSSD: 19.5 (12.4; 31.9) vs 24.3 (16.1; 34.8) ms, p=0.004 and HF: 172 (75; 399) vs 261 (112; 565) ms2, p=0.002) and BRS (6.13±3.12 vs 6.99±3.52 ms/mm Hg, p=0.036) were lower in women with PCOS compared with the controls. However, in the multivariate regression analysis, PCOS, body mass index and the free androgen index did not significantly associate with rMSSD, whereas blood pressure, insulin resistance and triglycerides did. CONCLUSIONS: We report here for the first time that late reproductive-aged women with PCOS display impaired cardiac autonomic function manifested as decreased vagal activity. Metabolic status, rather than hyperandrogenaemia and PCOS per se, was the strongest contributing factor. Given the link between cardiac morbidity and impaired autonomic function, the findings underline the importance of screening and treating metabolic abnormalities early on in women with PCOS.

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.

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.

Are 15-Year Trajectories of Low Back Pain and Sciatica Associated With Cardiovascular Autonomic Function in the General Population?: The Northern Finland Birth Cohort 1966 Study.

STUDY DESIGN: A population-based cohort study. OBJECTIVE: The aim of this study was to examine whether 15-year trajectories of low back pain (LBP) and sciatica are associated with cardiovascular autonomic function in a large general population sample. SUMMARY OF BACKGROUND DATA: Previous studies using mainly small patient samples have suggested that LBP and sciatica are associated with abnormal cardiovascular autonomic function, namely altered heart rate variability (HRV) and baroreflex sensitivity (BRS). We examined this association in a large general population sample. METHODS: The data collections of the Northern Finland Birth Cohort 1966 consisted of pain questionnaires at 31 and 46 years (history of LBP, sciatica, and other musculoskeletal pains during the previous year; yes/no for each) and measurements of HRV and BRS at 46 years (heart rate, HR; root mean square of successive differences in beat-to-beat intervals, rMSSD; low-frequency systolic blood pressure variability, SBPV; cross-spectral BRS, BRS; each while seated and standing). The data collections also comprised several confounders. Trajectories for LBP, sciatica, and both together ("no pain," "decreasing," "increasing," "long-term pain") were constructed and general linear models were used to perform comparisons between trajectories (for HR/rMSSD, n = 3398; for SBPV/BRS, n = 1667). RESULTS: In the crude models, LBP and sciatica were associated with higher HR, lower rMSSD, higher SBPV, and lower BRS, but these associations were mostly attenuated by adjustments. Regarding both LBP and sciatica, only the "increasing" trajectory was associated with two of the eight outcomes (standing SBPV, seated BRS) after adjustments. Regarding LBP, the "increasing" trajectory was associated with three (standing SBPV, seated BRS, standing BRS), the "long-term pain" trajectory with one (standing BRS), and the "decreasing" trajectory with one outcome (seated SBPV) after adjustments. Sciatica showed no association with the outcomes after adjustments. CONCLUSION: We conclude that the 15-year trajectories of LBP and sciatica do not have a consistent independent association with cardiovascular autonomic function among the general population. LEVEL OF EVIDENCE: 3.

Intensity and temporal patterns of physical activity and cardiovascular disease risk in midlife.

Physical activity (PA) and sedentary time (SED) are associated with the risk of cardiovascular disease (CVD), but the temporal patterns of these behaviors most beneficial for cardiovascular health remain unknown. We aimed to identify the intensity and temporal patterns of PA and SED measured continuously by an accelerometer and their relationship with CVD risk. At the age of 46 years, 4582 members (1916 men; 2666 women) of the Northern Finland Birth Cohort 1966 study underwent continuous measurement of PA with Polar Active (Polar Electro, Finland) accelerometers for one week. X-means clustering was applied based on 10 min average MET (metabolic equivalent) values during the measurement period. Ten-year risk of CVD was estimated using the Framingham risk model. Most of the participants had low risk for CVD. Four distinct PA clusters were identified that were well differentiable by the intensity and temporal patterns of activity (inactive, evening active, moderately active, very active). A significant difference in 10-year CVD risk across the clusters was found in men (p = 0.028) and women (p < 0.001). Higher levels of HDL cholesterol were found in more active clusters compared to less active clusters (p < 0.001) in both genders. In women total cholesterol was lower in the moderately active cluster compared to the inactive and evening active clusters (p = 0.001). Four distinct PA clusters were recognized based on accelerometer data and X-means clustering. A significant difference in CVD risk across the clusters was found in both genders. These results can be used in developing and promoting CVD prevention strategies.

Childhood growth patterns and cardiovascular autonomic modulation in midlife: Northern Finland 1966 Birth Cohort Study.

OBJECTIVES: To test the hypothesis that age and body mass index (BMI) at BMI peak during infancy and at BMI rebound in childhood are related to cardiovascular autonomic modulation in adulthood. METHODS: At the age of 46 years, a sample (n = 5861) of the participants of the Northern Finland Birth Cohort 1966 took part in follow-up examinations. Heart rate variability (HRV), baroreflex sensitivity (BRS) and low-frequency oscillations of systolic blood pressure (LFSBP) were measured during sympathetic stimulus by standing. BMI at various ages was calculated from frequent anthropometric measurements collected from child welfare clinical records. BRS and LFSBP were available for 1243 participants with BMI peak data and 1524 participants with BMI rebound data, and HRV for 2137 participants with BMI peak data and 2688 participants with BMI rebound data. RESULTS: Age at BMI rebound had a significant inverse association with LFSBP (beta = -0.071, p = 0.006) after all adjustments (p < 0.001) and was also directly associated with BRS (beta = 0.082, p = 0.001) independently of birth and maternal factors (p = 0.023). BMI at BMI peak and at BMI rebound was inversely associated with high-frequency component of HRV (HF) (beta = -0.045, p = 0.036 for BMI at peak; beta = -0.043, p = 0.024 for BMI at rebound) and directly associated with the ratio of low- and high-frequency components of HRV (LF/HF ratio) (beta = 0.084, p = < 0.001 for BMI at peak; beta = 0.069, p < 0.001 for BMI at rebound). These associations remained significant after all adjustments (p < 0.05 for all). CONCLUSIONS: This novel study shows that younger age at BMI rebound and higher BMI at BMI peak and at BMI rebound are associated with higher levels in markers suggestive of augmented sympathetic and reduced vagal cardiovascular modulation in midlife.