OBJECTIVE: Early pubertal onset in females is associated with increased risk for adult obesity and cardiovascular disease, but whether this relationship is independent of preceding childhood growth ...events is unclear. Furthermore, the association between male puberty and adult disease remains unknown. To clarify the link between puberty and adult health, we evaluated the relationship between pubertal timing and risk factors for type 2 diabetes and cardiovascular disease in both males and females from a large, prospective, and randomly ascertained birth cohort from Northern Finland. RESEARCH DESIGN AND METHODS: Pubertal timing was estimated based on pubertal height growth in 5,058 subjects (2,417 males and 2,641 females), and the relationship between puberty and body weight, glucose and lipid homeostasis, and blood pressure at age 31 years was evaluated with linear regression modeling. RESULTS: Earlier pubertal timing associated with higher adult BMI, fasting insulin, diastolic blood pressure, and decreased HDL cholesterol in both sexes (P < 0.002) and with higher total serum cholesterol, LDL cholesterol, and triglycerides in males. The association with BMI and diastolic blood pressure remained statistically significant in both sexes, as did the association with insulin levels and HDL cholesterol concentrations in males after adjusting for covariates reflecting both fetal and childhood growth including childhood BMI. CONCLUSIONS: We demonstrate independent association between earlier pubertal timing and adult metabolic syndrome-related derangements both in males and females. The connection emphasizes that the mechanisms advancing puberty may also contribute to adult metabolic disorders.
Context: Knowledge is scarce concerning the significance of thyroid dysfunction/antibodies during pregnancy in regard to pregnancy complications/later maternal morbidity.
Objective: The aim of this ...study was to evaluate the association between maternal thyroid dysfunction/antibodies during pregnancy and pregnancy complications or later maternal hypertension, diabetes, and thyroid disease.
Design and Setting: We studied a prospective population-based cohort, Northern Finland Birth Cohort 1986 (NFBC 1986), with follow-up of 20 yr. Medication and hospital discharge records were used to assess maternal morbidity to hypertension, diabetes, and thyroid diseases.
Participants: The study consisted of mothers of NFBC 1986 with early pregnancy serum samples for thyroid function and antibody analyses (n = 5805). Mothers were grouped and compared according to these test results.
Main Outcome Measures: We focused on preeclampsia and gestational diabetes during index pregnancy, later maternal hypertension, diabetes, and thyroid disease morbidity and total mortality.
Results: Thyroid dysfunction and antibodies were not associated with pregnancy complications. Overt hypothyroidism was associated with subsequent maternal thyroid disease hazard ratio (HR) (95% confidence interval), 17.7 (7.8–40.6) and diabetes 6.0 (2.2–16.4). Subclinical hypothyroidism 3.3 (1.6–6.9), TPO-Ab-positivity 4.2 (2.3–7.4), and TG-Ab-positivity 3.3 (1.9–6.0) were also associated with later thyroid disease. No association was found between thyroid dysfunction/antibodies and hypertension or overall mortality.
Conclusions: Thyroid dysfunction and antibodies during pregnancy seem to predict later thyroid disease. Overt hypothyroidism poses risk of diabetes.
Thyroid dysfunction and antibodies during pregnancy seem to predict later maternal morbidity to thyroid diseases.
Scope
Diet and exercise are significant players in obesity and metabolic diseases. Time‐restricted feeding (tRF) has been shown to improve metabolic responses by regulating circadian clocks but ...whether it acts synergically with exercise remains unknown. It is hypothesized that forced exercise alone or combined with tRF alleviates obesity and its metabolic complications.
Methods and results
Male C57bl6 mice are fed with high‐fat or a control diet for 12 weeks either ad libitum or tRF for 10 h during their active period. High‐fat diet (HFD)‐fed mice are divided into exercise (treadmill for 1 h at 12 m min−1 alternate days for 9 weeks and 16 m min−1 daily for the following 3 weeks) and non‐exercise groups. tRF and tRF‐Ex significantly decreased body weight, food intake, and plasma lipids, and improved glucose tolerance. However, exercise reduced only body weight and plasma lipids. tRF and tRF‐Ex significantly downregulated Fasn, Hmgcr, and Srebp1c, while exercise only Hmgcr. HFD feeding disrupted clock genes, but exercise, tRF, and tRF‐Ex coordinated the circadian clock genes Bmal1, Per2, and Rev‐Erbα in the liver, adipose tissue, and skeletal muscles.
Conclusion
HFD feeding disrupted clock genes in the peripheral organs while exercise, tRF, and their combination restored clock genes and improved metabolic consequences induced by high‐fat diet feeding.
High‐fat diet feeding disrupts metabolic and circadian clock genes in mice. Forced exercise, time‐restricted feeding, and their combinations resynchronize clock genes in peripheral organs and improve metabolic consequences. The combination of exercise and time‐restricted feeding results in the greatest reduction in body weight, plasma lipids, and improved insulin sensitivity compared to either exercise or time‐restricted feeding alone.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT ...is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies.
This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland (January 1, 2006-December 31, 2010). We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants (n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm -61.26 g (±SE 24.12, P < 0.01), preterm -232.90 g (±SE 17.24, P < .001), near term -171.50 g (±SE 17.52, P < .001), and at term -101.95 g (±SE 10.89, P < .001). Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm -61.54 g (±SE 28.62, P < .03), preterm -222.78 g (±SE 19.64, P < .001), near term -159.25 g (±SE 19.14, P < .001), and at term -91.62 g (±SE 11.86, P < .03). Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: -220.18 g (±SE 21.43, P < .001), -140.68 g (±SE 23.09, P < .001), and -89.38 g (±SE 14.16, P < .001), born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested.
In this study, ACT was consistently associated with reduction in birth size for infants born preterm, near term, or at term. Further investigation is warranted alongside reevaluation of guidelines. Efforts need to be made to correctly identify and target patients who will deliver preterm. Reduced growth should be considered when deliberating early care decisions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Observational findings for high‐density lipoprotein (HDL)‐mediated cholesterol efflux capacity (HDL‐CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic ...architecture of HDL‐CEC is limited.
Objectives
A large‐scale observational study on the associations of HDL‐CEC and other HDL‐related measures with CHD and the largest genome‐wide association study (GWAS) of HDL‐CEC.
Participants/methods
Six independent cohorts were included with follow‐up data for 14,438 participants to investigate the associations of HDL‐related measures with incident CHD (1,570 events). The GWAS of HDL‐CEC was carried out in 20,372 participants.
Results
HDL‐CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL‐C). In contradiction, almost all HDL‐related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL‐CEC independent of HDL‐C and triglycerides.
Conclusion
HDL‐CEC is not unequivocally associated with CHD in contrast to HDL‐C, apolipoprotein A‐I, and most of the HDL subclass particle concentrations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Our work is motivated by the search for metabolite quantitative trait loci (QTL) in a cohort of more than 5000 people. There are 158 metabolites measured by NMR spectroscopy in the 31‐year follow‐up ...of the Northern Finland Birth Cohort 1966 (NFBC66). These metabolites, as with many multivariate phenotypes produced by high‐throughput biomarker technology, exhibit strong correlation structures. Existing approaches for combining such data with genetic variants for multivariate QTL analysis generally ignore phenotypic correlations or make restrictive assumptions about the associations between phenotypes and genetic loci. We present a computationally efficient Bayesian seemingly unrelated regressions model for high‐dimensional data, with cell‐sparse variable selection and sparse graphical structure for covariance selection. Cell sparsity allows different phenotype responses to be associated with different genetic predictors and the graphical structure is used to represent the conditional dependencies between phenotype variables. To achieve feasible computation of the large model space, we exploit a factorisation of the covariance matrix. Applying the model to the NFBC66 data with 9000 directly genotyped single nucleotide polymorphisms, we are able to simultaneously estimate genotype–phenotype associations and the residual dependence structure among the metabolites. The R package BayesSUR with full documentation is available at https://cran.r‐project.org/web/packages/BayesSUR/
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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