The effect of vitamin D supplementation on the incidence of type 2 diabetes in healthy older adults not at high risk for diabetes (FIND): a randomised controlled trial.

Aims/hypothesis: Vitamin D insufficiency is associated with an elevated risk of type 2 diabetes, but evidence from randomised trials on the benefits of vitamin D supplementation is limited, especially for average-risk populations. The Finnish Vitamin D Trial (FIND) investigated the effects of vitamin D supplementation at two different doses on the incidence of type 2 diabetes in a generally healthy older adult population.

Methods: FIND was a 5 year randomised placebo-controlled, parallel-arm trial among 2271 male and female participants aged ≥60 years and ≥65 years, respectively, from a general Finnish population who were free of CVD or cancer and did not use diabetes medications.

The effect of vitamin D supplementation on atrial fibrillation in generally healthy men and women: The Finnish Vitamin D Trial.

Atrial fibrillation is a common cardiac arrhythmia with high morbidity risk. Observational studies suggest that vitamin D deficiency is associated with higher atrial fibrillation risk but there is limited evidence whether vitamin D supplementation could affect the risk. In these post hoc analyses from the Finnish Vitamin D Trial, we compared the incidence of atrial fibrillation with 5-year supplementation of vitamin D (1600 IU/d or 3200 IU/d) vs placebo.

Multiplicative, additive, and interactive associations of 25-hydroxyvitamin D with lung and prostate cancer.

Results regarding the epidemiological association of vitamin D with lung (LCA) and prostate cancer (PCA) are controversial. This study tested whether serum 25-hydroxyvitamin D [25(OH)D] concentrations have interactive epidemiological associations with smoking, the number-one risk factor for LCA, and age, the number-one risk factor for PCA. Also, this study investigated whether the associations of 25(OH)D, smoking, age, alcohol consumption, body mass index, diet (the healthy Nordic diet score), and physical activity with incident LCA and PCA are multiplicative or additive.

How competing risks affect the epidemiological relationship between vitamin D and prostate cancer incidence? A population-based study.

We hypothesized that controversial results regarding the epidemiological relationship between circulating 25-hydroxyvitamin D, 25(OH)D, and risk of prostate cancer (PCA) incidence are partly due to competing risks. To test the hypothesis, we studied associations across 25(OH)D, PCA and death in 2578 middle-aged men belonging to the Kuopio Ischaemic Heart Disease Risk Factor Study. The men were free of cancer at baseline, and the mean (SD) follow-up time was 23.

Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial: a randomized controlled trial.

Background: Vitamin D insufficiency is associated with risks of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited.

Objectives: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidences.

Methods: The study was a 5-year, randomized, placebo-controlled trial among 2495 male participants ≥60 years and post-menopausal female participants ≥65 years from a general Finnish population who were free of prior CVD or cancer.

Metabolic Profiling of High Egg Consumption and the Associated Lower Risk of Type 2 Diabetes in Middle-Aged Finnish Men.

Scope: Higher egg intake was previously associated with a lower risk of developing type 2 diabetes (T2D) in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. Potential compounds that can explain this association are explored using nontargeted LC-MS-based metabolic profiling.

Methods And Results: Two hundred and thirty-nine baseline serum samples from the KIHD are analyzed in four groups: subjects with higher (mean intake one egg per day) or lower (mean intake two eggs per week) egg intake who developed T2D (cases) or remained heatlhy (controls) during the mean follow-up of 19.

In vivo transcriptome changes of human white blood cells in response to vitamin D.

In the vitamin D intervention study VitDbol (NCT02063334) blood samples were drawn directly before an oral bolus (2000 μg vitamin D) and 24 h later. The focus of phase II of VitDbol was the transcriptome-wide analysis of the effects of vitamin D gene expression in human peripheral blood mononuclear cells (PBMCs). All five participants responded in an individual fashion to the bolus by increases in serum levels of the vitamin D metabolites 25-hydroxyvitamin D (25(OH)D) and 1α,25-dihydroxyvitamin D (1,25(OH)D).

In vivo response of the human epigenome to vitamin D: A Proof-of-principle study.

In vitro cell culture studies showed that the hormonal form of vitamin D, 1α,25-dihydroxyvitamin D, significantly (p < 0.05) affects the human epigenome at thousands of genomic loci. Phase II of the VitDbol vitamin D intervention trial (NCT02063334) involved a proof-of-principle study of one individual, who was exposed three times every 28 days to an oral bolus (2000 μg) of vitamin D.

Follicle-Stimulating Hormone Levels and Subclinical Atherosclerosis in Older Postmenopausal Women.

Recent studies of perimenopausal women suggest that follicle-stimulating hormone (FSH) levels may be associated with atherosclerosis, independent of estradiol. Whether FSH is related to atherosclerosis in older postmenopausal women, who have completed the menopausal transition, remains unknown. We assessed the relationship of serum FSH and estradiol levels with carotid artery intima-media thickness (IMT) among 587 postmenopausal participants in the Kuopio Ischemic Heart Disease Risk Factor Study (Kuopio, Finland).

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.

Background: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.

Methods: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes.

Serum dihomo-γ-linolenic acid level is inversely associated with the risk of depression. A 21-year follow-up study in general population men.

Background: Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation.

Association of follicle-stimulating hormone levels and risk of type 2 diabetes in older postmenopausal women.

Objective: Recent studies of perimenopausal women have observed associations of follicle-stimulating hormone (FSH) levels with markers of insulin resistance, independent of estradiol. Whether FSH is related to type 2 diabetes (T2D) in older women who have completed the menopause transition remains unknown. We assessed the association of FSH levels with diabetes and measures of insulin resistance among 588 postmenopausal Finnish women.

Low serum 25-hydroxyvitamin D is associated with higher risk of frequent headache in middle-aged and older men.

Vitamin D has been suggested to have a role in various neurovascular diseases, but the data regarding headache is inconclusive. Our aim was to investigate the associations between serum 25-hydroxyvitamin D [25(OH)D], a marker for vitamin D status, and risk of frequent headache. The study population consisted of 2601 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) from eastern Finland, aged 42-60 years in 1984-1989.

Molecular evaluation of vitamin D responsiveness of healthy young adults.

Vitamin D has via its metabolites 25-hydroxyvitamin D (25(OH)D) and 1α,25-dihydroxyvitamin D (1,25(OH)D) direct effects on the transcriptome and the epigenome of most human cells. In the VitDbol study we exposed 35 healthy young adults to an oral vitamin D dose (2000μg) or placebo and took blood samples directly before the supplementation as well as at days 1, 2 and 30. Within 24h the vitamin D intake raised the average serum levels of both 25(OH)D and 1,25(OH)D by approximately 20%.

From pure compounds to complex exposure: Effects of dietary cadmium and lignans on estrogen, epidermal growth factor receptor, and mitogen activated protein kinase signaling in vivo.

Exposure to environmental endocrine active compounds correlates with altered susceptibility to disease in human populations. Chemical risk assessment is single compound based, although exposure often takes place as heterogeneous mixtures of man-made and natural substances within complex matrices like diet. Here we studied whether the effects of cadmium and enterolactone on endocrine endpoints in dietary exposure can be predicted based on pure compound effects.

Serum n-6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Background: The role of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations.

Objectives: We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations.

Glucose Metabolism Effects of Vitamin D in Prediabetes: The VitDmet Randomized Placebo-Controlled Supplementation Study.

Epidemiological evidence suggests a role for vitamin D in type 2 diabetes prevention. We investigated the effects of vitamin D3 supplementation on glucose metabolism and inflammation in subjects with prediabetes. A 5-month randomized, double-blind, placebo-controlled intervention with three arms (placebo, 40 μg/d, or 80 μg/d vitamin D3) was carried out among sixty-eight overweight (BMI 25-35) and aging (≥60 years) subjects from Finland, with serum 25-hydroxyvitamin D3 [25(OH)D3] < 75 nmol/L and either impaired fasting glucose or impaired glucose tolerance.

Relevance of vitamin D receptor target genes for monitoring the vitamin D responsiveness of primary human cells.

Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels.

The association between serum 25-hydroxyvitamin D3 concentration and risk of disease death in men: modification by magnesium intake.

Low vitamin D status increases the risk of death. Magnesium plays an essential role in vitamin D metabolism and low magnesium intake may predispose to vitamin D deficiency and potentiate the health problems. We investigated whether magnesium intake modifies the serum 25(OH)D3 concentration and its associations with mortality in middle-aged and older men.

Dissecting high from low responders in a vitamin D3 intervention study.

Vitamin D3 is a pleiotropic signaling molecule that has via activation of the transcription factor vitamin D receptor (VDR) a direct effect on the expression of more than 100 genes. The aim of this study was to find transcriptomic and clinical biomarkers that are most suited to identify vitamin D3 responders within 71 pre-diabetic subjects during a 5-month intervention study (VitDmet). In hematopoietic cells, the genes ASAP2, CAMP, CD14, CD97, DUSP10, G0S2, IL8, LRRC8A, NINJ1, NRIP1, SLC37A2 and THBD are known as primary vitamin D targets.

Changes in vitamin D target gene expression in adipose tissue monitor the vitamin D response of human individuals.

Scope: Vitamin D₃, its biologically most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and the vitamin D receptor (VDR) are important for adipose tissue biology.

Methods And Results: We extrapolated genomic VDR association loci in adipocytes from 55 conserved genome-wide VDR-binding sites in nonfat tissues. Taking the genes DUSP10, TRAK1, NRIP1, and THBD as examples, we confirmed the predicted VDR binding sites upstream of their transcription start sites and showed rapid mRNA up-regulation of all four genes in SGBS human pre-adipocytes.

Primary vitamin D receptor target genes as biomarkers for the vitamin D3 status in the hematopoietic system.

Vitamin D(3) belongs to the few nutritional compounds that has, via the binding of its metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. The relation of thousands of genomic VDR-binding sites to a few hundred primary 1,25(OH)(2)D(3) target genes is still largely unresolved. We studied chromatin domains containing genes for the adhesion molecules CD97 and LRRC8A, the glucose transporter SLC37A2 and the coactivator NRIP1.

Intake of fruit, berries, and vegetables and risk of type 2 diabetes in Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Background: Although higher intakes of fruit, berries, and vegetables (FBV) have been associated with reduced risk of type 2 diabetes (T2D) in some observational studies, the evidence is limited and inconclusive.

Objective: We assessed the relation of FBV intake and T2D incidence in Finnish men.

Design: We studied 2332 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study who were aged 42-60 y and free of T2D or impaired fasting glucose at baseline in 1984-1989.

Primary vitamin D target genes allow a categorization of possible benefits of vitamin D₃ supplementation.

Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants.

Serum 25-hydroxyvitamin D3 and the risk of pneumonia in an ageing general population.

Background: Vitamin D has been suggested to have a role in infection defence and on the immune system. We therefore investigated the effect of serum 25-hydroxyvitamin D₃ (25(OH)D₃) on the risk of incident hospitalised pneumonia in an ageing general population in eastern Finland.

Methods: The study population included 723 men and 698 women aged 53-73 years from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor study who were free of pneumonia, other pulmonary diseases and cancer at baseline in 1998-2001.