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Background Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression relevant to obesity, T2D and the metabolic syndrome using a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products. Results The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 h and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE genes. Conclusions Our preliminary studies have identified a large number of genes relevant to obesity, T2D and metabolic syndrome whose expression was changed significantly in human TPH1 cells following incubation with betel-nut derived arecoline or with MNPA. These findings require validation by further cell-based work and investigation amongst betel-chewing communities.

Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration 50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected., This Review highlights results from large randomized clinical trials performed during the period 2017–2020 and Mendelian randomization studies on vitamin D levels. Together, findings indicate that vitamin D supplementation alone in vitamin D-replete adults does not provide health benefits; however, vitamin D deficiency should always be corrected., Key points Vitamin D and calcium supplementation can cure nutritional rickets and can modestly decrease the risk of major fractures in older adults with poor vitamin D status or calcium intake.Large supplementation trials recruiting vitamin D-replete adults (serum 25OHD concentration >50 nmol/l) have demonstrated no effects on the incidence of cancer, cardiovascular events or type 2 diabetes mellitus (T2DM) and no benefits in terms of bone density and the risk of falls.Post-hoc analysis of large supplementation trials has suggested that supplementation of individuals with vitamin D deficiency modestly delays age-related bone loss and progression to T2DM, and improves lung function.A meta-analysis suggested that vitamin D supplementation results in a modest decrease in cancer mortality.Over 60 Mendelian randomization studies have examined causal links between genetically lower vitamin D levels and health outcomes; most studies generated null effects except four studies that demonstrated an increased risk of multiple sclerosis.In conclusion, supplementation of vitamin D-replete individuals does not generate overall health benefits; however, correction of severe vitamin D deficiency remains essential.

Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world’s population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

Discrepancies between current guidance from NICE on the treatment of vitamin D deficiency and the recommended daily amounts [RDAs] for its prevention in the UK

IntroductionSeveral studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population.MethodsParticipants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9–12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as “a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene”.Results820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8–66.5) and 65.5 (63.3–67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0–63.0) nmol/L and 41.3 (29.8–53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p ConclusionCirculating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.

Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.

Many diseases have large seasonal variations in which winter overall mortality rates are about 25% higher than in summer in mid-latitude countries, with cardiovascular diseases and respiratory infections and conditions accounting for most of the variation. Cancers, by contrast, do not usually have pronounced seasonal variations in incidence or mortality rates. This narrative review examines the epidemiological evidence for seasonal variations in blood pressure, cardiovascular disease rates and respiratory viral infections in relation to atmospheric temperature and humidity, and solar UV exposure through vitamin D production and increased blood concentrations of nitric oxide. However, additional mechanisms most likely exist by which solar radiation reduces the risk of seasonally varying diseases. Some studies have been reported with respect to temperature without considering solar UV doses, although studies regarding solar UV doses, such as for respiratory infections, often consider whether temperature can affect the findings. More research is indicated to evaluate the relative effects of temperature and sun exposure on the seasonality of mortality rates for several diseases. Since solar ultraviolet-B (UVB) doses decrease to vanishingly small values at higher latitudes in winter, the use of safe UVB lamps for indoor use in winter may warrant consideration.

Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence to link it with obesity, type 2 diabetes and the metabolic syndrome. We adopted a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products to identify gene expression changes relevant to obesity, type 2 diabetes and the metabolic syndrome. The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 hours and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (qCLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE. In summary, these pilot studies have identified a large number of genes whose expression was changed significantly in human TPH1 cells following incubation with arecoline or with 3-methylnitrosaminopropionaldehyde. These findings suggest that further investigation of these genes in betel-quid chewers with obesity and/or type 2 diabetes is warranted.

Vitamin D deficiency is common, world-wide, but vitamin D repletion throughout life, and into older age, has accepted health benefits for bone. Many mechanisms through which vitamin D also benefits soft tissues are understood, and clinical evidence of such benefits is now accumulating, especially following re-analyses of trial data, which are revealing previously missed health benefits with correction of deficiency.The sources of vitamin D, its activation, mechanistic effects; problems of trials of supplementation for reducing health risks, the benefits shown for mortality, cardiovascular disease, infection and cancer; the global problem of vitamin D deficiency; age-related reductions in vitamin D efficacy, and currently recommended intakes.High prevalence of vitamin D deficiency and insufficiency worldwide have proven ill-effects on health. Governmental efforts to improve population repletion by recommending minimal daily intakes does benefit some but is not effective at the population-level. However, food fortification with vitamin D3, already implemented in some countries, can solve this highly avoidable problem cost-effectively and is probably the best way to abolish vitamin D inadequacy, allowing public health benefits to emerge over time, thereby allowing future research on vitamin D to be directed at emerging issues on vitamin D.

To investigate seasonal variations of vitamin D status at different latitudes and if these changes are accompanied by corresponding variations in certain health parameters in children living in a broad latitudinal range in Iran.Longitudinal study.In total, 530 apparently healthy children aged 5-18 years were randomly selected from six regions of Iran with a latitudinal gradient from 29°N to 37·5°N. All anthropometric and biochemical assessments were performed twice during a year (summer, winter). High BMI (Z-score1), low HDL cholesterol (150 mg/dl) were considered cardiometabolic risk factors.Serum 25-hydroxyvitamin D (25(OH)D) showed between-season variation, with significantly higher concentrations (mean (sd)) in summer v. winter (43 (29) v. 27 (18) nmol/l; P33°N v.33°N: 4·5; 0·09, 9·0; P=0·04) were predictors of change of serum 25(OH)D between two seasons.Summertime improvement of vitamin D status was accompanied by certain improved cardiometabolic risk factors, notably serum TAG, total cholesterol and BMI, in children.

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Publications from clinical trials of vitamin D supplementation have increased substantially over the last 15 years. Yet, despite the growing number of randomized controlled trials, meta-analyses of these studies have drawn inconsistent conclusions. Many meta-analyses assume that vitamin D is a pharmacological agent, and give scant consideration of it being a nutrient. This limits their potential to detect beneficial effects in participants with vitamin D deficiency. An increasing body of evidence from both observational studies and clinical trials supports the presence of thresholds in vitamin D status below which disease risk increases and vitamin supplementation has beneficial effects. Future supplementation trials which seek to replicate these findings should recruit sufficient numbers of participants with low vitamin D levels, and not give low-dose vitamin D to the placebo group. If the presence of vitamin D thresholds for beneficial effects is confirmed, this would strengthen the need for vitamin D fortification of foods.

In their report on the roles of vitamin D status during early life development in Australia, Di Marco et al [...]

Context Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. Objective To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. Methods We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. Results Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups. Conclusions Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3., Data from this randomized controlled trial show that vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, and increases 24R-hydroxylation of 25(OH)D3.

Aims To investigate the effect of short‐term vitamin D supplementation on cardiometabolic outcomes among individuals with an elevated risk of diabetes. Methods In a double‐blind placebo‐controlled randomized trial, 340 adults who had an elevated risk of type 2 diabetes (non‐diabetic hyperglycaemia or positive diabetes risk score) were randomized to either placebo, 100 000 IU vitamin D2 (ergocalciferol) or 100 000 IU vitamin D3 (cholecalciferol), orally administered monthly for 4 months. The primary outcome was change in glycated haemoglobin (HbA1c) between baseline and 4 months, adjusted for baseline. Secondary outcomes included: blood pressure; lipid levels; apolipoprotein levels; C‐reactive protein levels; pulse wave velocity (PWV); anthropometric measures; and safety of the supplementation. Results The mean [standard deviation (s.d.)] 25‐hydroxyvitamin D [25(OH)D]2 concentration increased from 5.2 (4.1) to 53.9 (18.5) nmol/l in the D2 group, and the mean (s.d.) 25(OH)D3 concentration increased from 45.8 (22.6) to 83.8 (22.7) nmol/l in the D3 group. There was no effect of vitamin D supplementation on HbA1c: D2 versus placebo: −0.05% [95% confidence interval (CI) −0.11, 0.02] or −0.51 mmol/mol (95% CI −1.16, 0.14; p = 0.13); D3 versus placebo: 0.02% (95% CI −0.04, 0.08) or 0.19 mmol/mol (95% CI −0.46, 0.83; p = 0.57). There were no clinically meaningful effects on secondary outcomes, except PWV [D2 versus placebo: −0.68 m/s (95% CI −1.31, −0.05); D3 versus placebo −0.73 m/s (95% CI −1.42, −0.03)]. No important safety issues were identified. Conclusions Short‐term supplementation with vitamin D2 or D3 had no effect on HbA1c. The modest reduction in PWV with both D2 and D3 relative to placebo suggests that vitamin D supplementation has a beneficial effect on arterial stiffness.

This review was conducted to clarify both the complex interrelationship between adiposity and vitamin D and the clinical implications of vitamin D status on metabolic abnormalities associated with obesity. Obesity increases the risk of vitamin D deficiency, a finding consistently reported across all ages and in different population groups. According to genetic studies, this is driven by the effect of higher adiposity, which causes a reduction in circulating concentrations of 25-hydroxyvitamin D [25(OH)D, used as an indicator of vitamin D status]. Conversely, higher concentrations of 25(OH)D do not appear to affect the risk of obesity. Evidence from clinical trials using vitamin D supplementation to achieve weight reduction is limited. Some trials, however, have suggested that concomitant supplementation with vitamin D and calcium potentially reduces central fat deposits, especially in individuals with low dietary calcium intakes. Adiposity has important implications for the efficacy of vitamin D supplementation, and increases in 25(OH)D concentrations are generally lower in obese than in normal-weight individuals. Active hormonal vitamin D has many mechanistic effects, both physiologically and biochemically, that could counteract the harmful effects of obesity on metabolism and reduce the risks of metabolic abnormalities and tissue damage consequent to adiposity. Whether improvements in the overall obesogenic metabolic profile can be achieved by vitamin D supplementation, however, is still unknown. Refereed/Peer-reviewed

The widely used lipid-lowering drug niacin is reported to induce hyperglycemia during chronic and high-dose treatments, but the mechanism is poorly understood. Recently, the niacin receptor [G-protein-coupled receptor, (GPR) 109a], has been localized to islet cells while its potential role therein remains unclear. We, therefore, aimed at investigating how GPR109a regulates islet beta-cell function and its downstream signaling using high-fat diet-induced obese mice and INS-1E beta cells. Eight-week niacin treatment elevated blood glucose concentration in obese mice with increased areas under the curve at oral glucose and intraperitoneal insulin tolerance tests. Additionally, niacin treatment significantly decreased glucose-stimulated insulin secretion (GSIS) but induced peroxisome proliferator-activated receptor gamma (Pparg) and GPR109a expression in isolated pancreatic islets; concomitantly, reactive oxygen species (ROS) were transiently increased, with decreases in GSIS, intracellular cyclic adenosine monophosphate (cAMP) accumulation and mitochondrial membrane potential (ΔΨm), but with increased expression of uncoupling protein 2 (Ucp2), Pparg and Gpr109a in INS-1E cells. Corroborating these findings, the decreases in GSIS, ΔΨm and cAMP production and increases in ROS, Pparg and GPR109a expression were abolished in INS-1E cells by GPR109a knockdown. Our data indicate that niacin-induced pancreatic islet dysfunction is probably modulated through activation of the islet beta-cell GPR109a-induced ROS-PPARγ-UCP2 pathways.

International audience; The objective was to provide the current state of the art regarding the role of vitamin D in chronic diseases (osteoporosis, cancer, cardiovascular diseases, dementia, autism, type 1 and type 2 diabetes mellitus, male and female fertility). The document was drawn up by panelists that provided their contribution according to their own scientific expertise. Each scientific expert supplied a first draft manuscript on a specific aspect of the document’s topic that was subjected to voting by all experts as “yes” (agreement with the content and/or wording) or “no” (disagreement). The adopted rule was that statements supported by ≥75 % of votes would be immediately accepted, while those with \textless25 % would be rejected outright. Others would be subjected to further discussion and subsequent voting, where ≥67 % support or, in an eventual third round, a majority of ≥50 % would be needed. This document finds that the current evidence support a role for vitamin D in bone health but not in other health conditions. However, subjects with vitamin D deficiency have been found to be at high risk of developing chronic diseases. Therefore, although at the present time there is not sufficient evidence to recommend vitamin D supplementation as treatment of chronic diseases, the treatment of vitamin D deficiency should be desiderable in order to reduce the risk of developing chronic diseases.

The increased risk of vitamin D deficiency in obesity is well established. There is substantial variation in the estimated strength of the association between different population groups, likely reflecting methodological issues in measuring adiposity and 25(OH)D concentrations. Genetic studies have shown that higher body mass index (BMI) is a causal risk factor for low 25(OH)D concentrations and have also shown that higher 25(OH)D does not, in turn, affect BMI. Clinical trial evidence for benefits of vitamin D supplementation in terms of affecting weight gain or adiposity remains limited. There are some clinical trials, typically with concomitant calcium supplementation and in the presence of low-dietary calcium intakes, which have suggested potential reductions in central fat deposits. Vitamin D supplementation is notably less effective in increasing 25(OH)D concentrations in obese compared with normal-weight participants. Although causality of association remains to be established, at the physiological and biochemical level active hormonal vitamin D has been shown to have many mechanistic effects counteracting ill-effects of obesity, which can reduce the risks of tissue damage consequent to adiposity, and its related metabolic disorders.

International audience; Several reports describe U-shaped 25-hydroxyvitamin D [25(OH)D] concentration–health outcomes, including musculo-skeletal disorders such as falls and fractures, several cancers, cardiovascular disease (CVD), cognitive function, all-cause mortality rates, birth outcomes, allergic reactions, frailty, and some other disorders. This paper reviews reports of U-shaped outcome associations with vitamin D status for evidence of underlying pathophysiological processes, or of confounding, finding that some U-shaped associations appear to be biologically meaningful, but that many could well reflect confounding by factors such as lifestyle, or hypovitaminosis D-related disease onset being masked by self-supplementation that was begun too late to correct developing health problems but before baseline vitamin D status assessment. However, the various U-shaped associations for allergic reactions may be due to vitamin D modulation of the phenotype of the immune response, shifting the Th1-Th2 balance toward Th2 formation. For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates. Future observational studies, and randomized controlled trial data analyses, should include adjustment for data collected on prior long-term vitamin D supplementation and solar UVB exposure, as well as other potential confounders.

ObjectiveTo investigate whether intakes of Ca, vitamin D, casein and whey are associated with periodontitis and to investigate the possibility of interactions between them.DesignCross-sectional study. An Internet-based, 267-item FFQ was used to assess dietary intake. Intakes of casein (32·0 g/d), whey proteins (9·6 g/d) and vitamin D (5·8 μg/d) were classified as withinv.above the 50th percentile. Ca intake was classified as withinv.below age-specific recommendations. Severe periodontitis was defined as having ≥2 inter-proximal sites with clinical attachment loss ≥6 mm (not on the same tooth) and ≥1 inter-proximal site with pocket depth ≥5 mm. Since vitamin D influences Ca absorption, models were stratified by lower and higher (v. ≥5·8 µg/d) vitamin D intake.SettingDanish Health Examination Survey (DANHES) 2007–2008.SubjectsAdult participants (n3287) in the oral health study of DANHES 2007–2008.ResultsIntakes of Ca within recommendations (OR=0·76; 95 % CI 0·58, 0·99), whey ≥9·6 g/d (OR=0·75; 95 % CI 0·58, 0·97) and casein ≥32 g/d (OR=0·75 95 % CI 0·58, 0·97) were associated with lower likelihood of severe periodontitis after adjustment for age, gender, education, smoking, sucrose intake, alcohol consumption, number of teeth, daily brushing, regular visits to the dentist and chronic illness, irrespective of vitamin D intake levels. Intake of vitamin D alone was not associated severe with periodontitis.ConclusionsIntakes of Ca, casein and whey protein were inversely associated with periodontitis. Consumption of foods rich in Ca, casein and whey (e.g. dairy foods) should be promoted, as they may contribute to the prevention of periodontitis. Further longitudinal studies are required to confirm these associations.

Background: Transgenerational effects of paternal Areca catechu nut chewing on offspring metabolic syndrome (MetS) risk in humans, on obesity and diabetes mellitus experimentally, and of paternal smoking on offspring obesity, are reported, likely attributable to genetic and epigenetic effects previously reported in betel-associated disease. We aimed to determine the effects of paternal smoking, and betel chewing, on the risks of early MetS in human offspring. Methods: The 13 179 parent-child trios identified from 238 364 Taiwanese aged ≥20 years screened at 2 community-based integrated screening sessions were tested for the effects of paternal smoking, areca nut chewing, and their duration prefatherhood on age of detecting offspring MetS at screen by using a Cox proportional hazards regression model. Results: Offspring MetS risks increased with prefatherhood paternal areca nutusage (adjusted hazard ratio, 1.77; 95% confidence interval [CI], 1.23–2.53) versus nonchewing fathers (adjusted hazard ratio, 3.28; 95% CI, 1.67–6.43) with >10 years paternal betel chewing, 1.62 (95% CI, 0.88–2.96) for 5 to 9 years, and 1.42 (95% CI, 0.80–2.54) for P trend =0.0002), with increased risk (adjusted hazard ratio, 1.95; 95% CI, 1.26–3.04) for paternal areca nut usage from 20 to 29 years of age, versus from >30 years of age (adjusted hazard ratio,1.61; 95% CI, 0.22–11.69). MetS offspring risk for paternal smoking increased dosewise ( P trend P trend =0.0009), independently. Conclusions: Longer duration of paternal betel quid chewing and smoking, prefatherhood, independently predicted early occurrence of incident MetS in offspring, corroborating previously reported transgenerational effects of these habits, and supporting the need for habit-cessation program provision.

Review of the evidence on hypovitaminosis D as a risk factor for metabolic syndrome and its sequelae, T2DM and CVD, suggests long-term vitamin D repletion could reduce these risks. There is mechanistic evidence for protective effects for MetS and the balance of evidence, (cross-sectional and prospective), supports this postulate. Much of the data so far available from randomized controlled trials is weakened by inadequate power, low vitamin D dosages, starting supplementation too late in life or after MetS disorders have developed or, most importantly, by non-inclusion of many recognizable confounders. On balance, therefore, maintenance of US 2010 recommended intakes for bone protection has the potential to prove protective for MetS. Supplementation has been shown to increase survival in patients with cardiac disorders; whether higher doses would provide useful protection for apparently healthy people in the general population awaits the outcomes of ongoing randomized-controlled trials that, it is hoped, will prove or disprove causality for hypovitaminosis D in MetS and its long-term ill-effects.

Background and objectiveGiven the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised thatUCP2polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in theUCP2gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242).Design and methodsThe study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test.ResultsIn the meta-analysis of the three cohorts, none of the threeUCP2polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations).ConclusionIn conclusion, our findings in 20 242 individuals suggest thatUCP2gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.

Summary Objective The objective of the present study was to explore the association of serum vitamin D concentration and polymorphism in the vitamin D receptor (VDR), with knee pain and radiographic knee osteoarthritis (OA) among men and women in a large population-based UK cohort study. Methods Seven hundred and eighty-seven participants in the Hertfordshire Cohort Study (399 men, 388 women; mean age 65.6±2.7years) underwent a questionnaire on knee pain and radiographic knee examination. This study examined the association of Fok1, Cdx2 and Apa1 polymorphism in the gene for the VDR and serum 25(OH)D concentration with knee pain and radiographic knee OA by a generalized estimating equations population averaged logistic regression analysis in the Hertfordshire Cohort Study. Results There were no associations of Fok1, Cdx2 and Apa1 polymorphisms of the VDR with knee OA except for Aa for Apa1 compared with AA [Odds ratio (OR) 0.59, 95% confidence interval (CI) 0.36–0.95, P =0.031]. While, ff for Fok1 (OR 1.60, 95% CI 1.07–2.39, P =0.022) and AA for Cdx2 polymorphism (OR 2.21, 95% CI 1.07–4.56, P =0.032) was significantly associated with higher prevalence of knee pain compared with FF for Fok1 and GG for Cdx2, respectively. None of these are statistically significant after adjusting for the three polymorphisms tested. 25(OH)D level was not significantly associated with radiographic knee OA, while, low tertile of 25(OH)D level tended to be associated with knee pain compared with high tertile of 25(OH)D level. Conclusion The present cross-sectional study using a large-scale population from the Hertfordshire Cohort study indicated that vitamin D may be associated with pain rather than radiographic change, but the evidence for an association between vitamin D genetic variation and pain in knee OA is very weak in the present study. Further replication of our results will be required to elucidate the association of vitamin D and knee OA.

Background There is considerable interest in the possible role of vitamin D in respiratory disease, but only one population-based study has reported associations with lung function. Methods The cross-sectional relationships of total dietary vitamin D intake, serum 25 hydroxy vitamin D (25(OH)D) concentrations and three vitamin D receptor (VDR) polymorphisms (Apa1, Fok1 and Cdx2) with lung function and spirometrically-defined chronic obstructive pulmonary disease (COPD) were investigated in men and women aged 59–73 years in the Hertfordshire Cohort Study, UK. Results After controlling for confounders, total vitamin D intake was positively associated with forced expiratory volume in 1 s (FEV 1 ; difference in FEV 1 between top and bottom quintiles of intake 0.079 l (95% CI 0.02 to 0.14), p trend=0.007, n=2942), ratio of FEV 1 to forced vital capacity (FEV 1 /FVC; p trend=0.008) and negatively associated with COPD (OR comparing top and bottom quintiles 0.57 (95% CI 0.38 to 0.87), p trend=0.02). In contrast, serum 25(OH)D concentrations were not related to FEV 1 (p trend=0.89, n=1197) but were positively associated with COPD (p trend=0.046). VDR genotypes were unrelated to lung function and did not modify the effects of dietary intake or 25(OH)D concentrations on lung function. Conclusions The results of this study did not confirm a positive association between blood 25(OH)D concentrations and adult lung function. The apparent relationships with dietary vitamin D are likely to be explained by other highly correlated nutrients in the diet.

Background: Metabolic consequences of vitamin D deficiency have become a recent research focus. Maternal vitamin D status is thought to influence musculoskeletal health in children, but its relation with offspring metabolic risk is not known. Objective: We aimed to examine the association between maternal vitamin D status and anthropometric variables, body composition, and cardiovascular risk markers in Indian children. Design: Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 28‐32 wk gestation in 568 women who delivered at Holdsworth Memorial Hospital, Mysore, India. Anthropometric variables, glucose and insulin concentrations, blood pressure, and fasting lipid concentrations were measured in the offspring at 5 and 9.5 y of age. Muscle-grip strength was measured by using a handheld dynamometer at age 9.5 y. Arm-muscle area was calculated as a measure of muscle mass. Fasting insulin resistance was calculated by using the homeostasis model assessment equation. Results: Sixty-seven percent of women had vitamin D deficiency [serum 25(OH)D concentration ,50 nmol/L]. At ages 5 and 9.5 y, children born to vitamin D‐deficient mothers had smaller arm-muscle area in comparison with children born to mothers without deficiency (P , 0.05). There was no difference in grip strength between offspring of women with and without vitamin D deficiency. At 9.5 y, children of vitamin D‐deficient mothers had higher fasting insulin resistance than did children of nondeficient women (P = 0.04). There were no associations between maternal vitamin D status and other offspring risk factors at either age. Conclusion: Intrauterine exposure to low 25(OH)D concentrations is associated with less muscle mass and higher insulin resistance in children. Am J Clin Nutr 2011;93:628‐35.

Prevalence of hypovitaminosis D in Western populations is high; pregnant women are identified as a high-risk group, especially if dark skinned. Consequences of severe clinical vitamin D deficiency in pregnancy can be life threatening to the newborn, while lesser degrees of hypovitaminosis D may have important long-term implications for offspring health. Past experiences with routine provision of 10mg/d (400 IU/d) to all pregnant mothers suggest that this dose is sufficient to prevent overt neonatal complications of vitamin D deficiency. Recent data suggest that supplementation with dosages above 10mg/d may be required for optimal health in the mother and child; however, further research is required for the assessment of the benefits and safety of supplementation with higher dosages. Lack of unified advice on vitamin D supplementation of pregnant mothers in the UK hinders the implementation of primary prevention strategies and is likely to leave some deficient mothers without supplementation. Refereed/Peer-reviewed

OBJECTIVE—Accumulating epidemiological evidence suggests that hypovitaminosis D may be associated with type 2 diabetes and related metabolic risks. However, prospective data using the biomarker serum 25-hydroxyvitamin D [25(OH)D] are limited and therefore examined in the present study. RESEARCH DESIGN AND METHODS—A total of 524 randomly selected nondiabetic men and women, aged 40–69 years at baseline, with measurements for serum 25(OH)D and IGF-1 in the population-based Ely Study, had glycemic status (oral glucose tolerance), lipids, insulin, anthropometry, and blood pressure measured and metabolic syndrome risk (metabolic syndrome z score) derived at baseline and at 10 years of follow-up. RESULTS—Age-adjusted baseline mean serum 25(OH)D was greater in men (64.5 nmol/l [95% CI 61.2–67.9]) than women (57.2 nmol/l [54.4,60.0]) and varied with season (highest late summer). Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: β = −0.0023, P = 0.019; 2-h glucose: β = −0.0097, P = 0.006), insulin resistance (fasting insulin β = −0.1467, P = 0.010; homeostasis model assessment of insulin resistance [HOMA-IR]: β = −0.0059, P = 0.005), and metabolic syndrome z score (β = −0.0016, P = 0.048) after adjustment for age, sex, smoking, BMI, season, and baseline value of each metabolic outcome variable. Associations with 2-h glucose, insulin, and HOMA-IR remained significant after further adjustment for IGF-1, parathyroid hormone, calcium, physical activity, and social class. CONCLUSIONS—This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism and warrant investigation in larger, specifically designed prospective studies and randomized controlled trials of supplementation.

OBJECTIVE—Hypovitaminosis D and reduced IGF-1 are associated, individually, with metabolic syndrome. Physiological interactions between vitamin D and IGF-1 are reported; this is the first study to investigate their combined associations with metabolic syndrome prevalence. RESEARCH DESIGN AND METHODS—Data on 25-hydroxyvitamin D (25(OH)D), IGF-1, and metabolic syndrome abnormalities (abdominal obesity; raised A1C, blood pressure, and triglycerides; and low HDL cholesterol) were collected from 6,810 British white subjects in the 1958 cohort, surveyed during 2002–2004 (age 45 years). RESULTS—IGF-1 concentrations increased with 25(OH)D up to ∼75–85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 (P = 0.025) on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D (P > 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P ≤ 0.006). Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1 (odds ratio for highest vs. lowest third of both 0.26 [95% CI 0.17–0.40], P < 0.0001; adjusted for sex, month, hour, inactivity, alcohol consumption, smoking, and social class). 25(OH)D was associated with the prevalence of high A1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations (P ≤ 0.004 for all comparisons). CONCLUSIONS—Serum 25(OH)D is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.