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. Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: ␤ ϭ Ϫ0.0023, P ϭ 0.019; 2-h glucose: ␤ ϭ Ϫ0.0097, P ϭ 0.006), insulin resistance (fasting insulin ␤ ϭ Ϫ0.1467, P ϭ 0.010; homeostasis model assessment of insulin resistance [HOMA-IR]: ␤ ϭ Ϫ0.0059, P ϭ 0.005), and metabolic syndrome z score (␤ ϭ Ϫ0.0016, P ϭ 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. RESULTS-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. Diabetes 57:2619-2625, 2008 T hough the most well-known role of vitamin D is the regulation of calcium absorption and bone metabolism, it is becoming clear that this hormone has pleiotropic effects with possible roles in the pathogenesis of cancer (1), cardiovascular disease (2), multiple sclerosis (3), and type 1 diabetes (4). Recent epidemiological evidence (5-9) also points to a potential association of vitamin D insufficiency with adverse metabolic risk, including that for type 2 diabetes (10,11). While the exact mechanisms that underlie the multiple effects of vitamin D on different tissues are not currently understood, one unifying factor is the expression of vitamin D receptors (VDRs) in Ͼ30 tissues, including pancreatic islet cells (12). There is some evidence that polymorphisms in the VDR gene may be associated with insulin resistance, insulin secretion, and fasting glucose concentrations

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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 toϳ75-85 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 ϭ 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 Ͼ 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P Յ 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 Ͻ 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 Յ 0.004 for all comparisons). (1,2); however, for both factors, lower concentrations have been associated with disturbed glucose metabolism (3-8), high blood pressure (9 -11), adverse lipid profiles (2,12,13), and cardiovascular disease (8,14,15) independently of body mass. The evidence for associations between vitamin D and IGF-1 axes with metabolic risk includes prospective studies, clinical trials, and dose-related effects, suggesting that associations may prove to be causal. Mechanisms by which vitamin D and IGF-1 axes may lead to human disease are, however, not fully understood, and despite evidence for physiological interaction between these risk factors (16 -18), little is known about their joint effects, and we can find no previous studies investigating their combined associations with metabolic syndrome. CONCLUSIONS-SerumVitamin D is a hormone precursor, which before exerting its metabolic effects undergoes two successive hydroxylations.

Background/Objectives: Vitamin D is required for bone growth and normal insulin secretion. Maternal hypovitaminosis D may impair fetal growth and increase the risk of gestational diabetes. We have related maternal vitamin D status in pregnancy to maternal and newborn glucose and insulin concentrations, and newborn size, in a South Indian population. Subjects/Methods: Serum 25 hydroxy vitamin D (25(OH)D) concentrations, glucose tolerance, and plasma insulin, proinsulin and 32-33 split proinsulin concentrations were measured at 30 weeks gestation in 559 women who delivered at the Holdsworth Memorial Hospital, Mysore. The babies' anthropometry and cord plasma glucose, insulin and insulin precursor concentrations were measured. Results: In total 66% of women had hypovitaminosis D (25(OH)D concentrations o50 nmol l À1 ) and 31% were below 28 nmol l À1 . There was seasonal variation in 25(OH)D concentrations (Po0.0001). There was no association between maternal 25(OH)D and gestational diabetes (incidence 7% in women with and without hypovitaminosis D). Maternal 25(OH)D concentrations were unrelated to newborn anthropometry or cord plasma variables. In mothers with hypovitaminosis D, higher 25(OH)D concentrations were associated with lower 30-min glucose concentrations (P ¼ 0.03) and higher fasting proinsulin concentrations (P ¼ 0.04). Conclusions: Hypovitaminosis D at 30 weeks gestation is common in Mysore mothers. It is not associated with an increased risk of gestational diabetes, impaired fetal growth or altered neonatal cord plasma insulin secretory profile.

Betel nut (Areca catechu) is chewed regularly by at least 10% of the world population, imported by immigrant users wherever they settle, and is the fourth most widely used addictive substance. It is thought, by users, to soothe the digestion and to be a stimulant and its use has a major role in social situations. Specific arecal alkaloids act as competitive inhibitors of GABA receptors and have widespread effects in the body, including actions on the brain, cardiovascular system, lungs, gut and pancreas. Nitrosated derivatives of arecal alkaloids, proven carcinogens inducing tumours throughout the upper gut and foregut derivatives in animals, are also associated with increased tumour risks in man. These nitrosated compounds are also diabetogenic in CD1 mice, producing a type 2 diabetes with obesity. Increased central obesity is found in association with betel usage in man as well as increases in circulating markers of inflammatory and cardiovascular damage. The effects of chronic betel usage in man are at least as diverse as those of smoking and the habit increases the risks of ill health.