Vitamin D and serum leptin: a systematic review and meta-analysis of observational studies and randomized controlled trials.

We aimed to investigate the potential association between vitamin D and serum leptin levels by pooling together the results from observational studies and clinical trials. A systematic literature search of PubMed, Scopus and Google Scholar was conducted up to March 2015. The analysis of observational studies was conducted on six papers that reported nine correlation coefficients using Fisher's Z and its standard error. Then, effect sizes of eligible trials were pooled using random-effects models (the DerSimonian-Laird estimator). Results of observational studies showed an inverse association between leptin and 25-hydroxyvitamin D (25(OH)D) (Fisher's Z=-0.93, 95% CI: -0.95, -0.91). After combining trials, pooled mean difference (PMD) for 25(OH)D was 24.06 ng/ml (95% CI, 17.27-30.85; P<0.001) with significant heterogeneity among studies (P<0.001; I2=89.1%). Raising 25(OH)D was associated with significant increase in leptin level (PMD=4.60 ng/ml, 95% CI, 0.55-8.66, P=0.026) with significant heterogeneity (P<0.001; I2=96.4%). Population with diabetes (PMD: 13.63 ng/ml), age younger than 50 years (PMD: 1.884 ng/ml), doses less than 1000 IU/day (PMD: 1.53 ng/ml), duration less than 24 weeks (PMD: 14.668 ng/ml) and baseline 25(OH)D <50 nmol/l (PMD: 13.483 ng/ml) were sources of heterogeneity. Current evidence indicates that inverse association between leptin level and 25(OH)D concentration was observed in observational studies, which was not demonstrated in intervention studies with high heterogeneity. Clearly, there is a need for properly designed and large prospective dose-response trials with long-term follow-up to assess the sources of heterogeneity.

The interactive effect of improvement of vitamin D status and VDR FokI variants on oxidative stress in type 2 diabetic subjects: a randomized controlled trial.

BACKGROUND/OBJECTIVES: The objectives were to evaluate the effects of improvement of vitamin D status on biomarkers of oxidative stress (OS) in type 2 diabetic (T2D) subjects and whether vitamin D receptor (VDR)-FokI polymorphisms could modulate the response to vitamin D3 intake. SUBJECTS/METHODS: Subjects with T2D were allocated to one of the two groups to receive either plain doogh (PD; containing 150 mg calcium and no vitamin D/250 ml, n1=50) or vitamin D3-fortified doogh (FD; containing 500 IU/250 ml, n1=50) twice a day for 12 weeks. Outcomes were changes in serum 25-hydroxyvitamin D (25(OH)D), superoxide dismutase, glutathione (GSH), total antioxidant capacity (TAC) and malondialdehyde (MDA). VDR genotypes in 140 T2D subjects in FD were determined by FokI restriction enzyme. RESULTS: After 12 weeks, serum 25(OH)D increased significantly in FD (from 38.5±202.2 to 72.0±23.5, P<0.001) as compared with PD (from 38.8±22.8 to 33.4±22.8, P=0.28). Comparisons between FD and PD revealed significant differences in changes of serum MDA (-0.54±0.82 µmol/l vs. +0.17±1 µmol/l, P<0.001), GSH (+8.4±40.1 ng/l vs -13.1±29.4 ng/l, P=0.002) and TAC (+0.14±0.43 mmol/l vs. +0.02±0.45 mmol/l bovine serum albumin equivalent, P=0.03). Although there was no significant association between FokI genotypes and OS biomarkers, ff variant subgroup showed the weakest response to vitamin D. CONCLUSIONS: Improvement of vitamin D status via daily intake of FD ameliorates OS biomarkers in T2D subjects and the interactive effect of FokI genotypes cannot be ruled out.

Calcium-vitamin D-fortified milk is as effective on circulating bone biomarkers as fortified juice and supplement but has less acceptance: a randomised controlled school-based trial.

BACKGROUND: Hypovitaminosis D, especially during cold seasons, is quite prevalent among primary school children in Tehran. The present study aimed to compare the efficacy of calcium-vitamin D-fortified-milk, -orange juice and supplement in primary school children. METHODS: Children aged 9-12 years from both sexes were randomly assigned to one of six groups to receive plain milk, fortified milk, plain orange juice, fortified orange juice, supplement or placebo. Both fortified-milk and -juice contained 100 IU of vitamin D and 500 mg of calcium per 200 mL package, whereas supplement contained 200 IU of vitamin D and 500 mg of calcium. The duration of intervention was 12 weeks, from November 2008 to March 2009. RESULTS: A total of 410 children completed the study. Regression analysis with adjustment for both sex and initial values of 25(OH)D revealed that consumption of either supplement, fortified orange juice or fortified milk resulted in a 20.8 nm [confidence interval (CI) = 17.4-23.9], 9.9 nm (CI = 7.4-12.3) or 6.9 nm (CI = 3.3-10.5) increase in circulating 25(OH)D compared to the related control groups. However, changes in serum osteocalcin and intact parathyroid hormone in the supplement group did not differ from those of fortified milk or plain milk. The increment of osteocalcin in both plain milk and fortified milk was more than in fortified orange juice, although the difference was statistically insignificant. CONCLUSIONS: Despite having double amount of vitamin D and being more effective in raising serum 25(OH)D, supplementation did not confer additional benefit in terms of osteocalcin and intact parathyroid hormone compared to either fortified or plain milk.

Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.

BACKGROUND: Both poor vitamin D status and oxidative stress (OS) have been independently associated with late diabetic complications, including cardiovascular disease (CVD). The present study aimed to examine the effect of daily intake of vitamin D alone or in combination with calcium as a fortified Persian yogurt drink (doogh) on OS over 12 weeks. METHODS: Ninety patients with type 2 diabetes aged 30-50 years from both sexes were randomly allocated to one of the three groups to receive two 250-mL bottles of doogh a day, which was either plain (PD; containing 150 mg per 250 mL of calcium and no detectable vitamin D), vitamin D-fortified (DD; containing 150 mg of calcium + 500 IU vitamin D per 250 mL) or calcium-vitamin D-fortified (CDD; 250 mg od calcium + 500 IU vitamin D per 250 mL). RESULTS: Although mean (SD) serum concentrations of protein carbonyl significantly decreased in both DD and CDD groups [-2.07 (4.39) nm, P = 0.015 and -4.4 (7.64) nm, P = 0.003, respectively], the change in PD group was not significant [-0.54 (6.96) nm, P = 0.674]. A similar pattern was observed for cardiac myeloperoxidase [PD: -19.4 (75.9) µg L(-1) , P = 0.173; DD: -21.8 (54.2) µg L(-1) , P = 0.035, CDD: -48.5 (76.9) µg L(-1) , P = 0.002]. Superoxide dismutase increased significantly only in DD and CDD [56.9 (74.0) U L(-1) , P < 0.001 and 51.6 (119.9) U L(-1) , P = 0.025, respectively]. Changes of serum advanced glycation end-products showed a significant between-group difference among PD, DD and CDD [239.4 (388.4) U L(-1) , -58.1 (147.6) U L(-1) and -143.7 (475.9) U L(-1)  × 10(3) , respectively, P = 0.003], which remained significant after controlling for changes of fasting serum glucose (P = 0.013) and glycated haemoglobin (P = 0.015). CONCLUSIONS: The findings of the present study demonstrated an OS attenuating effect of vitamin D. However, extra calcium did not convey additional benefit.

Evidence for augmented oxidative stress in the subjects with type 1 diabetes and their siblings: a possible preventive role for antioxidants.

BACKGROUND/OBJECTIVES: Oxidative stress (OS) is thought to be involved in both development of type 1 diabetes (T1D) and its further complications. In this study, certain biomarkers of OS were compared among the subjects with T1D, their non-diabetic siblings and unrelated healthy controls. SUBJECTS/METHODS: Known cases of T1D from both sexes aged 5-25 years were enrolled in a case-control study (n(1)=60). There were two control groups; non-diabetic siblings (n(2)=60) and unrelated apparently healthy subjects (n(3)=60). Anthropometric, dietary and laboratory assessments were done. RESULTS: There was no significant difference in dietary data among the groups. Total antioxidant capacity was significantly lower in T1D than both related and unrelated controls (1.6 ± 0.05, 1.7 ± 0.05 and 1.8 ± 0.06 mmol BSA equivalent/l, respectively, P=0.044). Both T1D subjects and their siblings showed lower glutathione peroxidase (GSH-px) levels (median (interquartile range): 22.2 (28.6), 29.9 (23) and 41.8 (73.6) U/ml, respectively, P=0.006). On the contrary, superoxide dismutase concentrations were significantly higher in T1D group and the siblings than unrelated healthy controls (243 (45.3), 157.8 (176.9) and 27.9 (8.7) U/l, respectively, P<0.001). Serum concentrations of GSH correlated with energy intake in the siblings (r=0.521, P<0.001) and unrelated controls (r=0.268, P=0.042) but not in T1D group. The associations remained significant after controlling for blood glucose (r=0.437, P=0.001 and r=0.420, P=0.011, respectively) in both the groups. CONCLUSION: Augmented OS in the siblings may indicate an increased requirement for antioxidants in genetically diabetes-prone subjects.

Vitamin D status and the predictors of circulating T helper 1-type immunoglobulin levels in Iranian subjects with type 1 diabetes and their siblings: a case-control study.

BACKGROUND: Vitamin D status has been linked to both T helper (Th)1/Th2 balance and susceptibility to type 1 diabetes (T1D). The present study aimed to evaluate vitamin D status and its relation to Th1/Th2 balance in subjects with T1D, their siblings and unrelated healthy controls during autumn and winter 2008-2009. METHODS: A case-control study was conducted on subjects with T1D (n(1) = 60) and two control groups comprising nondiabetic siblings (n(2) = 60) and unrelated healthy controls (n(3) = 60). Assessments of dietary intake, anthropometry, intact parathyroid hormone (iPTH) and 25(OH)D were performed. Serum levels of immunoglobulin (Ig)G(2) and IgE, as well as the IgG2/IgE ratio, were used to evaluate Th1/Th2 balance. Vitamin D status was defined based on circulating 25(OH)D as deficiency: <27.5 nm; insufficiency 27.5 ≤ 25(OH)D <50 nm; and sufficiency ≥50 nm. RESULTS: Vitamin D status did not differ significantly among the groups. Similarly, no significant difference in 25(OH)D, iPTH, IgG(2), IgE and IgG(2)/IgE was found. In multiple regression analysis of pooled data, PTH and body mass index were the predictors of IgG(2)/IgE. In the diabetic group, both PTH and age and, in siblings, PTH only, were the predictors of IgG(2)/IgE ratio. CONCLUSIONS: These data suggest PTH as the major predictor of immune deviance towards the Th1 response in both type 1 diabetic subjects and their siblings. Considering that the active form of vitamin D suppresses PTH production, it is hypothesised that vitamin D replenishment of just those who are genetically prone to the disease (i.e. siblings) may be regarded as a preventive measure against T1D.

Physiological dose of lycopene suppressed oxidative stress and enhanced serum levels of immunoglobulin M in patients with Type 2 diabetes mellitus: a possible role in the prevention of long-term complications.

OBJECTIVE: This study was undertaken to evaluate the antioxidant effects of lycopene in physiological doses and its possible effects on the immune response in patients with Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A total of 35 patients with T2DM of both sexes aged 54+/-9 yr were enrolled in a double-blind placebo-controlled clinical trial conducted for 2 months. After a 2-week lycopene-free diet washout period, patients were allocated to either lycopene supplementation group (10 mg/day) (no.=16) or placebo group (no.=19), which were age- and sex matched. Patients were instructed to keep their diet and physical activity as unchanged as possible. RESULTS: While dietary intake of energy and body weight did not change, the ratio of serum total antioxidant capacity (TAC) to malondialdehyde (MDA) increased significantly in the lycopene group compared to the placebo group (p=0.007). Though a statistically significant increase in serum concentrations of lycopene (p<0.001) was not accompanied by enhanced delayed-type hypersensitivity response, a significant negative correlation was found between serum levels of lycopene and immunoglobulin (Ig)G (r=-0.338, p=0.008). Interestingly, variations of serum levels of lycopene directly correlated with those of IgM (r=0.466, p=0.005). There was an insignificant decrement in serum anti-oxidized LDL IgG levels in the lycopene group. CONCLUSIONS: Lycopene, probably by increasing TAC and inhibiting MDA-LDL formation, may attenuate T cell-dependent adaptive (pro-atherogenic) immune response. Meanwhile, with enhancement of innate immunity and hence prevention of ox-LDL uptake by macrophage and foam cell formation, lycopene may be effective in prevention of long-term diabetic complications, notably cardiovascular disease.

Social factors and pregnancy weight gain in relation to infant birth weight: a study in public health centers in Rasht, Iran.

OBJECTIVES: This study aimed to examine the relationship between total pregnancy weight gain, maternal educational level, working status and infant birth weight among mothers and infants in urban health centers in Rasht, Iran. DESIGN: Pregnant women from six different public health centers in urban areas were studied in a prospective design. Data on women's age, parity, level of education, working status, infant birth weight, mothers' height, and prepregnancy weight and total weight gain during pregnancy were collected. The subjects were grouped based on their prepregnancy BMI and according to Institute of Medicine (IOM) recommendation for total pregnancy weight gain. The subjects were also categorized based on their years of schooling as less, intermediately and highly educated. In this study women were considered as either housewives or employed. SETTING: Public health centers in urban areas in Rasht, Iran. SUBJECTS: A total of 1914 pregnant women were studied. RESULTS: These data showed that pregnancy weight gain was not different between women with normal prepregnancy weight and underweight when educational levels and working status were taken into account. Besides, pregnancy weight gain was positively related to the level of education. Analysis of variance showed that infant birth weights were not similar in mothers who gain weight less, within and above recommended ranges. In all, 60% of the normal weight women and 56.7% of the underweight women had weight gain less than the lower cutoffs of IOM recommendation. Results of logistic regression analysis showed that low level of mother's education was the only predictor for low birth weight (LBW) (>12 y education OR = 0.27(0.10-0.69)) and 5-12 y education OR = 0.62 (0.2-0.94). CONCLUSION: These results showed that pregnancy weight gain lower recommended ranges are highly prevalent in Iranian women in public health centers in urban areas in Rasht. Moreover, mother's level of educational level may be considered as the most important determinant of birth weight and LBW in this population.

Serum antibodies to the major proteins found in cow's milk of Iranian patients with Type 1 diabetes mellitus.

The purpose of this study was to assess the humoral immune response to cow's milk proteins in Iranian children with Type 1 diabetes mellitus (T1DM). Eighty children aged 4-17 yr with T1DM from two centres in Iran (the Iranian Association of Diabetes in Tehran and Center for Diabetes Research in Hamedan), 37 apparently healthy siblings of diabetic patients (related controls), 82 apparently healthy age- and sex- matched controls (unrelated controls), and 32 patients aged 11-15 yr with auto-immune thyroiditis were examined for specific whole antibodies (Igs), IgG, and IgM to the major proteins found in cow's milk or to ovo-albumin by enzyme-linked immunosorbent assay (ELISA). A crude extract was made from 2.5% fat pasteurized cow's milk. This extract, together with individual commercial major proteins of cow's milk, was then used as antigen to evaluate the humoral immune response of the subjects to the individual proteins found in cow's milk or to cow's milk as a whole. A questionnaire on medical history, duration of exclusive and non-exclusive breast-feeding and daily intake of dairy products was completed before blood sampling. Diabetic children had significantly higher serum levels of Igs, IgG and IgM to the proteins found in cow's milk than unrelated healthy controls (p<0.001). Healthy siblings of diabetic patients, compared to unrelated controls, had significantly higher levels of serum Igs and IgG to cow's milk proteins (p<0.05 and p<0.01, respectively). Serum levels of Igs and IgG to the cow's milk proteins showed a significantly negative correlation with duration of non-exclusive breast-feeding but positive correlation with daily intake of dairy products. These correlations were stronger when calculated just within the T1DM group. In this group, serum levels of IgM to cow's milk proteins also showed a positive correlation with daily intake of dairy products. Though serum levels of IgG to casein were insignificantly higher in diabetic children than in healthy controls, there was a significant negative correlation between serum levels of IgG to casein and duration of non-exclusive breast-feeding. Again in the T1DM group, this correlation was stronger. There was no significant difference in serum levels of Igs, IgG or IgM to other major proteins of cow's milk or to ovo-albumin between groups. It was concluded that though high levels of Igs or IgG were found to cow's milk proteins, especially casein, it seems unrelated to the early introduction of cow's milk into an infant diet and the onset of T1DM in Iranian subjects.

Glycemic optimization may reduce lipid peroxidation independent of weight and blood lipid changes in Type 2 diabetes mellitus.

The aim of this study was to determine the effect of diet-therapy on lipid peroxidation in patients with Type 2 diabetes mellitus (T2DM). Fifteen T2DM patients of both sexes, aged between 35-70 years, were given the diet suggested for patients with diabetes by the American Diabetic Association. This diet comprised 50-60% carbohydrate, 10-15% protein, 20-30% fat and about 35 g fiber was given for weight maintenance. Weight and body mass index did not change significantly during 8 weeks of study. Also, no statistically significant difference was observed in serum total cholesterol, triglycerides, LDL- and HDL-cholesterol from before to after dietary intervention. However, the levels of fasting blood sugar, HbA1c and malondialdehyde were lowered significantly after dietary intervention. It was concluded that glycemic optimization, independent of weight and blood lipid profile, through a well-designed diet is likely to be the most effective factor in reducing the process of oxidative stress in T2DM. This may have preventive implications for such diabetic complications as atherosclerosis.