Aya Mousa

Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial

BackgroundDespite Australia’s sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity.Methods/DesignFifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers.DiscussionThe trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes.Trial registrationClinicaltrials.gov ID: NCT02112721.

Effect of vitamin D supplementation on inflammation: protocol for a systematic review

Introduction The extraskeletal role of vitamin D is being increasingly recognised. This has important clinical implications, as vitamin D deficiency has reached epidemic proportions worldwide. Vitamin D has proposed anti-inflammatory properties, yet the role of vitamin D supplementation in reducing inflammation remains largely unknown. The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation, and to identify relevant knowledge gaps in the field. Methods and analysis Medline, CINAHL, EMBASE and All EBM will be systematically searched for randomised controlled trials (RCTs) and systematic reviews of RCTs, comparing vitamin D supplementation with placebo, usual care or other pharmacological or non-pharmacological interventions. One reviewer will assess articles for eligibility according to prespecified selection criteria, after which 2 independent reviewers will perform data extraction and quality appraisal. Meta-analyses will be conducted where appropriate. Ethics and dissemination Formal ethical approval is not required as no primary data is collected. This systematic review will identify potential clinical implications of vitamin D deficiency and supplementation, and will be disseminated through a peer-reviewed publication and at conference meetings, to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases. PROSPERO registration number CRD42016037104.

25-hydroxyvitamin D is associated with adiposity and cardiometabolic risk factors in a predominantly vitamin D-deficient and overweight/obese but otherwise healthy cohort.

Vitamin D deficiency has reached epidemic proportions worldwide and has recently been linked to cardiometabolic risk factors including obesity, insulin resistance, hypertension, dyslipidemia, as well as type 2 diabetes and cardiovascular disease. The objective of this study was to examine the associations between circulating 25-hydrovitamin D (25(OH)D) levels and cardiometabolic risk factors using direct measures of adiposity, glucose intolerance, and insulin resistance, as well as lipids, blood pressure, and plasma markers of inflammation. We measured circulating 25(OH)D, physical activity (International Physical Activity Questionnaire- IPAQ), anthropometry (body mass index (BMI), waist-to-hip ratio (WHR), % body fat (dual energy X-ray absorptiometry)), metabolic parameters (fasting and 2-h plasma glucose levels during oral glucose tolerance test; insulin sensitivity (M, hyperinsulinaemic-euglycaemic clamp), and cardiovascular and inflammatory profiles (blood pressure (BP), pulse pressure (PP), mean arterial pressure (MAP), plasma lipid levels, white blood cell count (WBC), and plasma high-sensitivity C-reactive protein levels (hsCRP)) in 111 healthy, non-diabetic adults (66 males/45 females; age 31.1±9.2years; % body fat 36.0±10.2%). Mean 25(OH)D was 39.8±19.8 nmol/L with no difference between genders (p=0.4). On univariate analysis, 25(OH)D was associated with% body fat (r=-0.27; p=0.005), 2-h glucose (r=-0.21; p=0.03), PP (r=0.26; p=0.006), and insulin sensitivity (r=0.20, p=0.04), but not with age, BMI, WHR, fasting glucose, BP, MAP, lipids, or inflammatory markers (all p>0.05). After adjusting for age and sex, 25(OH)D remained associated with% body fat (β=-0.12%; p=0.003), 2-h glucose (β=-0.13mmol/L; p=0.02), PP (β=0.12mmHg; p=0.009), and insulin sensitivity (β=0.22mg/kg/min; p=0.03), and became associated with fasting glucose (β=-0.04mmol/L; p=0.04) and hsCRP (β=-0.51mg/L; p=0.04). After adjusting for age, sex, and % body fat, 25(OH)D was no longer associated with insulin sensitivity, 2-h glucose, or hsCRP, but remained associated with fasting glucose (β=-0.05mmol/L; p=0.03) and PP (β=0.10mmHg; p=0.03). 25(OH)D remained associated with fasting glucose (β=-0.06mmol/L; p=0.02) after hsCRP and physical activity were added to the model with % body fat, age, and sex. ​These cross-sectional data suggest that associations between vitamin D and cardiometabolic risk among healthy, non-diabetic adults are largely mediated by adiposity. Large-scale intervention and mechanistic studies are needed to further investigate whether vitamin D has an independent role in the prevention and/or management of cardiometabolic risk and disease.

Relationship between vitamin D and gestational diabetes in overweight or obese pregnant women may be mediated by adiponectin

SCOPE Maternal vitamin D deficiency has been implicated in adverse pregnancy outcomes. However, the association between vitamin D and inflammation, particularly adipokines, remains unexplored in pregnancy. METHODS AND RESULTS In 102 overweight or obese pregnant women at high-risk of gestational diabetes mellitus (GDM), we investigated relationships between maternal 25-hydroxyvitamin D (25(OH)D) concentrations at 12-15 wk gestation (baseline) and serum lipids, inflammatory markers, novel adipokines (omentin-1, visfatin, high molecular weight (HMW) adiponectin), and subsequent pregnancy outcomes (GDM, preeclampsia, preterm birth [PTB]). After adjustment for maternal factors (age, BMI, parity, ethnicity, and smoking status), baseline 25(OH)D concentrations were inversely associated with total cholesterol and triglycerides, and positively associated with HMW-adiponectin. Higher baseline 25(OH)D concentrations were associated with decreased fasting and 1-h post-OGTT glucose and reduced risk of GDM at 26-28 wk, as well as with longer gestation and reduced risk of PTB upon additional adjustment for caesarean section. Adding HMW-adiponectin to the multivariable models attenuated most associations, and HMW-adiponectin was a significant predictor in the models. CONCLUSION Our findings suggest that lower maternal 25(OH)D concentrations in overweight/obese pregnant women at high-risk of GDM are associated with increased cardiometabolic risks during pregnancy and adverse pregnancy outcomes, and that these associations may be mediated by HMW-adiponectin.

Plasma 25-Hydroxyvitamin D Is Related to Protein Signaling Involved in Glucose Homeostasis in a Tissue-Specific Manner

Vitamin D has been suggested to play a role in glucose metabolism. However, previous findings are contradictory and mechanistic pathways remain unclear. We examined the relationship between plasma 25-hydroxyvitamin D (25(OH)D), insulin sensitivity, and insulin signaling in skeletal muscle and adipose tissue. Seventeen healthy adults (Body mass index: 26 ± 4; Age: 30 ± 12 years) underwent a hyperinsulinemic-euglycemic clamp, and resting skeletal muscle and adipose tissue biopsies. In this cohort, the plasma 25(OH)D concentration was not associated with insulin sensitivity (r = 0.19, p = 0.56). However, higher plasma 25(OH)D concentrations correlated with lower phosphorylation of glycogen synthase kinase-3 (GSK-3) αSer21 and βSer9 in skeletal muscle (r = −0.66, p = 0.015 and r = −0.53, p = 0.06, respectively) and higher GSK-3 αSer21 and βSer9 phosphorylation in adipose tissue (r = 0.82, p < 0.01 and r = 0.62, p = 0.042, respectively). Furthermore, higher plasma 25(OH)D concentrations were associated with greater phosphorylation of both protein kinase-B (AktSer473) (r = 0.78, p < 0.001) and insulin receptor substrate-1 (IRS-1Ser312) (r = 0.71, p = 0.01) in adipose tissue. No associations were found between plasma 25(OH)D concentration and IRS-1Tyr612 phosphorylation in skeletal muscle and adipose tissue. The divergent findings between muscle and adipose tissue with regard to the association between 25(OH)D and insulin signaling proteins may suggest a tissue-specific interaction with varying effects on glucose homeostasis. Further research is required to elucidate the physiological relevance of 25(OH)D in each tissue.

Higher glomerular filtration rate is related to insulin resistance but not to obesity in a predominantly obese non-diabetic cohort

Glomerular hyperfiltration has been associated with obesity, insulin resistance, and systolic blood pressure (SBP). However, previous studies are limited by confounders such as pre-existing diabetes or hypertension, or have used indirect measures of adiposity and insulin sensitivity (IS). Therefore, we examined the relationship between estimated glomerular filtration rate (eGFR) and IS measured by the hyperinsulinaemic euglycaemic clamp in a healthy population on no medications. We performed oral glucose tolerance test (OGTT) and measured % body fat (DEXA), BMI, blood pressure and M-value (hyperinsulinaemic euglycaemic clamp) in 104 individuals (44 females and 60 males). The majority of the study population (n = 89, 85.6%) were classified on their BMI as overweight/obese. eGFR was related to age, BMI, M-value (IS), 2-hour glucose levels post OGTT and white blood cell count (WBC) (all p < 0.05); but not to SBP (p = 0.1) or fasting glucose levels (p = 0.2). After adjustment for gender, BMI, SBP and WBC, the inverse association between eGFR and M-value (p = 0.001), and 2-hour glucose post OGTT (p = 0.02) persisted. In conclusion, although eGFR has been associated with BMI and blood pressure in previous studies, in our healthy population, eGFR was more closely related to markers of glucose metabolism (IS and 2-hour glucose post OGTT) than to BMI and blood pressure.

Effects of vitamin D supplementation on inflammatory markers in heart failure: a systematic review and meta-analysis of randomized controlled trials

Vitamin D is reported to have anti-inflammatory properties; however the effects of vitamin D supplementation on inflammation in patients with heart failure (HF) have not been established. We performed a systematic review and meta-analysis examining effects of vitamin D supplementation on inflammatory markers in patients with HF. MEDLINE, CINAHL, EMBASE, All EBM, and Clinical Trials registries were systematically searched for RCTs from inception to 25 January 2017. Two independent reviewers screened all full text articles (no date or language limits) for RCTs reporting effects of vitamin D supplementation (any form, route, duration, and co-supplementation) compared with placebo or usual care on inflammatory markers in patients with heart failure. Two reviewers assessed risk of bias and quality using the grading of recommendations, assessment, development, and evaluation approach. Seven studies met inclusion criteria and six had data available for pooling (n = 1012). In meta-analyses, vitamin D-supplemented groups had lower concentrations of tumor necrosis factor-alpha (TNF-α) at follow-up compared with controls (n = 380; p = 0.04). There were no differences in C-reactive protein (n = 231), interleukin (IL)-10 (n = 247) or IL-6 (n = 154) between vitamin D and control groups (all p > 0.05). Our findings suggest that vitamin D supplementation may have specific, but modest effects on inflammatory markers in HF.

Bioavailable and free 25-hydroxyvitamin D and vitamin D binding protein in polycystic ovary syndrome: Relationships with obesity and insulin resistance

Polycystic ovary syndrome (PCOS) is a common condition characterised by both reproductive and metabolic features (obesity, insulin resistance, diabetes risk). Some evidence suggests that women with PCOS have lower vitamin D levels compared to healthy controls. Vitamin D binding protein (DBP) is the main carrier of vitamin D in circulation and plays an important role in regulating vitamin D concentration and bioavailability for target tissues. To our knowledge, no previous studies have examined DBP, bioavailable and free 25-hydroxyvitamin D (25(OH)D) in women with PCOS. The primary aim of this study was to compare DBP, bioavailable and free 25(OH)D concentrations in women with PCOS and controls. The secondary aim was to investigate relationships between DBP, bioavailable and free 25(OH)D and metabolic features (anthropometric measures, insulin resistance, and lipid profile). In a cross sectional study using bio-banked samples, we measured 25(OH)D, DBP and albumin. Bioavailable and free 25(OH)D were calculated using previously validated formula. BMI, body composition (dual X-ray absorptiometry, DXA), insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR)) and glucose infusion rate (GIR) from hyperinsulinaemic euglycaemic clamp and serum lipids (ELISA) were also measured in a physically and biochemically well-characterised cohort of women with and without PCOS. We studied 90 women with PCOS and 59 controls aged 18-48 years. DBP concentrations were lower in PCOS compared to controls (median [IQR]: 443.40 [314.4] vs 482.4 [156.8] μg/ml, p=0.02). No significant differences were found in bioavailable or free 25(OH)D concentrations between groups. DBP was not associated with BMI, percent body fat or markers of insulin resistance (all p>0.2). High-density lipoprotein (HDL) was the main determinant of DBP in the overall cohort (β=-0.12, p=0.02), after adjusting for covariates including PCOS/control status, age, BMI, total 25(OH)D and HOMA-IR. In PCOS, total and free 25(OH)D were related to markers of insulin resistance and lipids. Only the associations between free 25(OH)D and triglycerides (p=0.02), and HDL (p=0.03) remained significant after adjusting for age and BMI. In conclusion, women with PCOS had lower DBP, but similar bioavailable or free 25(OH)D concentrations compared to controls, independent of BMI and age. DBP was not associated with insulin resistance or BMI in PCOS. Further studies are needed to investigate the pathophysiology and clinical implications of reduced DBP in PCOS.

Shared Medical Appointments May Be Effective for Improving Clinical and Behavioral Outcomes in Type 2 Diabetes: A Narrative Review

Type 2 diabetes mellitus (T2DM) is a complex chronic disease affecting over 400 million people worldwide. Managing T2DM and its associated complications in individual patient consultations poses substantial challenges to physicians due to limited time and resources and lack of access to multidisciplinary teams. Shared medical appointments (SMAs) are consecutive medical consultations provided by a physician in a group setting, where integrated medical care and patient education are delivered in a single session. SMAs allow physicians to deliver the same level of care to multiple patients at the same time, thereby maximizing available resources. However, the effectiveness and practicality of SMAs in the management of T2DM remains unknown. This narrative review summarizes current and emerging evidence regarding the effectiveness of SMAs in improving clinical outcomes in patients with T2DM, as well as whether SMAs are associated with reduced costs and improved diabetes-related behavioral and lifestyle changes. An extensive literature search was conducted on major electronic databases including PubMed and Google Scholar using keywords, including SMAs, group visits, and T2DM to identify all studies of SMAs in patients with T2DM. Studies in type 1 diabetes or mixed or unspecified populations were excluded, as well as studies where SMAs did not involve a physician since these do not meet the classical definition of a SMA. Nineteen studies were identified and are included in this review. Overall, current evidence suggests that SMAs delivered regularly over time may be effective in improving glycemic outcomes, diabetes knowledge, and some diabetes-related behaviors. However, the main limitation of existing studies was the paucity of comparisons with standard care which limits the ability to draw conclusions regarding whether SMAs are superior to standard care in T2DM management. Moreover, the small number of studies and substantial heterogeneity in study designs, populations, and interventions creates difficulties in establishing the practicality and efficiency of SMAs in the clinical care setting. We conclude that there remains a need for larger studies to identify populations who may or may not benefit from the SMA model of care and to clarify the potential benefits and barriers to implementing SMAs into routine diabetes care.

Vitamin D supplementation for improvement of chronic low-grade inflammation in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

Background Vitamin D has been proposed to have anti‐inflammatory properties; however, the effect of vitamin D supplementation on inflammation in type 2 diabetes has not been established. Objective The aim of this systematic review and meta‐analysis was to examine the effect of vitamin D supplementation on inflammatory markers in patients with type 2 diabetes and to identify relevant gaps in knowledge. Data sources MEDLINE, CINAHL, Embase, and EBM Reviews were searched systematically from inception to January 25, 2017. Study selection Randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation (any form, route, and duration, and with any cosupplementation) compared with placebo or usual care on inflammatory markers in patients with type 2 diabetes were selected. Data extraction Study and sample characteristics and aggregate outcome data were extracted, risk of bias was determined, and quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results Twenty‐eight RCTs were included, 20 of which had data available for pooling. In meta‐analyses of 20 RCTs (n = 1270 participants), vitamin D‐supplemented groups had lower levels of C‐reactive protein (standardized mean difference [SMD] −0.23; 95%CI, −0.37 to −0.09; P = 0.002) and tumor necrosis factor &agr; (SMD −0.49; 95%CI, −0.84 to −0.15; P = 0.005), a lower erythrocyte sedimentation rate (SMD −0.47; 95%CI, −0.89 to −0.05; P = 0.03), and higher levels of leptin (SMD 0.42; 95%CI, 0.04‐0.81; P = 0.03) compared with control groups. No differences were observed for adiponectin, interleukin 6, or E‐selectin (all P > 0.05). In meta‐regression and subgroup analyses, age, sex, body mass index, duration of diabetes, baseline vitamin D status, and dose and duration of supplementation did not alter the results. Conclusions This meta‐analysis provides level 1 evidence that vitamin D supplementation may reduce chronic low‐grade inflammation in patients with type 2 diabetes. Systematic Review Registration PROSPERO CRD42016047755. Available at: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=47755 (9/15/2016).