Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Serum 25(OH)D and Type 2 Diabetes Association in a General Population Study protocol: a randomised placebo-controlled clinical trial to study the effect of vitamin D supplementation on glycaemic control in type 2 Diabetes Mellitus SUNNY trial Effect of high doses of vitamin D on arterial properties, adiponectin, leptin and glucose homeostasis in type 2 diabetic patients. Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. Effects of Calcium Plus Vitamin D Supplementation on Anthropometric Measurements and Blood Pressure in Vitamin D Insufficient People with Type 2 Diabetes: A Randomized Controlled Clinical Trial The effects of vitamin D supplementation on adiponectin level and insulin resistance in first-degree relatives of subjects with type 2 diabetes: a randomized double-blinded controlled trial Effect of Therapeutic Dose of Vitamin D on Serum Adiponectin and Glycemia in Vitamin D-Insufficient or Deficient Type 2 Diabetic Patients Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Vitamin D and calcium intake in relation to type 2 diabetes in women. Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes. Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial.
Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity . This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity . Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D ( 25(OH)D ) is inversely associated with insulin resistance , although direct measurements of insulin sensitivity are required for confirmation . Reported associations with insulin secretion , however , are contradictory . Available prospect i ve studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk . There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity , likely due to differences in subject population s , length of interventions , and forms of vitamin D supplementation . Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis . The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies . Future studies , including cross-sectional and prospect i ve , should be performed in population s at high risk for both vitamin D deficiency and type 2 diabetes mellitus . Well- design ed , placebo-controlled , r and omized intervention studies are required to establish a true protective influence of  vitamin D on glucose homeostasis BACKGROUND A suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies , but evidence from trials is lacking . OBJECTIVE We determined whether vitamin D supplementation , with or without calcium , improved glucose homeostasis in adults at high risk of diabetes . DESIGN Ninety-two adults were r and omly assigned in a 2-by-2 factorial- design , double-masked , placebo-controlled trial to receive either cholecalciferol ( 2000 IU once daily ) or calcium carbonate ( 400 mg twice daily ) for 16 wk . The primary outcome was the change in pancreatic β cell function as measured by the disposition index after an intravenous-glucose-tolerance test . Other outcomes were acute insulin response , insulin sensitivity , and measures of glycemia . RESULTS Participants had a mean age of 57 y , a body mass index ( BMI ; in kg/m(2 ) ) of 32 , and glycated hemoglobin ( Hb A(1c ) ) of 5.9 % . There was no significant vitamin D × calcium interaction on any outcomes . The disposition index increased in the vitamin D group and decreased in the no-vitamin D group ( adjusted mean change ± SE : 300 ± 130 compared with -126 ± 127 , respectively ; P = 0.011 ) , which was explained by an improvement in insulin secretion ( 62 ± 39 compared with -36 ± 37 mU · L(-1 ) · min , respectively ; P = 0.046 ) . Hb A(1c ) increased less , but nonsignificantly , in the vitamin D group than in the no-vitamin D group ( 0.06 ± 0.03 % compared with 0.14 ± 0.03 % , respectively ; P = 0.081 ) . There was no significant difference in any outcomes with calcium compared with no calcium . CONCLUSION In adults at risk of type 2 diabetes , short-term supplementation with cholecalciferol improved β cell function and had a marginal effect on attenuating the rise in Hb A(1c ) . This trial was registered at clinical trials.gov as NCT00436475 OBJECTIVE This study aim ed to examine vitamin D status as a determinant for development of type 2 diabetes and deterioration of glucose homeostasis . RESEARCH DESIGN AND METHODS A r and om sample of the general population of Copenhagen , Denmark , was taken as part of the Inter99 study . Included were 6,405 men and women aged 30–65 years at baseline ( 1999–2001 ) , with 4,296 participating in the follow-up examination 5 years later ( 2004–2006 ) .  Vitamin D was determined at baseline as serum 25-hydroxyvitamin D [ 25(OH)D ] . Diabetes was defined based on an oral glucose tolerance test and a glycosylated hemoglobin ( HbA1c ) test . Secondary outcomes included continuous markers of glucose homeostasis . RESULTS The risk of incident diabetes associated with a 10 nmol/L increase in 25(OH)D was odds ratio ( OR ) 0.91 ( 95 % CI 0.84–0.97 ) in crude analyses . The association became statistically nonsignificant after adjustment for confounders , with an OR per 10 nmol/L of 0.94 ( 0.86–1.03 ) . Low 25(OH)D status was significantly associated with unfavorable longitudinal changes in continuous markers of glucose homeostasis after adjustment for confounders . Fasting and 2-h glucose and insulin as well as the degree of insulin resistance increased significantly more during follow-up among those with low 25(OH)D levels compared with those with higher levels . CONCLUSIONS Low 25(OH)D status was not significantly associated with incident diabetes after adjustment for confounders . However , it was significantly associated with unfavorable longitudinal changes in continuous markers of glucose homeostasis , indicating that low vitamin D status could be related to deterioration of glucose homeostasis Background Besides the classical role of vitamin D on calcium and bone homeostasis , vitamin D deficiency has recently been identified as a contributing factor in the onset of insulin resistance in type 2 diabetes mellitus . However , it is uncertain whether vitamin D deficiency and poor glycaemic control are causally interrelated or that they constitute two independent features of type 2 diabetes mellitus . There are limited clinical trials carried out which measured the effect of vitamin D supplementation on glycaemic control . The objective of this study is to investigate the effect of vitamin D supplementation on glycaemic control and quality of life in patients with type 2 diabetes mellitus . Methods / design In a r and omised double-blind placebo-controlled trial conducted in five general practice s in the Netherl and s three hundred patients with type 2 diabetes mellitus treated with lifestyle advises or metformin or sulphonylurea-derivatives are r and omised to receive either placebo or 50,000 IU Vitamin D3 at monthly intervals . The primary outcome measure is the change in glycated haemoglobin level between baseline and six months . Secondary outcome measures include blood pressure , anthropometric parameters , lipid profile , insulin resistance , quality of life , advanced glycation end products and safety profiles . Quality of life will be measured by The Short Form ( SF-36 ) Health Survey question naire . Advanced glycation end products are measured by an AGE-reader . Discussion This trial will be the first study exploring the effect of vitamin D supplementation on both glycaemic control and quality of life in patients with type 2 diabetes mellitus . Our findings will contribute to the knowledge of the relationship between vitamin D status and insulin resistance in patients with type 2 diabetes mellitus . Trial registration The Netherl and s trial register : BACKGROUND & AIMS Vitamin D supplementation has the potential to alleviate the cardiovascular damage in diabetic patients . The present study was design ed to evaluate long term impact of high doses of vitamin D on arterial properties , glucose homeostasis , adiponectin and leptin in patients with type 2 diabetes mellitus . METHODS AND RESULTS In r and omized , placebo-controlled study 47 diabetic patients were assigned into two groups : Group 1 received oral daily supplementation with vitamin D at a dose of 1000 U/day for 12 months . Group 2 received matching placebo capsules . Blood sampling for metabolic parameters , including fasting glucose , lipid profile , HbA1C , insulin , hs-CRP , 25 OH Vit D , adiponectin and leptin was performed at baseline and at the end of the study . Insulin resistance was assessed by homeostasis model assessment ( HOMA-IR ) . Central aortic augmentation index ( AI ) was evaluated using SphygmoCor . RESULTS The two groups were similar at baseline in terms of hemodynamic parameters . After 12 months , AI decreased significantly during the treatment period in patients received vitamin D ( p < 0.0001 ) and did not change in placebo group . Glucose homeostasis parameters , leptin as well as leptin adiponectin ratio did not change in both groups . 25 OH Vit D level significantly increased ( p = 0.022 ) and circulating adiponectin marginally increased ( p = 0.065 ) during 12 month treatment period in active treatment and did not change in placebo group . CONCLUSIONS High doses of  vitamin D supplementation in diabetic patients was associated with significant decrease in AI during one year treatment . This beneficial vascular effect was not associated with improvement in glucose homeostasis parameters Objectives To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity , insulin secretion , β-cell function , inflammation and metabolic markers . Design 6-month r and omized , placebo-controlled trial . Participants Ninety-five adults with serum 25-hydroxyvitamin D [ 25(OH)D ] ≤55 nmol/L at risk of type 2 diabetes ( with prediabetes or an AUSDRISK score ≥15 ) were r and omized . Analyses included participants who completed the baseline and final visits ( treatment n = 35 ; placebo n = 45 ) . Intervention Daily calcium carbonate ( 1,200 mg ) and cholecalciferol [ 2,000–6,000 IU to target 25(OH)D > 75 nmol/L ] or matching placebos for 6 months .  Measurements Insulin sensitivity ( HOMA2%S , Matsuda index ) , insulin secretion ( insulinogenic index , area under the curve ( AUC ) for C-peptide ) and β-cell function ( Matsuda index x AUC for C-peptide ) derived from a 75 g 2-h OGTT ; anthropometry ; blood pressure ; lipid profile ; hs-CRP ; TNF-α ; IL-6 ; adiponectin ; total and undercarboxylated osteocalcin . Results Participants were middle-aged adults ( mean age 54 years ; 69 % Europid ) at risk of type 2 diabetes ( 48 % with prediabetes ) . Compliance was > 80 % for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group ( 91 % achieved > 75 nmol/L ) , but remained unchanged in controls . There were no significant changes in insulin sensitivity , insulin secretion and β-cell function , or in inflammatory and metabolic markers between or within the groups , before or after adjustment for potential confounders including waist circumference and season of recruitment . In a post hoc analysis restricted to participants with prediabetes , a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity ( HOMA%S and Matsuda ) was observed . Conclusions Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity , insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes . However , in participants with prediabetes , supplementation with vitamin D and calcium may improve insulin sensitivity . Trial Registration Australian New Zeal and Clinical Trials Registry Background : Diabetes mellitus ( DM ) and vitamin D deficiency are major health concerns around the world . Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity . Objectives : We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism , components of metabolic syndrome ( MetS ) and specific inflammatory biomarkers . Patients and Methods : A double blind , r and omized clinical trial was conducted in King Khalid University Hospital , Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control , MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha ( TNF-α ) , Interleukin ( IL-6 ) , leptin , adiponectin and vascular cell adhesion molecule-1 ( VCAM-1 ) . Twenty-two patients with type II diabetes with insulin resistance , glycated hemoglobin ( HbA1c ) ≥ 6 ( 42 mmol/mol ) and serum 25(OH)D < 50 nmol/L were r and omized using a computer program to receive either supplementation with cholecalciferol ( 5000 IU/day ) or placebo for 12 weeks . The primary outcome was change in HbA1c levels from baseline . Results : Median [ IQR ] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [ 48 , 67.3 ] nmol/L ( P = 0.002 ) . There was no significant difference in the change of HbA1c between the groups ( P = 0.5 ) with a decrease of -0.1 % [ -1 , 0.5 ] in the vitamin D group and an increase of 0.15 % [ 0.1 , 0.2 ] in the placebo group . A significant improvement was observed in the homeostasis model of assessment of β-cell activity ( HOMA-%B ) ( P = 0.03 ) with vitamin D supplementation compared to baseline . Conclusions : Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved β-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity CONTEXT To the best of our knowledge , no study has examined the effects of vitamin D-calcium cosupplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient type 2 diabetics . OBJECTIVE This study was performed to assess the effects of vitamin D and calcium supplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient people with type 2 diabetes . METHODS Totally , 118 diabetic patients were enrolled in this r and omized , placebo-controlled clinical trial . After matching for age , sex , body mass index , type and dose of hypoglycemic agents , and duration of diabetes , subjects were r and omly assigned into 4 groups receiving the following : 1 ) 50000 IU/wk vitamin D + calcium placebo ; 2 ) 1000 mg/d calcium + vitamin D placebo ; 3 ) 50 000 IU/wk vitamin D + 1000 mg/d calcium ; or 4 ) vitamin D placebo + calcium placebo for 8 weeks . Blood sampling was done for the quantification of inflammatory biomarkers and adipocytokines at the study baseline and after 8 weeks of intervention . RESULTS Calcium ( changes from baseline : -75 ± 19 ng/ml , P = .01 ) and vitamin D alone ( -56 ± 19 ng/mL , P = .01 ) and joint calcium-vitamin D supplementation ( -92 ± 19 ng/mL , P = .01 ) result ed in a significant reduction in serum leptin levels compared with placebo ( -9 ± 18 ng/mL ) . This was also the case for serum IL-6 , such that calcium ( -2 ± 1 pg/mL , P < .001 ) and vitamin D alone ( -4 ± 1 pg/mL , P < .001 ) and their combination ( -4 ± 1 pg/mL , P < .001 ) led to significant reductions compared with placebo ( 3 ± 1 pg/mL ) . After adjustment for potential confounders , individuals in the calcium ( -3.1 ± 1.3 , P < .05 ) , vitamin D ( -3.1 ± 1.3 , P < .05 ) , and joint calcium-vitamin D groups ( -3.4 ± 1.3 , P < .05 ) had greater reductions in serum TNF-α concentrations compared with placebo ( 0.1 ± 1.2 ) . Individuals who received joint calcium-vitamin D supplements tended to have a decrease in serum high-sensitivity C-reactive protein levels compared with placebo after controlling for baseline levels ( -1.14 ± 0.25 vs 0.02 ± 0.24 ng/mL , P = .09 ) . CONCLUSION Joint calcium-vitamin D supplementation might improve systemic inflammation through decreasing IL-6 and TNF-α concentrations in vitamin D-insufficient people with type 2 diabetes Background : Up to 75 % of the risk of type 2 diabetes is attributable to obesity . Therefore , finding a way to control obesity can be useful for management of diabetes . Objective : This study was performed to assess the effects of vitamin D3 and calcium supplementation on anthropometric measurements and blood pressure in vitamin D insufficient people with type 2 diabetes . Methods : One hundred eighteen patients with diabetes were enrolled in this r and omized placebo-controlled clinical trial . All subjects were r and omly assigned into 4 groups receiving ( 1 ) 50,000 IU/wk vitamin D3 plus ( equal to 7143 IU/d ) calcium placebo ; ( 2 ) 1000 mg/d calcium plus vitamin D3 placebo ; ( 3 ) 50,000 IU/wk vitamin D3 ( equal to 7143 IU/d ) plus 1000 mg/d calcium ; or ( 4 ) vitamin D3 placebo plus calcium placebo for 8 weeks . Anthropometric measurements and blood pressure were assessed at study baseline and after 8 weeks of intervention . Results : A greater reduction in body mass index was observed in calcium plus vitamin D group than other groups ( p = 0.03 ) . Comparison of changes in waist circumference among 4 groups revealed no significant difference in crude model ( p = 0.21 ) and when the effect of confounders was taken into account ( p = 0.08 ) . Calcium supplementation result ed in a significant reduction in hip circumference compared to other groups ( p < 0.001 ) . Systolic blood pressure significantly decreased in the calcium plus vitamin D group compared to placebo ( −7.3 ± 8.7 mmHg vs 0.5 ± 8.2 mmHg ; p = 0.001 ) . However , calcium and vitamin D supplementation had no significant effects on diastolic blood pressure . Conclusion : Calcium – vitamin D3 cosupplementation can have beneficial effect on body mass index ( BMI ) , hip circumference , and systolic blood pressure in vitamin D – insufficient type 2 diabetics Background Despite the certain role of both vitamin D and adiponectin in the regulation of insulin sensitivity , the interaction between these two agents has remained uncertain . Objective The present study aim ed to determine whether vitamin D is able to change plasma adiponectin and affect glucose homeostasis and insulin sensitivity in first-degree relatives of subjects with type 2 diabetes . Methods This r and omized clinical trial was conducted at Clinic of Shahid Sadoughi Hospital in Yazd , Iran , from January 25 , 2012 to December 25 , 2014 . In this r and omized , double-blinded controlled trial , 64 first-degree relatives of type 2 diabetic patients were assigned r and omly to receive either vitamin D supplement ( 50000 IU vitamin D tablet weekly ) plus lifestyle change as the intervention group ( n = 32 ) or placebo plus lifestyle change as the control group ( n = 32 ) for twelve weeks ( three months ) . Results Fifty-three patients ( 28 in the intervention group and 25 in the control group ) completed the study . Serum levels of vitamin D  increased while insulin level and consequently insulin resistance ( calculated by HOMA formula ) significantly decreased in the case group ( p-value < 0.001 for all variables ) . Although the values of these three biomarkers showed a slight increase in control group , the changes were not statistically significant . The levels of the changes in other markers including adiponectin , Fasting Blood Sugar ( FBS ) , triglyceride , and total cholesterol remained insignificant in both study groups after completing interventions compared with before interventions . Conclusion This study showed that decreased insulin resistance is expected by administrating vitamin D supplement in first-degree relatives of the patients with diabetes mellitus . Trial Registration The trial was registered at the Iranian Registry of Clinical Trials ( http://www.i rct .ir ) with the I RCT ID : 201105176430N1 . Funding The authors received no financial support for the research or publication of this article Background : Lower vitamin D status has been reported in diabetic patients . Serum 25-hydroxyvitamin D and adiponectin were inversely associated with type 2 diabetes and insulin resistance . Vitamin D may involve in regulation of the adiponectin levels , which is directly related to insulin sensitivity . Objectives : The aim of this study was to investigate the effect of therapeutic dose of vitamin D on serum adiponectin and insulin resistance in vitamin D-insufficient or deficient type 2 diabetic patients . Material s and Methods : This double-blind , r and omized , clinical trial was conducted on 81 type 2 diabetic patients with vitamin D level of 10 - 30 ng/mL. Intervention was 50000 IU vitamin D or placebo once a week for 8 weeks . At the beginning and end of the study , blood sample s were collected after 12 hours of fasting and serum glucose , insulin , 25-hydroxyvitamin D , and adiponectin were measured . Insulin resistance was calculated by homeostasis model assessment ( HOMA-IR ) . Results : After 8-week intervention , serum 25-hydroxyvitamin D significantly increased and reached the normal levels in patients receiving vitamin D ( P < 0.001 ) and the levels of fasting serum glucose , insulin , and HOMA-IR were significantly decreased ( P = 0.04 , 0.02 and 0.007 , respectively ) . No significant changes were observed in these levels in the placebo group . Significant differences were observed in mean changes in the above-mentioned variables between the two groups ( P = 0.01 , 0.04 and 0.006 , respectively ) . No significant changes were found in serum adiponectin in the vitamin D and placebo groups ( P = 0.83 ) . Conclusions : Therapeutic dose of vitamin D can improve vitamin D status and glycemic indicators . But it seems that an 8-week intervention period was not sufficient to reveal the possible effects of vitamin D on serum adiponectin levels Background & the purpose of the study Prevalence of type 2 diabetes mellitus ( T2DM ) is increasing worldwide . To reduce its risk and progression , preventive strategies are needed . Vitamin supplementation such as vitamin D is one of the strategies . This study was design ed to investigate the effect of injection of vitamin D on insulin resistance and anthropometric parameters in T2DM . Methods This r and omized double-blind clinical trial was conducted with 42 diabetic patients in two groups ; intervention group with  single intramuscular injection of 300,000 International Unit ( IU ) of vitamin D3 and the placebo group . After recording demographic and anthropometric factors ( waist circumference , blood pressure and body mass index ) , fasting blood sample s was taken for measurement of blood glucose , 25-hydroxyvitamin D3 ( 25-OHD3 ) , insulin , glycosylated hemoglobin A1c ( HbA1c ) and estimation of Homeostasis Model Assessment Index ( HOMA ) in two times ; before study and after three months . Results Two groups had similar baseline characteristics ( each group = 21 subjects ) . Three months after vitamin D injection , HbA1c , anthropometric factors and HOMA index in intervention group stayed constant , however , serum 25- OHD3 was significantly increased ( p = 0.007 ) . Conclusion The present data is not convincing and further studies with large sample sizes are needed to show the definite effect of injection of vitamin D on control of diabetes and its risk Context Patients with HIV who initiate antiretroviral therapy ( ART ) lose bone mineral density ( BMD ) . The role of supplementation with vitamin D and calcium in preventing such loss is unknown . Contribution In a r and omized clinical trial of patients with HIV who were initiating ART , BMD , 25-hydroxyvitamin D , parathyroid hormone , phosphate metabolism , and markers of bone turnover were measured at baseline . Patients who then received vitamin D3 plus calcium along with ART had smaller declines in BMD of the hip and spine than those who received placebo along with ART . Caution Nearly all of the patients were men . Implication Supplementation with vitamin D and calcium may prevent bone loss  in patients with HIV initiating ART .  Antiretroviral therapy ( ART ) has transformed HIV infection from a terminal disease to a manageable chronic illness . Although incidence of AIDS-defining conditions has decreased , it has increased for other comorbid conditions ( 1 ) , including osteoporosis and fragility fractures ( 27 ) . Both viral and host factorsHIV infection mediated by certain viral proteins , HIV-associated inflammation , lifestyle and behavioral factors , underlying genetic predisposition , comorbid conditions , and ARTprobably contribute to bone loss and fracture risk ( 814 ) . Studies of ART initiation have confirmed that 2 % to 6 % of hip and spine BMD is lost over the first 24 to 48 weeks after initiation , with subsequent stabilization ( 1518 ) . The magnitude of bone loss is similar to that seen with glucocorticoids or during the first year of menopausal transition ( 19 , 20 ) . Initial loss is marked by an increase in serum bone resorption markers followed by a delayed compensatory increase in bone formation markers ( 21 ) ; therefore , this catabolic window , a high bone turnover state with excess resorption , may be a central mechanism of bone loss with ART initiation . Tenofovir disoproxil fumarate ( TDF ) , a nucleotide analogue reverse transcriptase inhibitor , has been associated with greater bone loss than other reverse transcriptase inhibitors ( 15 , 16 ) . Use of TDF is associated with increased parathyroid hormone ( PTH ) , elevated vitamin D binding protein , and reduced free 1,25-dihydroxyvitamin D [ 1,25-(OH)2D3 ] levels ( 22 , 23 ) , suggesting that functional vitamin D deficiency with TDF use potentially contributes to excess bone loss . Initiation of efavirenz ( EFV ) , a nonnucleoside reverse transcriptase inhibitor , is associated with a 6.2- to 12.5-nmol/L decrease in 25-hydroxyvitamin D [ 25-(OH)D ] levels ( 24 , 25 ) . Efavirenz induces cytochrome P450 enzymes involved in vitamin D metabolism and may accelerate the catabolism of 25-(OH)D and 1,25-(OH)2D3 , the latter being the active vitamin D metabolite ( 26 ) . These ART agents are combined with emtricitabine ( FTC ) , a nucleoside analogue reverse transcriptase inhibitor , into a fixed-dose combination , once-a-day pill ( EFV/FTC/TDF ) that is highly effective for treating HIV ( 27 ) . Beyond effects on bone metabolism , vitamin D has immunomodulatory effects mediated through the vitamin D receptor present on cells in both the innate and the adaptive immune system ( 28 , 29 ) . Vitamin D increases monocyte expression of CD14 and cathelicidin , molecules involved in innate immune responses ( 30 , 31 ) ; down-regulates cytokine expression in activated T cells ; and suppresses T-cell proliferation and production of interferon- and interleukin (IL)-2 , thus reducing the net state of inflammation ( 32 , 33 ) . These pathways are particularly relevant in HIV infection , in which excess monocyte and T-cell activation are important drivers of morbidity and mortality ( 3437 ) . We hypothesized that high-dose vitamin D and calcium supplementation would attenuate bone loss associated with initiation of EFV/FTC/TDF . In addition , we evaluated immunomodulatory effects of vitamin D in the setting of HIV treatment . We report the results of the AIDS Clinical Trials Group A5280 trial , a multicenter , r and omized , double-blind , placebo-controlled study assessing the effect of daily oral doses of 4000 IU of vitamin D3 and 1000 mg of calcium carbonate in adults with HIV initiating their first ART regimen with EFV/FTC/TDF . Methods Patients with ART-naive HIV without evidence of resistance to the antiretrovirals in the regimen and with HIV-1 RNA levels greater than 1000 copies/mL were eligible if they met the following criteria : screening 25-(OH)D level between 25 and 188 nmol/L ; creatinine clearance of 60 mL/min/1.73 m2 or greater , estimated by the CockcroftGault formula ; and serum calcium level less than 2.6 mmol/L. We excluded patients with daily calcium supplementation greater than 500 mg , daily vitamin D supplementation greater than 800 IU , any bisphosphonate use , recent steroid or chemotherapy treatments , clinical ly active thyroid disease , active substance or alcohol abuse , history of fragility fracture , documented osteoporosis , nephrolithiasis , or weight greater than 136 kg ( limit of the dual-energy x-ray absorptiometry [ DXA ] scanner ) . Pregnant and breastfeeding women were also excluded . We did 3-day dietary recalls at entry to estimate vitamin D and calcium intake . Patients were r and omly assigned to 4000 IU of cholecalciferol ( vitamin D3 ) daily plus 500 mg of calcium carbonate twice daily or identically matching placebos ( Tishcon ) and were counseled to take with food to facilitate absorption . Some experts consider the current upper U.S. Dietary Reference Intake of 2000 IU to be below actual physiologic requirements ; therefore , we tested the highest supplementation without risk for toxicity ( 3840 ) . A dose of 4000 IU of vitamin D3 is the highest daily dose considered safe for adults by the Institute of Medicine ( 41 ) and has previously been evaluated in persons with HIV with excellent tolerability and safety data ( 42 ) . Patients were r and omly assigned in a 1:1 ratio using permuted blocks stratified by screening serum 25-(OH)D levels ( 50 and > 50 nmol/L ) . R and omization was done using Web-based access to a central computer system maintained by the Frontier Science & Technology Research Foundation ( Buffalo , New York ) . The institutional review boards of all participating sites approved the study , and all patients provided written informed consent . The primary end point was percentage of change in total hip BMD from baseline to 48 weeks . Secondary end points included percentage of change in lumbar spine BMD at 48 weeks , change in plasma 25-(OH)D and PTH levels , markers of bone turnover , soluble inflammatory biomarkers , and CD4 cell counts at 24 and 48 weeks . Incidence of hypercalcemia and nephrolithiasis was monitored . All DXA scans were read in a blinded fashion at the Body Composition Analysis Center at Tufts Medical Center ( Boston , Massachusetts ) using a st and ardized protocol . Biomarker Assays Screening was done at local laboratories certified by the Clinical Laboratory Improvement Amendments . Serum sample s were stored at 70C at the Irving Institute Biomarkers Core Laboratory at Columbia University Medical Center ( New York , New York ) and underwent batched analysis . We measured 25-(OH)D2 and 25-(OH)D3 by liquid chromatographymass spectrometry , intact PTH by a radioimmunoassay ( Scantibodies ) , procollagen-1 N-terminal peptide ( P1NP ) by a radioimmunoassay ( Immunodiagnostic Systems ) , C-terminal telopeptide of type 1 collagen ( CTX ) by an enzyme-linked immunosorbent assay [ ELISA ] ( Immunodiagnostic Systems ) , IL-6 by an ELISA ( R&D Systems ) , soluble tumor necrosis factor receptor ( sTNFR ) by an ELISA ( R&D Systems ) , and soluble CD14 by an ELISA ( R&D Systems ) . Inflammatory biomarkers were chosen based on association with relevant end points ( 4346 ) . All biomarkers , except for 25-(OH)D , were measured in duplicate , and values were averaged for analysis . Statistical Analysis To provide an intention-to-treat analysis , evaluations were done regardless of treatment change or discontinuation . Two patients who did not have the correct vitamin D test done at baseline were excluded from the efficacy analyses . Stratified Wilcoxon rank-sum tests were used to evaluate for distribution shifts between the treatment groups , which were stratified by screening vitamin D levels . Fisher exact tests and Wilcoxon rank-sum tests were used to evaluate for differences between groups for categorical and continuous secondary outcomes , respectively . Wilcoxon signed-rank tests were used to evaluate change within a treatment group . The 95 % CIs for median changes within a group were estimated using a distribution-free method via percentiles . For the BMD outcomes , modification of the treatment effect by screening vitamin D stratum was evaluated by means of linear regression . Analyses of the primary outcomes of change in hip and spine BMD from baseline to 48 weeks used a multiple-imputation approach to fill in missing data with a Markov-chain Monte Carlo method . A prespecified complete-case approach was used for analyses by stratum and to assess interactions . Five imputations were used , based on screening 25-(OH)D strata , age , sex , and race/ethnicity . All statistical tests were 2-sided and interpreted at the 5 % nominal level of significance without adjustment for multiple comparisons . Analyses were done using the FREQ , UNIVARIATE , REG , MI , and MIANALYZE procedures in SAS , version 9.2 ( SAS Institute ) , and STRATIFY and PAIRED procedures in Proc-StatXact , version 9 ( Cytel ) . Role of the Funding Source The National Institute of Allergy and Infectious Diseases funded the study . Industry sponsors ( Bristol-Myers Squibb , Gilead Science , and Tishcon ) provided antiretrovirals , vitamin D , calcium , and matching placebos , and additional funding was provided for completion of DXA scans and laboratory assays . The National Institute of Allergy and Infectious Diseases had no role in the design and conduct of the study ; collection , management , analysis , or interpretation of the data ; preparation , review , or approval of the manuscript ; or decision to su bmi t the manuscript for publication . The manuscript was review ed by AIMS To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25-hydroxyvitamin D levels . METHODS Double-blind , parallel group , placebo-controlled r and omized trial . A single dose of 100,000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter , when levels of circulating 25-hydroxyvitamin D were likely to be lowest . Patients were enrolled if their baseline 25-hydroxyvitamin D level was < 50 nmol/l .  Endothelial function and blood pressure were measured and fasting blood sample s were taken at baseline and 8 weeks after administration of vitamin D. RESULTS Forty-nine per cent of subjects screened had 25-hydroxyvitamin D levels < 50 nmol/l . Thirty-four subjects completed the study , with a mean age of 64 years and a baseline 25-hydroxyvitamin D level of 38.3 nmol/l .  Vitamin D supplementation  increased 25-hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation ( FMD ) of the brachial artery by 2.3 % . The improvement in FMD remained significant after adjusting for changes in blood pressure .  Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo ; this did not correlate with change in FMD . CONCLUSIONS Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotl and . A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency OBJECTIVE The purpose of this study was to prospect ively examine the association between vitamin D and calcium intake and risk of type 2 diabetes .  RESEARCH DESIGN AND METHODS In the Nurses ' Health Study , we followed 83,779 women who had no history of diabetes , cardiovascular disease , or cancer at baseline for the development of type 2 diabetes .  Vitamin D and calcium intake from diet and supplements was assessed every 2 - 4 years . During 20 years of follow-up , we documented 4,843 incident cases of type 2 diabetes . RESULTS After adjusting for multiple potential confounders , there was no association between total vitamin D intake and type 2 diabetes . However , the relative risk ( RR ) of type 2 diabetes was 0.87 ( 95 % CI 0.75 - 1.00 ; P for trend = 0.04 ) comparing the highest with the lowest category of vitamin D intake from supplements . The multivariate RRs of type 2 diabetes were 0.79 ( 0.70 - 0.90 ; P for trend < 0.001 ) comparing the highest with the lowest category of calcium intake from all sources and 0.82 ( 0.72 - 0.92 ; P for trend < 0.001 ) comparing the highest with the lowest category of calcium intake from supplements . A combined daily intake of > 1,200 mg calcium and > 800 IU vitamin D was associated with a 33 % lower risk of type 2 diabetes with RR of 0.67 ( 0.49 - 0.90 ) compared with an intake of < 600 mg and 400 IU calcium and vitamin D , respectively . CONCLUSIONS The results of this large prospect i ve study suggest a potential beneficial role for both vitamin D and calcium intake in reducing the risk of type 2 diabetes CONTEXT Systemic inflammation is thought to have a central role in diabetic long-term complications . OBJECTIVE The aim of this study was to investigate the effects of vitamin D either with or without extra calcium on certain inflammatory biomarkers in the subjects with type 2 diabetes ( T2D ) . DESIGN , SETTING , AND PARTICIPANTS This was a double-blind , r and omized , controlled trial conducted over 12 wk in 90 T2D subjects aged 30 - 60 yr from both sexes . INTERVENTION Subjects were r and omly allocated to one of three groups to receive two 250-ml bottles a day of plain Persian yogurt drink or doogh ( PD , containing 150 mg calcium and no detectable vitamin D(3)/250 ml ) , vitamin D-fortified doogh ( DD , containing 500 IU vitamin D(3 ) and 150 mg calcium/250 ml ) , or calcium + vitamin D(3)-fortified doogh ( CDD , containing 500 IU vitamin D(3 ) and 250 mg calcium/250 ml ) . OUTCOME MEASURES The changes in inflammatory markers were evaluated . RESULTS Compared to the baseline values , highly sensitive C-reactive protein , IL-1β , IL-6 , fibrinogen , and retinol binding protein-4 concentrations significantly decreased in both the DD and CDD groups . Although the decrement in highly sensitive C-reactive protein and fibrinogen was more in CDD compared to DD ( -4.0 ± 8.5 vs. -1.3 ± 2.8 mg/liter , and -0.40 ± 0.74 and -0.20 ± 0.52 mg/liter , respectively ) , the differences were not significant . There was a significant increase in serum adiponectin in both the DD and CDD groups ( 51.3 ± 65.3 vs. 57.1 ± 33.8 μg/liter ; P < 0.05 ) . Mean adiponectin changes in CDD were significantly higher than in PD ( P = 0.021 ) . CONCLUSIONS Daily intake of vitamin D-fortified doogh improved inflammatory markers in T2D subjects , and extra calcium conferred additional benefit only for the antiinflammatory adipokine , i.e. adiponectin BACKGROUND Low serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations have been associated with insulin resistance , the metabolic syndrome , and type 2 diabetes . Because many non-Western immigrants in the Netherl and s are vitamin D deficient , obese , and at high risk of diabetes , vitamin D supplementation may contribute to prevent diabetes and insulin resistance . OBJECTIVE We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight , vitamin D-deficient , non-Western immigrants at high risk of diabetes . DESIGN The study was a 16-wk , r and omized , placebo-controlled trial . A total of 130 non-Western immigrants with prediabetes ( fasting glucose concentration > 5.5 mmol/L or r and om glucose concentration from 7.8 to 11.1 mmol/L ) and vitamin D deficiency ( serum 25[OH]D concentration < 50 nmol/L ) were r and omly assigned after stratification by sex to receive either cholecalciferol ( 1200 IU/d ) or a placebo for 16 wk . All participants received 500 mg Ca/d as calcium carbonate . The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment . Secondary outcomes were insulin-sensitivity variables , β cell-function variables , and metabolic syndrome . RESULTS Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups . After 4 mo of therapy , the mean between-group difference was 38 nmol/L ( 95 % CI : 32.1 , 43.9 nmol/L ; P < 0.001 ) . There was no significant effect on insulin sensitivity and β cell function . In a post hoc analysis , when patients with diabetes at baseline were excluded , a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L ( P = 0.040 ) . CONCLUSIONS Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome . However , after the exclusion of diabetic subjects , an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827
Evidence from trials with vitamin D and /or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in population s at high risk ( i.e. glucose intolerance ) .
Vitamin D and calcium insufficiency may negatively influence glycemia , whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism
CONTEXT Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus ( type 2 DM ) .