Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials.

BACKGROUND: The role of vitamin D in people who are at risk for type 2 diabetes remains unclear. PURPOSE: To evaluate whether administration of vitamin D decreases risk for diabetes among people with prediabetes. DATA SOURCES: PubMed, Embase, and ClinicalTrials.gov from database inception through 9 December 2022. STUDY SELECTION: Eligible trials that were specifically designed and conducted to test the effects of oral vitamin D versus placebo on new-onset diabetes in adults with prediabetes. DATA EXTRACTION: The primary outcome was time to event for new-onset diabetes. Secondary outcomes were regression to normal glucose regulation and adverse events. Prespecified analyses (both unadjusted and adjusted for key baseline variables) were conducted according to the intention-to-treat principle. DATA SYNTHESIS: Three randomized trials were included, which tested cholecalciferol, 20 000 IU (500 mcg) weekly; cholecalciferol, 4000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, versus matching placebos. Trials were at low risk of bias. Vitamin D reduced risk for diabetes by 15% (hazard ratio, 0.85 [95% CI, 0.75 to 0.96]) in adjusted analyses, with a 3-year absolute risk reduction of 3.3% (CI, 0.6% to 6.0%). The effect of vitamin D did not differ in prespecified subgroups. Among participants assigned to the vitamin D group who maintained an intratrial mean serum 25-hydroxyvitamin D level of at least 125 nmol/L (≥50 ng/mL) compared with 50 to 74 nmol/L (20 to 29 ng/mL) during follow-up, cholecalciferol reduced risk for diabetes by 76% (hazard ratio, 0.24 [CI, 0.16 to 0.36]), with a 3-year absolute risk reduction of 18.1% (CI, 11.7% to 24.6%). Vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio, 1.30 [CI, 1.16 to 1.46]). There was no evidence of difference in the rate ratios for adverse events (kidney stones: 1.17 [CI, 0.69 to 1.99]; hypercalcemia: 2.34 [CI, 0.83 to 6.66]; hypercalciuria: 1.65 [CI, 0.83 to 3.28]; death: 0.85 [CI, 0.31 to 2.36]). LIMITATIONS: Studies of people with prediabetes do not apply to the general population. Trials may not have been powered for safety outcomes. CONCLUSION: In adults with prediabetes, vitamin D was effective in decreasing risk for diabetes. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42020163522).

Effect of vitamin D supplementation on circulating fibroblast growth factor-23 concentration in adults with prediabetes.

BACKGROUND: Recent meta-analyses report that vitamin D supplementation increases blood fibroblast growth factor-23 (FGF23) level. OBJECTIVES: To determine the effect of 4000 IU/day of vitamin D3 for 12 months on circulating FGF23 levels. We also examined the association of the achieved 25-hydroxyvitamin D level [25(OH)D] with the FGF23 level at 12 months and with 12-month changes in FGF23. METHODS: An ancillary analysis among adults 70 years and older with prediabetes who participated in a trial comparing vitamin D3 4000 IU/day with placebo. Plasma intact FGF23 and serum 25(OH)D were measured at baseline and month 12 (M12). RESULTS: Characteristics of the 52 participants (vitamin D3 n = 28; placebo n = 24) did not differ significantly aside from more women than men in the vitamin D3 group. Mean ± SD age was 73.8 ± 3.7 years, BMI 31.3 ± 4.2 kg/m2, and glomerular filtration rate (GFR) 76.3 ± 11.8 mL/min/1.73m2 Baseline serum 25(OH)D level was 33.4 ± 10.8 ng/mL and increased at M12 to 54.9 ± 14.8 ng/mL in the vitamin D3 group versus 33.4 ± 14.9 in the placebo (p < 0.001). At baseline, GFR was inversely associated with FGF23 (r = - 0.349, p = 0.011). Change in FGF23 level at M12 did not differ significantly between vitamin D3 and placebo. In all participants combined, the achieved serum 25(OH)D level at M12 was not significantly associated with the M12 plasma FGF23 or the M12 change in FGF23. CONCLUSION: In obese older adults with sufficient vitamin D status and normal renal function, vitamin D3 4000 IU/day for 12 months did not significantly alter plasma intact FGF23 levels. CLINICALTRIALS: gov NCT 01,942,694, registered 9/16/2013.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience.

AIMS: To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record-supported and conventional recruitment methods. METHODS: Observational analysis of recruitment approaches in the vitamin D and type 2 diabetes (D2d) study, a multicenter trial in participants with prediabetes. Outcomes were adoption of electronic health record-supported recruitment approaches by sites, number of participants screened, recruitment performance (proportion screened who were randomized), and characteristics of participants from electronic health record-supported versus non-electronic health record methods. RESULTS: In total, 2423 participants were randomized: 1920 from electronic health record (mean age of 60 years, 41% women, 68% White) and 503 from non-electronic health record sources (mean age of 56.9 years, 58% women, 61% White). Electronic health record-supported recruitment was adopted by 21 of 22 sites. Electronic health record-supported recruitment was associated with more participants screened versus non-electronic health record methods (4969 vs 2166 participants screened), higher performance (38.6% vs 22.7%), and more randomizations (1918 vs 505). Participants recruited via electronic health record were older, included fewer women and minorities, and reported higher use of dietary supplements. Electronic health record-supported recruitment was incorporated in diverse clinical environments, engaging clinicians either at the individual or the healthcare system level. CONCLUSION: Establishing electronic health record-supported recruitment approaches across a multicenter prediabetes/diabetes trial is feasible and can be adopted by diverse clinical environments.

Association between body weight and composition and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program.

OBJECTIVE: We examined associations between body weight and plasma 25-hydroxyvitamin D concentration (25OHD) in prediabetes and sought to estimate the impact of adiposity on these associations. METHODS: The study was conducted in the placebo (n = 1082) and intensive lifestyle (n = 1079) groups of the Diabetes Prevention Program (DPP), a multicenter trial to prevent type 2 diabetes in adults with prediabetes. Weight and 25OHD were measured at baseline, month 6, years 1 and 2. In a subset (n = 584), visceral (VAT) and subcutaneous (SAT) adiposity were assessed by computed tomography at baseline and year 1. RESULTS: In cross-sectional analyses, baseline body weight, total fat, VAT, and SAT were inversely associated with plasma 25OHD concentration after multivariable adjustment. VAT accounted for 40 % [95 % CI 11, 69] of the association of body weight with plasma 25OHD concentration. There was no significant contribution by total fat or SAT. Two-year changes in plasma 25OHD concentration varied inversely with changes in body weight (p < 0.0001). One-year changes in total fat, VAT, or SAT were not significant mediators of the association between change in plasma 25OHD concentration and body weight. CONCLUSION: Our study found an inverse association between body weight and plasma 25OHD concentration at baseline and over a 2-year period in adults with prediabetes. These findings in the DPP, a weight loss intervention study, raise the possibility that weight loss increases plasma 25OHD concentration. Whether adiposity mediates this association remains inconclusive.

Combined Diet and Physical Activity Promotion Programs to Prevent Type 2 Diabetes Among Persons at Increased Risk: A Systematic Review for the Community Preventive Services Task Force.

BACKGROUND: Trials have shown efficacy of rigorous diet and physical activity promotion programs to reduce diabetes incidence and improve glycemic measures in adults at increased risk for type 2 diabetes. PURPOSE: To evaluate diet and physical activity promotion programs for persons at increased risk for type 2 diabetes, primarily to reduce diabetes risk and decrease body weight and glycemia. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, CAB Abstracts, Global Health, and Ovid HealthSTAR from 1991 through 27 February 2015, with no language restriction. STUDY SELECTION: 8 researchers screened articles for single-group or comparative studies of combined diet and physical activity promotion programs with at least 2 sessions over at least 3 months in participants at increased risk for type 2 diabetes. DATA EXTRACTION: 7 researchers extracted data on study design; participant, intervention, and outcome descriptions; and results and assessed study quality. DATA SYNTHESIS: 53 studies (30 of diet and physical activity promotion programs vs. usual care, 13 of more intensive vs. less intensive programs, and 13 of single programs) evaluated 66 programs. Compared with usual care, diet and physical activity promotion programs reduced type 2 diabetes incidence (risk ratio [RR], 0.59 [95% CI, 0.52 to 0.66]) (16 studies), decreased body weight (net change, -2.2% [CI, -2.9% to -1.4%]) (24 studies) and fasting blood glucose level (net change, -0.12 mmol/L [-2.2 mg/dL] [CI, -0.20 to -0.05 mmol/L {-3.6 to -0.9 mg/dL}]) (17 studies), and improved other cardiometabolic risk factors. Evidence for clinical events was limited. More intensive programs were more effective. LIMITATIONS: Wide variation in diet and physical activity promotion programs limited identification of features most relevant to effectiveness. Evidence on clinical outcomes and in children was sparse. CONCLUSION: Combined diet and physical activity promotion programs are effective at decreasing diabetes incidence and improving cardiometabolic risk factors in persons at increased risk. More intensive programs are more effective. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention Community Preventive Services Task Force.

Effect of glycemic load on eating behavior self-efficacy during weight loss.

High eating behavior self-efficacy may contribute to successful weight loss. Diet interventions that maximize eating behavior self-efficacy may therefore improve weight loss outcomes. However, data on the effect of diet composition on eating behavior self-efficacy are sparse. To determine the effects of dietary glycemic load (GL) on eating behavior self-efficacy during weight loss, body weight and eating behavior self-efficacy were measured every six months in overweight adults participating in a 12-mo randomized trial testing energy-restricted diets differing in GL. All food was provided during the first six months and self-selected thereafter. Total mean weight loss did not differ between groups, and GL-level had no significant effect on eating behavior self-efficacy. In the combined cohort, individuals losing the most weight reported improvements in eating behavior self-efficacy, whereas those achieving less weight loss reported decrements in eating behavior self-efficacy. Decrements in eating behavior self-efficacy were associated with subsequent weight regain when diets were self-selected. While GL does not appear to influence eating behavior self-efficacy, lesser amounts of weight loss on provided-food energy restricted diets may deter successful maintenance of weight loss by attenuating improvements in eating behavior self-efficacy.

Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial.

INTRODUCTION: Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race. RESEARCH DESIGN AND METHODS: From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUCglu) during OGTT and least squares regression model to estimate A1c for a given AUCglu by race, controlling for potential confounders. RESULTS: 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUCglu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUCglu quintile were 0.15-0.20 and 0.02-0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants. CONCLUSIONS: Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population.

Navigating Complexities: Vitamin D, Skin Pigmentation, and Race.

Vitamin D plays a critical role in many physiological functions, including calcium metabolism and musculoskeletal health. This commentary aims to explore the intricate relationships among skin complexion, race, and 25-hydroxyvitamin D (25[OH]D) levels, focusing on challenges the Endocrine Society encountered during clinical practice guideline development. Given that increased melanin content reduces 25(OH)D production in the skin in response to UV light, the guideline development panel addressed the potential role for 25(OH)D screening in individuals with dark skin complexion. The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants' skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations. Lessons learned from the guideline development process emphasize the necessity of clarity when incorporating race and ethnicity into clinical guidelines. Such clarity is an essential step toward improving health outcomes and ensuring equitable healthcare practices.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D.

CONTEXT: Low vitamin D status is common and is associated with various common medical conditions. OBJECTIVE: To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. METHODS: We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. RESULTS: Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. CONCLUSION: The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals' and providers' values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

Relationship of cravings with weight loss and hunger. Results from a 6 month worksite weight loss intervention.

We examined the association of food cravings with weight loss and eating behaviors in a lifestyle intervention for weight loss in worksites. This research was part of a randomized controlled trial of a 6-month weight loss intervention versus a wait-listed control in 4 Massachusetts worksites. The intervention emphasized reducing energy intake by adherence to portion-controlled menu suggestions, and assessments were obtained in 95 participants at baseline and 6 months including non-fasting body weight, food cravings (Craving Inventory and Food Craving Questionnaire for state and trait) and the eating behavior constructs restraint, disinhibition and hunger (Eating Inventory). There were statistically significant reductions in all craving variables in the intervention group compared to the controls. Within the intervention group, changes in craving-trait were significantly associated with weight loss after controlling for baseline weight, age, gender and worksite. However, in a multivariate model with craving-trait and eating behaviors (restraint, disinhibition and hunger), hunger was the only significant predictor of weight change. In contrast to some previous reports of increased food cravings with weight loss in lifestyle interventions, this study observed a broad reduction in cravings associated with weight loss. In addition, greater reductions in craving-trait were associated with greater weight change, but craving-trait was not a significant independent correlate of weight change when hunger was included in statistical models. Studies are needed to examine the effectiveness of hunger suppressing versus craving-suppressing strategies in lifestyle interventions for obesity.

New-Onset Diabetes After COVID-19.

There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022, using Medical Subject Headings (MeSH) terms and free text words including "COVID-19," "SARS-CoV-2," "diabetes," "hyperglycemia," "insulin resistance," and "pancreatic ß-cell." We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain because of limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19, and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (eg, age), social determinants of health (eg, deprivation index), and pandemic-related effects both at the personal (eg, psychosocial stress) and the societal-community level (eg, containment measures). COVID-19 may have direct and indirect effects on pancreatic ß-cell function and insulin sensitivity related to the acute infection and its treatment (eg, glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (eg, type 1 or type 2), so that the pathophysiology, natural history, and optimal management can be studied.

Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study.

BACKGROUND: Higher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight. OBJECTIVES: This analysis aims to determine whether the effect of vitamin D differs among people of color and those with overweight/obesity (who have higher diabetes risk) compared with individuals who are White or have normal weight. METHODS: The D2d study is a randomized clinical trial in people with prediabetes that tested the effects of daily vitamin D3 4000 IU vs. placebo on diabetes risk (median followup 2.5 y). We compared baseline and intratrial mean 25(OH)D concentrations, defined as the mean of all available annual 25(OH)D values, among groups defined by self-reported race and body mass index (BMI). We used Cox proportional hazards models to assess the associations between intratrial mean 25(OH)D and diabetes risk by race- and BMI-based groups. RESULTS: Asian (n=130), Black (n=616), and White (n=1616) participants were included. Both baseline and intratrial mean 25(OH)D concentrations differed significantly by race groups (both P < 0.001) and were lower in Asian and Black vs. White participants, and in those with higher vs. lower BMI adjusted for race (both P < 0.001). Compared with those with lower concentrations, Black and White participants with intratrial mean 25(OH)D ≥ 40 ng/mL had significantly reduced diabetes risk [HR (95% CI): Black: 0.51 (0.29, 0.92); White: 0.42 (0.30, 0.60)] and with a similar reduction in diabetes risk among Asian participants: 0.39 (0.14, 1.11). Compared with those with lower concentrations, participants with baseline BMI < 40 kg/m2 who achieved intratrial mean 25(OH)D concentrations ≥ 40 ng/mL had a significantly reduced diabetes risk. There was no statistically significant interaction between intratrial 25(OH)D and race or between intratrial 25(OH)D and BMI on diabetes risk. CONCLUSIONS: Among people with prediabetes, particularly for Black and White race groups and those with BMI < 40 kg/m2, the optimal 25(OH)D concentration may be ≥ 40 ng/mL to optimize diabetes-prevention efforts. This trial was registered at clinicaltrials.gov as NCT01942694.

Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD. METHODS: Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)]. RESULTS: Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis. CONCLUSIONS: The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.

Effect of vitamin D on regression to normal glucose regulation and individual glycemic measures: A secondary analysis among participants adherent to the trial protocol in the randomized clinical trial vitamin D and type 2 diabetes (D2d) study.

AIMS: To examine the effect of vitamin D on regression to normal glucose regulation (NGR) and individual glycemic measures in the D2d study. METHODS: In per-protocol analyses, we examined time to new-onset diabetes; time to new-onset NGR defined as first occurrence of: 2-or-3 glycemic criteria in the normal range (NGR-1) or fasting plasma glucose (FPG) and 2-hour post-load-glucose (2hPG) in the normal range (NGR-2); proportion meeting NGR at the last study visit; and change in FPG, 2hPG, and HbA1c. RESULTS: Among 2423 participants, hazard ratio [HR] for diabetes was 0.84 [95%CI, 0.71, 0.99]). HR (95%CI) was 1.16 (0.99, 1.36) for new-onset NGR-1 and 1.06 (0.87, 1.30) for NGR-2. At the last visit, NGR-1 occurred in 12.4% vs. 9.5% participants in the vitamin D vs. placebo group (rate ratio for vitamin D 1.31 [1.02, 1.70]); whereas, NGR-2 occurred in 8.7% vs. 6.0% (rate ratio for vitamin D 1.45 [1.05, 2.00]). During follow-up, FPG, HbA1c, and 2hPG increased in both groups. Mean difference in FPG favored vitamin D (-0.80 mg/dL; 95%CI, -1.26, -0.33). CONCLUSIONS: In secondary analyses among participants adherent to the trial protocol, vitamin D lowered risk of developing diabetes and increased likelihood of NGR at the end of the study.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Secretion in Prediabetes.

CONTEXT: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on ß-cell function remain unclear. OBJECTIVE: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and ß-cell function. METHODS: This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. MAIN OUTCOME: Disposition index (DI), as an estimate of ß-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). RESULTS: Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). CONCLUSIONS: Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of ß-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.