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.

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.

Micro-CT of 3D vascular structures: clues for innovative scaffolds in organ engineering

Organ transplantation is the only definitive treatment for patients with incurable diseases of soft and hard tissue structures, including parenchyma and bones. However, shortage and aging of cadaveric and alive donors, and a number of other ethical and clinical issues render complex any organ transplant1. A recent hope has been raised by regenerative medicine and tissue engineering, but current methodologies are yet limited to the reconstruction of either tissue fragments or implantation of biocompatible scaffolds to be colonized by the regenerating areas. Although recent advancement in material science and stem cell biology has led to biocompatible scaffolds more efficient than in the past, still these constructs are designed without any anatomy of the vasculature intrinsic to the recipient organ, based on the assumption that nutrients and oxygen are supplied by diffusion from adjacent tissues2. Since in both parenchyma and bones the tissue mass grows around a complex vascular tree, we have recently developed an innovative bioengineering approach to reconstruct on the laboratory bench an entire bioartificial organ with a pre-formed internal vascular network acting as a natural scaffold for seeded stem cells, and as a guide for colonizing vessels, possibly improving the functional and transplantation performance of the bioconstruct 3. Micro-CT play a key role to obtain visual and numerical information on the complex vascular geometry of the organ to be engineered. We here present data on vascular casts of the rat lungs, and human kidney and thyroid gland, to be used in the development of STL- algorithms for CAD-based, inverse engineering of biomaterial replicas of soft tissue organ vasculature

Effect of vitamin D3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle

Introduction: This study sought to examine the effect of vitamin D3 (VD3) 3200 IU/d, calcifediol (HyD) 20mcg/d, or placebo on intramyonuclear vitamin D receptor (VDR) concentration, muscle fiber cross-sectional area (FCSA), and muscle satellite cell activation. Materials and methods: It was conducted on a subset of the VD3 (n = 12), HyD (n = 11), and placebo (n = 13) groups who participated in the 6-month randomized controlled HyD Osteopenia Study in postmenopausal women. Baseline and 6-month vastus lateralis muscle cross sections were probed for VDR, fiber type I and II, and PAX7 (satellite cell marker) using immunofluorescence. Results: Baseline mean ± SD age was 61 ± 4 years and serum 25-hydroxyvitamin D (25OHD) level was 55.1 ± 22.8 nmol/L. Baseline characteristics did not differ significantly by group. Six-month mean ± SD 25OHD levels were 138.7 ± 22.2 nmol/L (VD3), 206.8 ± 68.8 nmol/L (HyD), and 82.7 ± 36.1 nmol/L (placebo), ANOVA P 0.358). Conclusion: This study demonstrated no significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo. Type I FCSA significantly increased with VD3, but not with HyD at 6 months. As type I fibers are more fatigue resistant than type II, enlargement in type I suggests potential for improved muscle endurance. Although HyD resulted in the highest 25OHD levels, no skeletal muscle benefits were noted at these high levels. Clinical trial: NCT02527668. Keywords: Calcifediol; Muscle cross-sectional area; Muscle satellite cell; Vitamin D; Vitamin D receptor

Intra-trial Mean 25(OH)D and PTH Levels and Risk of Falling in Older Men and Women in the Boston STOP IT Trial

Context: Supplementation with vitamin D has the potential to both reduce and increase risk of falling, and parathyroid hormone (PTH) may contribute to fall risk. Objective: To assess the associations of intra-trial mean circulating levels of 25-hydroxyvitamin D [25(OH)D] and PTH on incident falls in healthy older adults. Design: Observational within a clinical trial. Setting: The Bone Metabolism Laboratory at the USDA Nutrition Center at Tufts University. Participants: 410 men and women age ≥65 years who participated in the 3-year Boston STOP IT trial to determine the effect of supplementation with 700 IU of vitamin D3 plus calcium on incident falls (secondary endpoint). Intra-trial exposures of 25(OH)D and PTH were calculated as the mean of biannual measures up to and including the first fall. Main outcome measures: Incidence of first fall. Results: Intra-trial mean 25(OH)D was significantly associated with risk of falling in a U-shaped pattern; the range associated with minimal risk of falling was approximately 20 to 40 ng/mL. PTH was not significantly associated with risk of falling. Conclusions: The findings highlight the importance of maintaining the circulating 25(OH)D level between 20 and 40 ng/mL, the range that is also recommended for bone health. At PTH levels within the normal range, there was no detectible independent association of PTH with fall risk. Keywords: 25(OH)D; PTH; falls; vitamin D supplementatio

A randomized study on the effect of vitamin D3 supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women

Context:Studies examining whether vitamin D supplementation increases muscle mass or muscle-specific vitamin D receptor (VDR) concentration are lacking.Objective:To determine whether vitamin D3 4000 IU/d alters muscle fiber cross-sectional area (FCSA) and intramyonuclear VDR concentration over 4 months.Design and Setting:Randomized, double-blind, placebo-controlled study in a single center.Participants:21 mobility-limited women (aged ≥65 years) with serum 25-hydroxyvitamin D (25OHD) levels 22.5-60 nmol/L.Main Outcome Measures:Baseline and 4-month FCSA and intramyonuclear VDR were measured from vastus lateralis muscle cross-sections probed for muscle fiber type (I/IIa/IIx) and VDR using immunofluorescence.Results:At baseline, mean (±SD) age was 78±5 years; body mass index (BMI) was 27±5 kg/m(2); 25OHD was 46.3±9.5 nmol/L; and a short physical performance battery score was 7.95±1.57 out of 12. At 4 months, 25OHD level was 52.5±17.1 (placebo) vs. 80.0±11.5 nmol/L (VD; P<0.01) and change in 25OHD level was strongly associated with percent change in intramyonuclear VDR concentration independent of group (r=0.87, P<0.001). By treatment group, percent change in intramyonuclear VDR concentration was 7.8±18.2% (placebo) vs. 29.7±11.7% (VD; P=0.03) with a more pronounced group difference in type II vs. I fibers. Percent change in total (type I/II) FCSA was -7.4±18.9% (placebo) vs. 10.6±20.0% (VD; P=0.048).Conclusion:Vitamin D3 supplementation increased intramyonuclear VDR concentration by 30% and increased muscle fiber size by 10% in older, mobility-limited, vitamin D-insufficient women. Further work is needed to determine whether the observed effect of vitamin D on fiber size is mediated by the VDR and to identify which signaling pathways are involved

Effects of Low Doses of L-Carnitine Tartrate and Lipid Multi-Particulate Formulated Creatine Monohydrate on Muscle Protein Synthesis in Myoblasts and Bioavailability in Humans and Rodents

The primary objective of this study was to investigate the potential synergy between low doses of L-carnitine tartrate and creatine monohydrate to induce muscle protein synthesis and anabolic pathway activation in primary human myoblasts. In addition, the effects of Lipid multi-particulates (LMP) formulation on creatine stability and bioavailability were assessed in rodents and healthy human subjects. When used individually, L-carnitine tartrate at 50 µM and creatine monohydrate at 0.5 µM did not affect myoblast protein synthesis and signaling. However, when combined, they led to a significant increase in protein synthesis. Increased AKT and RPS6 phosphorylation were observed with 50 µM L-carnitine tartrate 5 µM creatine in combination in primary human myoblasts. When Wistar rats were administered creatine with LMP formulation at either 21 or 51 mg/kg, bioavailability was increased by 27% based on the increase in the area under the curve (AUC) at a 51 mg/kg dose compared to without LMP formulation. Tmax and Cmax were unchanged. Finally, in human subjects, a combination of LMP formulated L-carnitine at 500 mg (from L-carnitine tartrate) with LMP formulated creatine at 100, 200, or 500 mg revealed a significant and dose-dependent increase in plasma creatine concentrations. Serum total L-carnitine levels rose in a similar manner in the three combinations. These results suggest that a combination of low doses of L-carnitine tartrate and creatine monohydrate may lead to a significant and synergistic enhancement of muscle protein synthesis and activation of anabolic signaling. In addition, the LMP formulation of creatine improved its bioavailability. L-carnitine at 500 mg and LMP-formulated creatine at 200 or 500 mg may be useful for future clinical trials to evaluate the effects on muscle protein synthesis