Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes.

BACKGROUND/OBJECTIVES: Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study. SUBJECTS/METHODS: In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. RESULTS: A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)). CONCLUSION: Vitamin D3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013.

Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes.

OBJECTIVE: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis. MEASUREMENTS: A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups. RESULTS: The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups. CONCLUSIONS: High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG.

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.).

Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts.

OBJECTIVE: To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes. RESEARCH DESIGN AND METHODS: This is a multicenter (n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D3) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140-199 mg/dL, and/or a hemoglobin A1c (HbA1c) 5.7-6.4% (39-46 mmol/mol). RESULTS: A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 59 (9.9) years and BMI 32 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c and lowest FPG concentration compared with white, Asian, and other races (P < 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA1c and FPG concentrations. CONCLUSIONS: D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria.

Diabetes Empowerment Council: Integrative Pilot Intervention for Transitioning Young Adults With Type 1 Diabetes.

BACKGROUND: The transition of young adults with type 1 diabetes (T1D) from pediatric to adult care is challenging and frequently accompanied by worsening of diabetes-related health. To date, there are no reports which prospectively assess the effects of theory-based psycho-behavioral interventions during the transition period neither on glycemic control nor on psychosocial factors that contribute to poor glycemic control. Therefore, the overall aim of this study was to develop and pilot test an integrative group intervention based on the underlying principles of self-determination theory (SDT), in young adults with T1D. METHODS: Fifty-one young adults with T1D participated in an education and case management-based transition program, of which 9 took part in the Diabetes Empowerment Council (DEC), a 12-week holistic, multimodality facilitated group intervention consisting of "council" process based on indigenous community practices, stress-reduction guided imagery, narrative medicine modalities, simple ritual, and other integrative modalities. Feasibility, acceptability, potential mechanism of effects, and bio-behavioral outcomes were determined using mixed qualitative and quantitative methods. RESULTS: The intervention was highly acceptable to participants, though presented significant feasibility challenges. Participants in DEC showed significant reductions in perceived stress and depression, and increases in general well-being relative to other control participants. Reduction in perceived stress, independent of intervention group, was associated with reductions in hemoglobin A1C. A theoretical model explaining the effects of the intervention included the promotion of relatedness and autonomy support, 2 important aspects of SDT. CONCLUSIONS: The DEC is a promising group intervention for young adults with T1D going through transition to adult care. Future investigations will be necessary to resolve feasibility issues, optimize the multimodality intervention, determine full intervention effects, and fully test the role of the underlying theoretical model of action.ClinicalTrials.gov Registration Number NCT02807155; Registration date: June 15, 2016 (retrospectively registered).

Individual and demographic consequences of reduced body condition following repeated exposure to high temperatures.

Although the lethal consequences of extreme heat are increasingly reported in the literature, the fitness costs of exposure to sublethal high air temperatures, typically identified in the 30-40 degrees C range, are poorly understood. We examine the effect of high (> or = 35 degrees C) daily maxima on body condition of a semiarid population of White-plumed Honeyeaters, Ptilotula penicillatus, monitored between 1986 and 2012. During this 26-yr period, temperature has risen, on average, by 0.06 degrees C each year at the site, the frequency of days with thermal maxima > or = 35 degrees C has increased and rainfall has declined. Exposure to high temperatures affected body condition of White-plumed Honeyeaters, but only in low-rainfall conditions. There was no effect of a single day of exposure to temperatures > or = 35 degrees C but repeated exposure was associated with reduced body condition: 3.0% reduction in body mass per day of exposure. Rainfall in the previous 30 d ameliorated these effects, with reduced condition evident only in dry conditions. Heat-exposed males with reduced body condition were less likely to be recaptured at the start of the following spring; they presumably died. Heat-exposed females, regardless of body condition, showed lower survival than exposed males, possibly due to their smaller body mass. The higher mortality of females and smaller males exposed to temperatures > or = 35 degrees C may have contributed to the increase in mean body size of this population over 23 years. Annual survival declined across time concomitant with increasing frequency of days > or = 35 degrees C and decreasing rainfall. Our study is one of few to identify a proximate cause of climate change related mortality, and associated long-term demographic consequence. Our results have broad implications for avian communities living in arid and semiarid regions of Australia, and other mid-latitudes regions where daily maximum temperatures already approach physiological limits in regions affected by both decreased precipitation and warming.

Diabetes management for low-income patients in Los Angeles: two strategies improved disease control in the short term.

Health care providers serving vulnerable patients in Los Angeles have developed programs intended to increase diabetes control through more-intensive patient education and engagement. We examined two programs, the first using a short-term intensive intervention by a care team including nurses and a specialist, and the second integrating case management and clinical pharmacy programs into primary care in a community clinic. We show evidence that both models improved short-term disease control, as measured by reductions in HbA1c and low-density lipoprotein (sometimes referred to as "bad" cholesterol). However, integrating case management and clinical pharmacy programs into a primary care setting was less labor-intensive and potentially less expensive than the care team intervention. The challenge is to understand the essential aspects of these interventions; refine their design so that they are more cost-effective and fiscally feasible; and identify long-term health and cost effects.

The carotenoid conundrum: improved nutrition boosts plasma carotenoid levels but not immune benefits of carotenoid supplementation.

Carotenoids are widely heralded as central to honest signaling due to their dual roles as pigments and antioxidants/immunostimulants. The aim of this study is to test if diet quality and carotenoids alone or in an interaction influence condition, carotenoid availability in plasma and immune responsiveness. Therefore, a diet experiment during the moult of great tits, Parus major, was performed. In a two-way design, we manipulated general quality (digestibility, protein and vitamin content) as well as carotenoid (lutein) content of semi-synthetic diets. Higher quality diet improved individual condition since birds had greater body mass, and to a lesser extent, higher hematocrit. In addition to the expected positive effect of carotenoid supplementation and individual lutein consumption on circulating lutein, there was a positive effect of enhanced diet quality on plasma carotenoid levels. Carotenoid supplementation, but not diet quality, improved the local inflammatory response and maintenance of body mass during a humoral immune reaction. The enhancement of circulating carotenoid levels by improved general quality of the diet or individual condition could provide a testable, mechanistic explanation for the variation in effects of carotenoid supplementation studies.