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).

Exploring the effect of vitamin D3 supplementation on surrogate biomarkers of cholesterol absorption and endogenous synthesis in patients with type 2 diabetes-randomized controlled trial.

BACKGROUND: Inverse associations have been reported between serum 25-hydroxyvitamin D [25(OH)D] and circulating cholesterol concentrations in observational studies. Postulated mechanisms include reduced bioavailability of intestinal cholesterol and alterations in endogenous cholesterol synthesis. OBJECTIVE: To explore the effect of daily supplementation with 4000 IU/d vitamin D3 for 24 wk on surrogate biomarkers of cholesterol absorption (campesterol and ß-sitosterol) and endogenous synthesis (lathosterol and desmosterol). METHODS: Ancillary study of The Vitamin D for Established Type 2 Diabetes (DDM2) trial. Patients with established type 2 diabetes (N = 127, 25-75 y, BMI 23-42 kg/m2) were randomly assigned to receive either 4000 IU vitamin D3 or placebo daily for 24 wk. Of participants without changes in cholesterol-lowering medications (n = 114), plasma surrogate cholesterol absorption and endogenous synthesis biomarker concentrations were measured and merged with available measures of serum LDL cholesterol and HDL cholesterol concentrations. RESULTS: At week 24, vitamin D3 supplementation significantly increased 25(OH)D concentrations (+21.5 ± 13.4 ng/mL) but not insulin secretion rates (primary outcome of the parent study) as reported previously. In this ancillary study there was no significant effect of vitamin D3 supplementation on serum cholesterol profile or surrogate biomarkers of cholesterol absorption and endogenous synthesis. Compared with participants not treated with cholesterol-lowering medications, those who were treated exhibited a greater reduction in plasma campesterol concentrations in the vitamin D3 but not placebo group (P-interaction = 0.011). Analyzing the data on the basis of cholesterol absorption status (hypo- versus hyperabsorbers) or cholesterol synthesis status (hypo- versus hypersynthesizers) did not alter these results. CONCLUSIONS: Vitamin D3 supplementation for 24 wk had no significant effect on surrogate biomarkers of cholesterol absorption or endogenous synthesis, consistent with the lack of effect on serum cholesterol profile. Vitamin D3 supplementation resulted in greater reduction in campesterol concentrations in participants not using compared with those using cholesterol-lowering medications. Further studies are required.This trial was registered at clinicaltrials.gov as NCT01736865.

The Calculation of the Glucose Management Indicator Is Influenced by the Continuous Glucose Monitoring System and Patient Race.

Objective: To determine whether the glucose management indicator (GMI), an estimate of hemoglobin A1c (HbA1c) derived from continuous glucose monitoring (CGM) mean glycemia, differs by CGM system and patient race. Methods: One hundred three patients with prediabetes or stable diabetes and a minimum of 10 days of CGM data collected with the FreeStyle Libre CGM system immediately before measurement of HbA1c were included in this clinic-based observational study that used data from electronic health records in an academic endocrinology clinic. HbA1c and Libre CGM-measured mean glucose were plotted to derive a race-agnostic and race-specific regression equations to calculate a Libre-specific GMI (GMILi). The mean GMI derived from the published formula (GMIP) was compared with GMILi. Results: Mean ± SD (standard deviation) age of patients was 61.9 ± 13.3 years; 50% were of nonwhite race and 77% had type 2 diabetes; mean HbA1c was 62 mmol/mol (7.8%). The mean (range) number of days with available CGM data was 26 (10-90). The mean ± SD GMILi was higher than the GMIP in the entire cohort (7.9% ± 1.0% vs. 7.5% ± 1.0%, respectively; P = 0.01) and among Asian patients (7.9% ± 0.9% vs. 7.2% ± 1.0%, respectively; P = 0.03). Conclusions: In a cohort with prediabetes or stable diabetes, the regression equation to calculate GMI varied by CGM system and patient race. The development of device- and race-specific regression equations for GMI may be warranted.

Combining Wireless Technology and Behavioral Economics to Engage Patients (WiBEEP) with cardiometabolic disease: a pilot study.

BACKGROUND: The long-term management of cardiometabolic diseases, such as type 2 diabetes and hypertension, is complex and can be facilitated by supporting patient-directed behavioral changes. The concurrent application of wireless technology and personalized text messages (PTMs) based on behavioral economics in managing cardiometabolic diseases, although promising, has not been studied. The aim of this pilot study was to evaluate the feasibility and acceptability of the concurrent application of wireless home blood pressure (BP) monitoring (as an example of "automated hovering") and PTMs (as an example of "nudging") targeting pharmacotherapy and lifestyle habits in patients with cardiometabolic disease (type 2 diabetes and/or hypertension). METHODS: The Wireless Technology and Behavioral Economics to Engage Patients (WiBEEP) with cardiometabolic disease study was a single-arm, open-label, 7-week-long pilot study in 12 patients (mean age 58.5 years) with access to a mobile phone. The study took place at Tufts Medical Center (Boston, MA) between March and September 2017. All patients received PTMs; nine patients received wireless home BP monitoring. At baseline, patients completed questionnaires to learn about their health goals and to assess medication adherence; at the end of week 7, all patients completed questionnaires to evaluate the feasibility and acceptability of the intervention and assess medication adherence. Hemoglobin A1c was ascertained from data collected during routine clinical care in 7 patients with available data. RESULTS: The majority of patients reported the text messages to be easy to understand (88%) and appropriate in frequency (71%) and language (88%). All patients reported BP monitoring to be useful. Mean arterial pressure was lower at the end-of-study compared to baseline (- 3.4 mmHg [95% CI, - 5 to - 1.8]. Mean change in hemoglobin A1c was - 0.31% [95% CI, - 0.56 to - 0.06]. CONCLUSIONS: Among patients with cardiometabolic disease, the combination of wireless BP monitoring and lifestyle-focused text messaging was feasible and acceptable. Larger studies will determine the long-term effectiveness of such an approach.

Effect of vitamin D supplementation on cardiovascular risk in type 2 diabetes.

BACKGROUND & AIMS: Whether vitamin D affects lipid profile and cardiovascular disease (CVD) risk is controversial. We evaluated the effect of oral daily vitamin D supplementation on lipid profile and CVD risk in patients with well-controlled type 2 diabetes. METHODS: Secondary analysis in the vitamin D for established type 2 diabetes (DDM2) study, a double-blind, randomized, placebo-controlled clinical trial. 127 patients (mean age 60 years) with stable (HbA1c ≤ 7.5%) diabetes managed with lifestyle only or lifestyle plus metformin were randomized to receive 4000 IU/day of vitamin D3 (n = 66) or placebo (n = 61) for 48 weeks. Changes in lipid profile (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides [TG] and TG/HDL ratio), C-reactive protein and CVD risk (calculated according the American College of Cardiology/American Heart Association [ACC/AHA] guidelines) were assessed at week 24 and 48. RESULTS: The mean [±SEM] plasma 25-hydroxyvitamin D [25(OH)D] level was higher in the vitamin D vs. the placebo group (20.5 ± 1.18 vs. -1.6 ± 1.2 ng/mL respectively; p < 0.001). There was no statistically significant change in lipid profile, C-reactive protein or CVD risk. Among patients who were not on cholesterol medication (n = 32), vitamin D supplementation reduced TG compared to placebo at week 48 (-18.74 ± 8.91 vs. 9.69 ± 8.60 mg/dL respectively; p = 0.032). CONCLUSION: One year supplementation with vitamin D3 at 4000 IU/day did not affect lipid profile, C-reactive protein and CVD risk in patients with stable type 2 diabetes not selected for vitamin D deficiency, with the exception of improvement of TG among patients not on cholesterol medication. REGISTRATION: ClinicalTrials.gov Identifier NCT01736865.

Vitamin D Supplementation in Patients With Type 2 Diabetes: The Vitamin D for Established Type 2 Diabetes (DDM2) Study.

CONTEXT: Observational data support a role for vitamin D in type 2 diabetes, but evidence from trials is inconclusive. OBJECTIVE: To evaluate the effect of vitamin D supplementation on ß-cell function and hemoglobin A1c (HbA1c) in patients with well-controlled type 2 diabetes. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTING: Tufts Medical Center, Boston, MA; VA Medical Center, Cincinnati, OH. PARTICIPANTS: A total of 127 patients (mean age, 60 years) with stable (HbA1c ≤7.5%) diabetes managed with lifestyle only or lifestyle plus metformin. INTERVENTION: Subjects were given 4000 units of vitamin D3 (cholecalciferol) daily or placebo for 48 weeks. MAIN OUTCOME MEASURE: Insulin secretion rate (ISR) was estimated from peripheral plasma C-peptide levels after a 3-hour 75-g oral glucose tolerance test done at baseline and week 24. Changes in HbA1c were assessed at 16, 24, 36, and 48 weeks. RESULTS: Baseline mean plasma 25-hydroxyvitamin D [25(OH)D] concentration was 26.6 ng/mL, mean HbA1c was 6.6%, and 78% of patients were on metformin. At week 24, mean 25(OH)D changed by 20.5 and -1.6 ng/mL in the vitamin D and placebo groups, respectively (P < 0.001). The vitamin D and placebo groups did not differ in change in ISR or HbA1c. Among patients treated with lifestyle only (n = 28), vitamin D supplementation reduced HbA1c compared with placebo (-0.1% vs 0.3%, respectively; P = 0.034) at week 24. This result was not observed at the other time points and could be due to chance. CONCLUSION: Vitamin D3 at 4000 IU/d did not change ISR or HbA1c in patients with well-controlled type 2 diabetes on metformin not selected for vitamin D deficiency.

The Role of Vitamin D in the Prevention of Type 2 Diabetes: To D or Not to D?

Evidence on biological plausibility from mechanistic studies and highly consistent data from observational studies raise the possibility that optimizing vitamin D status may reduce the risk of type 2 diabetes. However, the observational nature of cohort studies precludes a definitive assessment of cause and effect because residual confounding or reverse causation cannot be excluded. Confounding is especially problematic with studies of vitamin D because blood 25-hydoxyvitamin D concentration is not only an excellent biomarker of vitamin D status, reflecting intake or biosynthesis, but also an excellent marker of good overall health. Results from underpowered trials and post hoc analyses of trials designed for nondiabetic outcomes do not support a role of vitamin D supplementation for prevention of type 2 diabetes among people with normal glucose tolerance. Whether vitamin D supplementation may have a role in the prevention of diabetes in high-risk populations remains to be seen. Adequately powered, randomized trials in well-defined populations (e.g., prediabetes) are ongoing and expected to establish whether vitamin D supplementation lowers risk of diabetes.

Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway.

AIMS: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. METHODS: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC). RESULTS: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. CONCLUSIONS: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.

Comorbidities and crash involvement among younger and older drivers.

Previous studies identified comorbidities as predictors of older driver performance and driving pattern, while the direct impact of comorbidities on road crash risk in elderly drivers is still unknown. The present study is a cross-sectional aimed at investigating the association between levels of comorbidity and crash involvement in adult and elderly drivers. 327 drivers were stratified according to age range in two groups: elderly drivers (age ≥70 years old, referred as older) and adult drivers (age <70 years old, referred as younger). Driving information was obtained through a driving questionnaire. Distance traveled was categorized into low, medium and high on the basis of kilometers driven in a year. CIRS-illness severity (IS) and CIRS-comorbidity indices (CI) in all populations were calculated. Older drivers had a significantly higher crash involvements rate (p = .045) compared with the younger group based on the number of licensed drivers. Dividing comorbidity indices into tertiles among all licensed subjects, the number of current drivers significantly decreased (p<.0001) with increasing level of comorbidity. The number of current drivers among older subjects significantly decreased with increasing comorbidity level (p = .026) while no difference among younger group was found (p = .462). Among younger drivers with increasing comorbidity level, the number of road accidents significantly increased (p = .048) and the logistic regression analysis showed that comorbidity level significantly associated with crash involvement independent of gender and driving exposure. Older subjects with high level of comorbidity are able to self-regulate driving while comorbidity burden represents a significant risk factor for crash involvements among younger drivers.

Dipeptidyl peptidase-4 inhibitors have protective effect on cognitive impairment in aged diabetic patients with mild cognitive impairment.

BACKGROUND: Older adults with type 2 diabetes have an increased risk for mild and severe cognitive impairment probably as consequence of chronic hyperglycemia or fasting plasma glucose levels. Variability in glucose level and recurrent hypoglycemic episodes are also associated with cognitive impairment. Dipeptidyl peptidase-4 inhibitor (DPP-4I) therapy affects glycemic variability. The purpose of this study was to evaluate the effect of DPP-4I therapy on changes in cognitive function in older patients with type 2 diabetes complicated by mild cognitive impairment. METHODS: This retrospective longitudinal study used data from a database of 240 older patients with type 2 diabetes, "drug naive," affected by mild cognitive impairment, subsequently treated for 2 years with antidiabetic drugs (DPP-4I group: DPP-4I + metformin, n = 120; SU group: sulfonylurea + metformin, n = 120) and reassessed in our ambulatory by comprehensive clinical, cognitive, instrumental examinations, and continuous subcutaneous glucose monitoring. RESULTS: At baseline, larger mean amplitude of glycemic excursion values correlated with poorer Mini-Mental State Examination and composite cognitive function scores. We found that higher body mass index, higher 2-hour postprandial glucose, and greater mean amplitude of glycemic excursion values measured at baseline were significant independent predictors of cognitive worsening. In addition, reduction in mean amplitude of glycemic excursions and the use of DPP-4I therapy predicted improvement in cognitive functions. CONCLUSIONS: In older patients with type 2 diabetes affected by mild cognitive impairment, DPP-4I administration improves glucose control and protects against worsening in cognitive functioning.

Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR = 2.50 95% CI 1.45-4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff = 15.08 [7.60-22.57] p = 0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR = 3.88; 95% CI 1.582-9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.