Benjamin U. Nwosu

The Vitamin D Status in Inflammatory Bowel Disease

Context There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD). Aim To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls. Hypothesis Serum 25(OH)D concentration will be lower in patients with IBD compared to controls. Subjects and Methods A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Data were expressed as mean ± SD. Results Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045). Conclusion There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.

Serum 25-hydroxyvitamin D levels do not correlate with asthma severity in a case-controlled study of children and adolescents.

Abstract Background: There is no consensus on the association between vitamin D and asthma. Objective: To determine the relationship between 25-hydroxyvitamin D [25(OH)D] levels and asthma symptom severity in children and adolescents. Methods: A retrospective, case-control study of 263 subjects of ages 2–19 years with asthma who were compared to 284 non-asthmatic controls of similar ages. Subjects were excluded if they had diseases of calcium or vitamin D metabolism or were receiving calcium or vitamin D supplementation. Serum 25(OH)D was measured in all subjects. Asthma symptom severity, usually stratified into 6 steps, was stratified into five steps [1–5] based on the number and dose of controller medications used as outlined by the National Heart, Lung, and Blood Institute’s guidelines. Mean 25(OH)D values were compared between the asthmatic patients and controls, as well as among the five steps of asthma symptom severity. Results were adjusted for age, sex, BMI, race and severity of asthma symptoms. Results: There was no difference in 25(OH)D between asthmatic patients and controls (28.64±10.09 vs. 28.42±11.47, p=1.0). However, there was a significant difference in 25(OH)D between obese and non-obese asthmatic patients (23.33±7.67 vs. 30.16±10.20, p<0.0001), as well as obese and non-obese controls (24.56±9.90 vs. 29.50±11.66, p=0.003). Mean 25(OH)D levels did not vary significantly among the five steps of asthma symptom severity. Conclusions: There were no differences in mean 25(OH)D levels between asthmatic patients and controls. Mean 25(OH)D level was significantly lower in both the obese asthmatic patients and obese controls. Asthma severity had no relationship to mean 25(OH)D levels.

The effects of vitamin D supplementation on hepatic dysfunction, vitamin D status, and glycemic control in children and adolescents with vitamin D deficiency and either type 1 or type 2 diabetes mellitus.

Background The effects of vitamin D supplementation on mild hepatic dysfunction and glycemic control are unclear in children and adolescents with either type 1 (T1D) or type 2 diabetes (T2D). Hypothesis Vitamin D supplementation will improve hepatic dysfunction and glycemic control. Aim To determine the effect of vitamin D supplementation on alanine transaminase (ALT), hemoglobin A1c (HbA1c), and serum 25-hydroxyvitamin D [25(OH)D] concentration. Subjects and Methods A retrospective study of 131 subjects with either T1D (n = 88∶46 females, 42 males), or T2D (n = 43∶26 females, 17 males) of ages 3–18 years between 2007–2013. All subjects had (1) a diagnosis of diabetes for >12 mo, (2) received vitamin D supplementation for the management of vitamin D deficiency (3) had baseline and subsequent simultaneous measurements of HbA1c, ALT, and 25(OH)D. Vitamin D deficiency was defined as 25(OH)D concentration of <50 nmol/L (20 ng/mL). Results At baseline, vitamin D deficiency occurred in 72.1% of patients with T2D and in 37.5% of T1D patients (p<0.001). Patients with T2D had significantly higher values for BMI SDS (p<0.001), alanine transaminase (ALT) (p = 0.001), but lower 25(OH)D (p<0.001), and no difference in HbA1c (p = 0.94), and total daily dose (TDD) of insulin per kg body weight (p = 0.48) as compared to T1D patients. After 3 months of vitamin D supplementation, there was a significant increase in 25(OH)D in both T2D (p = 0.015), and T1D patients (p<0.001); significant reduction in BMI SDS (p = 0.015) and ALT (p = 0.012) in T2D, but not in T1D. There was a clinically-significant decrease in HbA1c in T2D from 8.5±2.9% at baseline to 7.7±2.5 at 3 mo, but not in T1D, 8.5±1.2 to 8.53±1.1%. Conclusions Vitamin D supplementation in subjects with T2D was associated with statistically significant decreases in BMI SDS, ALT, and a clinically-significant decrease in HbA1c.

A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes.

Context Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear. Objective To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D. Hypothesis Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D. Design, Setting, and Participants A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage. Results Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups. Conclusions This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group. Trial Registration ClinicalTrial.gov NCT01334125

Short Stature with Normal Growth Hormone Stimulation Testing: Lack of Evidence for Partial Growth Hormone Deficiency or Insensitivity

Objectives: To test the hypothesis that children with short stature and peak stimulated GH (pGH) of 7–10 µg/l have partial GH deficiency and to test the hypothesis that short children with normal pGH but low IGF-I levels have partial GH deficiency or partial GH insensitivity. Design and Patients: Retrospective analysis of the clinical and biochemical profiles of 76 children who underwent an evaluation for short stature (height <5th percentile) that included two, sex steroid-primed GH stimulation tests. Results: Patients with pGH <7 µg/l (n = 14) differed significantly from those with pGH >7 µg/l (n = 62), having greater midparental height (MPH) SDS, a greater disparity between height SDS and MPH SDS, and lower IGF-I SDS. Patients with pGH of 7–10 µg/l (n = 12) did not have characteristics intermediate between those with pGH <7 µg/l and those with pGH ≧10 µg/l, but instead resembled those with pGH ≧10 µg/l. Patients with pGH ≧7 µg/l, but low IGF-I (<–2 SDS) (n = 5), did not show characteristics intermediate between those with pGH <7 µg/l and those with pGH ≧7 µg/l and normal IGF-I. Conclusions: These data do not support either the hypothesis that children with pGH of 7–10 µg/l have partial GH deficiency or the hypothesis that children with normal pGH but subnormal IGF-I levels have partial GH deficiency or insensitivity.

Hepatic dysfunction is associated with vitamin D deficiency and poor glycemic control in diabetes mellitus.

Abstract Background/Aims: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (TIDM) and type 2 diabetes (T2DM). Methods: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11–21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student’s t-test. Results: Vitamin D deficiency (25OHD <15 ng/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3±2.0 vs. 22.4±1.4, p<0.001; ALT 30.6±1.8 vs. 18.7±1.3, p<0.001) compared to T1DM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (β=–0.42, p=0.02), compared to T1DM subjects (β=–0.06, p=0.62). Conclusions: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.

The nondietary determinants of vitamin D status in pediatric inflammatory bowel disease

OBJECTIVES The aim of this study was to investigate the relationships between 25-hydroxy vitamin D (25[OH]D) and markers of vitamin D status in inflammatory bowel disease (IBD). METHODS We conducted a retrospective case-control study of 59 pediatric patients with IBD (age 16.4 ± 2.2 y) and 116 controls (age 14.6 ± 4.4 y), to investigate the association between 25(OH)D and albuminemia for protein-losing enteropathy (PLE) and hepatic dysfunction; alanine transaminase (ALT) for hepatic inflammation; erythrocyte sedimentation rate (ESR) for intestinal inflammation; body mass index (BMI) for adiposity; seasons and skin pigmentation for insolation. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L; abnormal liver enzyme by ALT >40 U/L; overweight status by BMI of ≥85th but <95th percentile, and obesity by BMI ≥95th percentile. Seasons were categorized as summer, winter, spring, and fall. RESULTS Patients with IBD had a higher prevalence of vitamin D deficiency (42.4% versus 26.7%; P = 0.04), elevated ALT (16.9% versus 2.6%; P < 0.001), and lower albumin (41.1 ± 4.8 versus 45.1 ± 3.8; P < 0.001) than controls. In both the IBD cohort and controls, 25(OH)D was highest in summer and lowest in winter, and significantly higher in white than in non-white patients. ESR varied significantly with 25(OH)D (R(2) = 0.24; β = -0.32; P = 0.010), and only patients with IBD with elevated ESR had lower 25(OH)D than controls (49.5 ± 25.2 versus 65.3 ± 28.0 nmol/L; P = 0.045). CONCLUSION Intestinal inflammation, not the loss of albumin-bound vitamin D in the gut, is the primary intestinal determinant of vitamin D status in IBD. The extraintestinal determinants are seasons and skin pigmentation, but not adiposity and hepatic inflammation.

Vitamin D3 Supplemental Treatment for Mania in Youth with Bipolar Spectrum Disorders

OBJECTIVE We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD). METHODS The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6-17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation. RESULTS Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=-3.66, p=0.002, df=15) and Childrens Depression Rating Scale (CDRS) scores (t=-2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14). CONCLUSIONS Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

The Vitamin D Status of Prison Inmates

Introduction There is no comprehensive, systematic analysis of the vitamin D status of prisoners in the scientific literature. Objective To investigate the vitamin D status and its determinants in US prison inmates. Hypothesis Given the uniformity of dietary intake amongst inmates, vitamin D status will be determined by non-dietary factors such as skin pigmentation, security level-, and the duration of incarceration. Subjects and Methods A retrospective study of 526 inmates (males, n = 502, age 48.6±12.5 years; females, n = 24, age 44.1±12.2) in Massachusetts prisons. Vitamin D sufficiency, insufficiency, and deficiency were respectively defined as a 25(OH)D concentration 75 nmol/L; 50 to 75 nmol/L; and <50 nmol/L. The Massachusetts Department of Correction Statement of Nutritional Adequacy stated that each inmate received the recommended daily allowance of vitamin D daily. Security level of incarceration was designated as minimum, medium, and maximum. Racial groups were categorized as Black, white, Asian, and Others. Results Serum 25(OH)D levels peaked in summer and autumn, and decreased in winter and spring. Vitamin D deficiency occurred in 50.5% of blacks, 29.3% of whites, and 14.3% of Asian inmates (p = 0.007). Black inmates had significantly lower serum 25(OH)D level than white inmates at the maximum security level (p = 0.015), medium security level (p = 0.001), but not at the minimum security level (p = 0.40). After adjusting for covariates black inmates at a maximum security level had a four-fold higher risk for vitamin D deficiency than white inmates at the same security level (OR 3.9 [95% CI 1.3–11.7]. Conclusions The vitamin D status of prison inmates is determined by skin pigmentation, seasons, and the security level of incarceration.