Genetic testing for maturity-onset diabetes of the young resulting in an upgraded genetic classification of an HNF1A gene variant: a case report

The frequent misdiagnosis of MODY (Maturity-Onset Diabetes of the Young) subtypes makes it necessary to clarify the clinical spectrum of the disease phenotypes in suspected subjects so that accurate diagnosis and management plans can be introduced as early as possible in the course of the disease. We report the case of a MODY subtype that was initially characterized as variant of uncertain significance (VUS) but was later changed to a likely pathogenic variant following our report of two cases where the full expression of the clinical phenotype was described. HNF1A-MODY (Maturity Onset Diabetes of the Young type 3) is one of the most common subtypes of MODY. Due to its variable clinical presentation, and the concerns with being misdiagnosed as either type 1 or type 2 diabetes, DNA sequencing is needed to confirm the diagnosis. This case report illustrates the clinical scenario leading to the identification of the gene variant c.416T>C(p. Leu139Pro) in the HNF1A gene, initially reported as a VUS and later upgraded to a likely pathogenic variant. Though the mutation was described in two Czech family members in 2020, the clinical course and phenotype was not characterized. Therefore, there was the need to fully describe the spectrum of the disease arising from the mutation. The case report fully describes the clinical spectrum of this mutation and provides much needed clinical management approaches to the wider scientific community

Vitamin D status in irritable bowel syndrome and the impact of supplementation on symptoms: what do we know and what do we need to know?

BACKGROUND: Low vitamin D status is associated with risk of colorectal cancer and has been implicated in inflammatory bowel disease. Irritable bowel syndrome (IBS) is a chronic, relapsing, functional bowel disorder. A nascent literature suggests a role for vitamin D in IBS, but this has not been collated or critiqued. To date, seven studies have been published: four observational studies and three randomised controlled trials (RCTs). All observational studies reported that a substantial proportion of the IBS population was vitamin D deficient. Two intervention studies reported improvement in IBS symptom severity scores and quality of life (QoL) with vitamin D supplementation. There are limited data around the role of vitamin D in IBS. CONCLUSIONS: The available evidence suggests that low vitamin D status is common among the IBS population and merits assessment and rectification for general health reasons alone. An inverse correlation between serum vitamin D and IBS symptom severity is suggested and vitamin D interventions may benefit symptoms. However, the available RCTs do not provide strong, generalisable evidence; larger and adequately powered interventions are needed to establish a case for therapeutic application of vitamin D in IBS

The Progression of Prediabetes to Type 2 Diabetes in Children and Adolescents in the United States: Current Challenges and Solutions

Prediabetes, the precursor of type 2 diabetes (T2D), is on the rise among children and adolescents in the United States. The natural history of prediabetes is poorly characterized in children compared to adults. The available data indicate a phenotype of an accelerated β-cell failure in youth with prediabetes. Data from randomized controlled trials showed no benefit on β-cell preservation or A1c in youth with prediabetes from therapeutic agents such as metformin and insulin. As a result, the American Diabetes Association recommends only lifestyle intervention, but not therapeutic agents, for the management of prediabetes in children and adolescents. These recommendations for lifestyle modification in youth, largely derived from data in adults, lack the precision necessary for efficacy in youth. However, a recent 4-year real-world study on youth reported that adherence to nutrition visits was associated with a 4-fold reduction in the likelihood of progressing from prediabetes to T2D. The finding that this reversal is associated with reduced insulin resistance (IR) and not with decreased body weight is novel and provides the foundation for trialing investigational products that may protect β-cells and reduce IR and/or body weight. This study provides the much-needed foundation for further exploration of the impact of lifestyle modification in conjunction with other approaches for the reversal of prediabetes in youth. The systematization of the protocol for medical nutrition therapy for the reversal of prediabetes in youth will ensure optimal and consistent results from adherent patients. This communication provides updates on the pathobiology of prediabetes in youth and a clear direction for efficacious studies in the field

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.

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).Vitamin D supplementation will improve hepatic dysfunction and glycemic control.To determine the effect of vitamin D supplementation on alanine transaminase (ALT), hemoglobin A1c (HbA1c), and serum 25-hydroxyvitamin D [25(OH)D] concentration.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).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%.Vitamin D supplementation in subjects with T2D was associated with statistically significant decreases in BMI SDS, ALT, and a clinically-significant decrease in HbA1c

Tobacco smoke exposure is an independent predictor of vitamin D deficiency in US children.

IMPORTANCE:The role of tobacco-smoke exposure on serum vitamin D concentration in US pediatric population is not known. We hypothesized that tobacco smoke exposure would increase the prevalence of vitamin D deficiency in US children. METHODS:Representative national data were accessed from the National Health and Nutrition Examination Survey (NHANES) 2009-2010 databank on 2,263 subjects of ages 3 to 17 years. Subjects were categorized into two groups based on their age: children, if <10 years; and youth if 10 to 17 years. Descriptive and multiple logistic regression analyses were conducted to determine the effect of serum cotinine-verified tobacco smoke exposure on vitamin D status after controlling for key sociodemographic confounders. Vitamin D deficiency was defined as 25(OH)D <20 ng/mL, insufficiency as 25(OH)D of 20-29.9 ng/mL, and sufficiency as 25(OH)D of ≥30 ng/mL. Tobacco smoke exposure status was defined by serum cotinine concentration as follows: unexposed and non-smoking (<0.05 ng/mL) and exposed (passive and active smokers combined) (≥0.05ng/mL). Specifically, passive and active smoking were defined as cotinine of 0.05-10 ng/mL, and ≥10ng/mL respectively. RESULTS:The prevalence of second-hand smoke exposure was 42.0% (95%CI, 36.7%-47.5%); while the prevalence of active smoking among teenagers was 9.0% (95%CI, 6.2%-12.5%). Vitamin D deficiency occurred at a frequency of 15.1% in children unexposed to tobacco smoke, 20.9% in children exposed to passive tobacco smoke, and 18.0% among actively smoking youth (p<0.001). Tobacco smoke exposure independently predicted vitamin D deficiency after controlling for age, sex, race, BMI, maternal education, and family socio-economic status (OR:1.50; 95%CI, 1.14-1.85, p = 0.002). CONCLUSIONS:This analysis of a nationwide database reports that tobacco smoke exposure is an independent predictor of vitamin D deficiency in US children

Correction: Vitamin D status in pediatric irritable bowel syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0172183.]

Vitamin D status in pediatric irritable bowel syndrome.

IMPORTANCE:Irritable bowel syndrome (IBS) is associated with significant morbidity in children and adolescents, and the therapeutic efficacy of available treatment options is limited. The role of vitamin D supplementation in pediatric IBS is unclear as the vitamin D status of pediatric patients with IBS is unknown. Equally, the relationship of vitamin D status with psychosomatic symptoms in children and adolescents is unclear. AIM:To characterize the vitamin D status of pediatric patients with IBS using a case-control study design. HYPOTHESIS:Serum 25-hydroxyvitamin D [25(OH)D] concentration will be similar between patients with IBS and controls. SUBJECTS AND METHODS:A retrospective case-controlled study of 116 controls (age 14.6 ± 4.3 y), female (n = 67; 58%) and 55 subjects with IBS (age 16.5 ± 3.1y), female (n = 44; 80%). Overweight was defined as BMI of ≥85th but 90% of IBS subjects had vitamin D deficiency at a cut-off point of 50% of the subjects with IBS had vitamin D deficiency. This is a much higher prevalence of vitamin D deficiency compared to IBD and other malabsorption syndromes. Monitoring for vitamin D deficiency should be part of the routine care for patients with IBS. Randomized control trials are warranted to determine the role of adjunctive vitamin D therapy in pediatric IBS

A 9-month analysis of the changes in hemoglobin A1c (HbA1c) level following a three-month vitamin D supplementation in patients with either type 1 diabetes or type 2 diabetes.

<p>There was a statistically-significant, but clinically non-significant rise in HbA1c level over 9 months in T1D (8.5±1.2 through 8.9±1.2%, ANOVA p = 0.001). In T2D, there was a clinically significant decrease in HbA1c <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099646#pone.0099646-Thomas1" target="_blank">[36]</a> in the first 3 months (during the period of vitamin D supplementation) from 8.5±2.9% at baseline through 7.7±2.5% at 3 mo, followed by a slow return to pretreatment values of 8.2±2.3% at 9 mo. There was however, no statistical significant difference in HbA1c between the time points (ANOVA p = 0.52).</p

Comparison of the characteristics of patients with type 1 diabetes vs. type 2 diabetes.

<p>* = p values by Chi Square for proportions; SDS = standard deviation score; 25(OH)D = 25hydroxyvitamin D.</p