Dextrose-Sulfonylurea Challenge as a Screening Test for Monogenic Diabetes in Patients Diagnosed with Type 1 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 310-LB
Author(s):  
AURELIA C.H. WOOD ◽  
MARIA S. REMEDI ◽  
COLIN NICHOLS ◽  
BESS A. MARSHALL
Keyword(s):  
Type 1 Diabetes ◽  
Screening Test ◽  
Monogenic Diabetes

scholarly journals Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes

2014 ◽  
Vol 16 (3) ◽  
pp. 227-233 ◽  
Author(s):  
Rachelle G. Gandica ◽  
Wendy K. Chung ◽  
Liyong Deng ◽  
Robin Goland ◽  
Mary Pat Gallagher
Keyword(s):  
Type 1 Diabetes ◽  
Monogenic Diabetes

scholarly journals Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

2021 ◽  
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stress Response ◽  
Stress Responses ◽  
Disease Process ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Expression ◽  
Increased Risk ◽  
Gene And Protein Expression

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized <i>in situ</i> using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

scholarly journals Monogenic causes in the Type 1 Diabetes Genetics Consortium cohort; low genetic risk for autoimmunity in case selection

2021 ◽  
Author(s):  
Luc Marchand ◽  
Meihang Li ◽  
Coralie Leblicq ◽  
Ibrar Rafique ◽  
Tugba Alarcon-Martinez ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Large Scale ◽  
Wolfram Syndrome ◽  
Monogenic Diabetes ◽  
Therapeutic Implications ◽  
Pathogenic Variants ◽  
Affected Parent ◽  
Diabetes Genetics

Abstract: Hypothesis About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. Methods As proof of principle, we examined by exome sequencing families with two or more children, recruited by the Type 1 Diabetes Genetics Consortium and selected for negativity for two autoantibodies and absence of risk HLA haplotypes. Results We examined 46 families that met the criteria. Of the 17 with an affected parent, seven (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including five with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. Conclusions Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that non-syndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.

scholarly journals Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Sven Pörksen ◽  
◽  
Lene Bjerke Laborie ◽  
Lotte Nielsen ◽  
Marie Louise Max Andersen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Monogenic Diabetes ◽  
Onset Type ◽  
New Onset

scholarly journals Application of NGS to improve the effectiveness of molecular genetic diagnostics of monogenic forms of diabetes in children

2020 ◽  
pp. 86-88
Author(s):  
О.С. Глотов ◽  
Е.А. Серебрякова ◽  
М.Е. Туркунова ◽  
Е.Б. Башнина ◽  
А.С. Глотов ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Genetic Variants ◽  
Wide Spectrum ◽  
Direct Sequencing ◽  
Monogenic Diabetes ◽  
Genetic Diagnostics ◽  
Number Of Patients

Исследованы образцы ДНК 60 пациентов с подозрением на наличие моногенного сахарного диабета (МСД-MODY) путем секвенирования NGS панели 13 генов MODY и 22 гена «неонатального» диабета и синдромальных форм диабета. МСД был подтвержден у 55% (n=33). Из 33 пациентов 27 (81,8%) имели мутации (варианты) в MODY генах. Наиболее часто встречались варианты в гене GCK-31,6% (n=19). Спектр вариантов в гене GCK включал 13 миссенс мутаций, 3 нонсенс, 4 со сдвигом рамки считывания и 1 в промоторной области. Были также выявлены варианты в других генах: HNF1A (n=3), WFS1(n=4), PAX4 (n=1), EIF2AK3 (n=1, гомозигота), GATA6 (n=1), KCNJ11(n=1), ABCC8 (n=1), SLC19A2 (n=2), BLK (n=2). Из 38 детектированных вариантов 15 оказались новыми. Высокая выявляемость может быть связана как с особенностями нашей группы, так и с использованным биоинформатическим подходом. Молекулярно-генетическая верификация диагноза при помощи NGS секвенирования позволяет повысить эффективность диагностики, прогнозировать течение заболевания и вносить коррективы в лечение СД. The present study included 60 unrelated Russian children with non-type 1 diabetes mellitus diagnosed before the age of 18 years. Genetic variants were analyzed using whole-exome sequencing (WES) in a panel of 35 genes causative of maturity onset diabetes of the young (MODY) and transient or permanent neonatal diabetes. Verification of the WES results was performed using PCR-direct sequencing. A total of 38 genetic variants were identified in 33 out of 60 patients (55%). The majority of patients (27/33, 81.8%) had variants in MODY-related genes: GCK (n=19), HNF1A (n=2), PAX4 (n=1), ABCC8 (n=1), KCNJ11 (n=1), GCK+HNF1A (n=1), GCK+BLK (n=1) and GCK+BLK+WFS1 (n=1). A total of 6 patients (6/33, 18.2%) had variants in MODY-unrelated genes: GATA6 (n=1), WFS1 (n=3), EIF2AK3 (n=1) and SLC19A2 (n=1). A total of 15 out of 38 variants were novel, including GCK, HNF1A, BLK, WFS1, EIF2AK3 and SLC19A2. To summarize, the present study demonstrates a high frequency and a wide spectrum of genetic variants causative of monogenic diabetes in Russian children with non-type 1 diabetes mellitus. The spectrum includes previously known and novel variants in MODY-related and unrelated genes, with multiple variants in a number of patients. The prevalence of GCK variants indicates that diagnostics of monogenic diabetes in Russian children may begin with testing for MODY2. However, the remaining variants are present at low frequencies in 9 different genes, altogether amounting to ~50% of the cases and highlighting the efficiency of using WES in non-GCK-MODY cases.

scholarly journals Parent and Pediatrician Preferences for Type 1 Diabetes Screening in the U.S.

2020 ◽  
Author(s):  
Jessica L. Dunne ◽  
Anne Koralova ◽  
Jessie Sutphin ◽  
Jesse S. Bushman ◽  
Barbara Fontanals-Ciera ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Screening Test ◽  
The United States ◽  
Screening Tests ◽  
Relative Importance ◽  
Mode Of Administration ◽  
Monitoring Programs ◽  
Equal Importance ◽  
Insulin Dependence

<a><b>Objective:</b> The purpose of this study was to use a discrete-choice experiment methodology to understand the relative importance of the attributes of screening tests for type 1 diabetes among parents and pediatricians in the United States.</a> <p><b>Research Design and Methods:</b> Online surveys presented hypothetical Screening Test profiles from which respondents chose their preferred test profile. Survey attributes were based on likely screening test options and included the mode of administration, where and when the test was conducted, the type of education and monitoring available to lower the risk of diabetic ketoacidosis (DKA), and whether a treatment was available that would delay onset of insulin dependence. Data were analyzed using random-parameters logit models.</p> <p><b>Results:</b> Parents placed the highest relative importance on monitoring programs that could reduce the risk of DKA to 1%, followed by treatment to delay onset of insulin dependence by 1 or 2 years, and, finally, avoiding a $50 out-of-pocket cost. Pediatricians placed equal importance on monitoring programs that reduced a patient’s risk of DKA to 1% and on avoiding a $50 out-of-pocket cost for the screening test, followed by the option of a treatment to delay the onset of insulin dependence. The mode of administration and location and timing of the screening were much less important to both parents and pediatricians<i>.</i></p> <p><b>Conclusions:</b> Parents and pediatricians preferred screening tests that were accompanied by education and monitoring plans to reduce the risk of DKA, had available treatment to delay type 1 diabetes, and had lower out-of-pocket costs.</p>

scholarly journals The epidemiology and genetic analysis of children with idiopathic type 1 diabetes in the state of Qatar

2021 ◽  
Author(s):  
Tasneem Abdel-Karim ◽  
Basma Haris ◽  
Houda Afyouni ◽  
Shayma Mohammed ◽  
Amel Khalifa ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Wolfram Syndrome ◽  
Insulin Requirement ◽  
Monogenic Diabetes ◽  
C Peptide ◽  
Peptide Level ◽  
Uncertain Significance ◽  
Age Of Diagnosis ◽  
History Of

Abstract Background To study the epidemiology, describe the clinical characteristics and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes. Methods Prospective study of type 1 diabetes patients attending Sidra Medicine from 2018-2020. Autoantibodies (GAD65, IAA, IA-2A and ZnT8) measured and genetic testing undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes compared to patients with autoimmune type 1 diabetes. Results 1157 patients had type 1 diabetes of which 63 were antibody negative. Upon genome sequencing, four had MODY, two had Wolfram syndrome, one had H syndrome and three had variants of uncertain significance in MODY genes. 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10-14 years and C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average BMI was in the normal range and 33% of the patients had history of DKA. Conclusions 4% of children have Idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the two groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is not known but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

scholarly journals Is Hypoglycemia Caused by G6PD Deficiency?

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A388-A389
Author(s):  
Shubham Agarwal ◽  
Zubina Unjom ◽  
Janice L Gilden ◽  
Aditi Singh ◽  
Shayaan Shaik
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Hemolytic Anemia ◽  
G6pd Deficiency ◽  
Screening Test ◽  
Screening Tests ◽  
Normal Male ◽  
Oral Glucose

Abstract Background: Individuals with G6PD deficiency are mostly asymptomatic but develop hemolytic anemia with the use of certain medications, chemicals, or food. Hemolytic anemia episodes in patients with G6PD deficiency have been observed to occur following hypoglycemia. Case: An 18-year-old, vigorously exercising African American male was referred to the endocrine clinic for post-prandial hypoglycemia (Blood glucose (BG) of 47 mg/dl) accompanied by palpitations, lightheadedness, dyspnea, diaphoresis, and tremulousness. He admitted to having short symptomatic episodes, almost daily over four years. His mother has sickle cell trait, and due to the need for blood typing, a qualitative direct fluoroscopic screening test was positive for G6PD deficiency. Physical examination revealed a height of 5’2” with a weight of 126 lbs. (BMI: 22.7 kg/m2), blood pressure of 97/55 mmHg, and heart rate of 62/minute. The patient was a normal male with low set ears, and no other abnormalities, except for questionable non-genetic short stature. Fingerstick BG was 62 mg/dl. Lab tests showed a fasting BG of 90 mg with concomitant proinsulin of 8.2 pmol/l (≤ 18.8 pmol/l), fasting insulin of 8.98 mIU/l (≤ 25 mIU/l), 2-hour post-prandial insulin of 33.4 µIU/ml (5.0–55.0 µIU/ml), and a c-peptide 1.24 ng/ml (0.81–3.85 ng/ml). Uric acid, TSH, Free T4, LH, FSH, Prolactin, IGF-1, PTH, free and total testosterone were all normal. Fasting cortisol level was normal with an elevated ACTH of 72 pg/ml (0–47 pg/ml), low 25-hydroxyvitamin D at 18.5 ng/ml (30–100 ng/ml), and a flat oral glucose tolerance test. A continuous glucose monitor revealed average daily glucose of 85 mg/dl with 34% of the time spent &lt; 80 mg/dl. A high carbohydrate diet with frequent meals improved symptoms with normal fingerstick BG. However, due to the concern that hypoglycemia can be related to G6PD deficiency, hemoglobin electrophoresis, and gene testing for G6PD were done to confirm this diagnosis, and they were both normal. In addition, a bone density scan was done, which revealed osteopenia. He was started on vitamin D supplementation. Conclusion: Case reports exist of G6PD deficient hospitalized patients with type 1 diabetes mellitus and DKA in recovery, who have had new onset hemolytic anemia, proposing that relative hypoglycemia can be responsible for this effect. Multiple screening tests have been developed for the detection of G6PD deficiency, which assay the normal function of the enzyme and reduction of NADP to NADPH. However, confirmatory testing needs to be conducted if the screening test is positive. Although this adds to the burden of testing, screening tests can result in false positives and lead to a misdiagnosis, as in our case. References: Messina MF et al. Hemolytic crisis in a non-ketotic and euglycemic child with glucose-6-phosphate dehydrogenase deficiency and onset of type 1 diabetes mellitus. J Pediatr Endocrinol Metab. 2004 Dec;17(12):1671–3

scholarly journals The prevalence of celiac disease in Saudi patients with type 1 diabetes mellitus

2021 ◽  
Vol 41 (2) ◽  
pp. 71-77
Author(s):  
Mohammed Zaid Aljulifi ◽  
Moeber Mahzari ◽  
Lujain Alkhalifa ◽  
Esra Hassan ◽  
Abdullah Mohammed Alshahrani ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Type 1 Diabetes Mellitus ◽  
Screening Test ◽  
Villous Atrophy ◽  
Endoscopic Biopsy ◽  
Thyroid Disorder ◽  
Adolescents And Adults

BACKGROUND: Celiac disease (CD) is an autoimmune disease that is highly associated with type 1 diabetes mellitus (T1DM). The reported prevalence of CD in patients with T1DM in Saudi Arabia varies and the number of studies is limited. OBJECTIVES: Determine the prevalence of CD diagnosed with anti-tissue transglutaminase (anti-tTG) antibodies or by endoscopic biopsy in adolescents and adults with T1DM. DESIGN: Cross-sectional, retrospective medical record review. SETTING: Tertiary care center. PATIENTS AND METHODS: The study population included adolescents and adults with T1DM who were screened for CD between 2010 and 2019. The study variables included age, sex, age at diagnosis of T1DM, age of positive celiac screening, glycated hemoglobin (HbA1c), total daily insulin dose, frequency of diabetic ketoacidosis (DKA) and other autoimmune diseases. MAIN OUTCOME MEASURES: The prevalence of celiac disease in adolescents and adults with T1DM. SAMPLE SIZE: 539 patients. RESULTS: The prevalence of positive celiac test results was 11.5% (n=62). A small proportion (n=5, 8%) of the positive CD group was diagnosed with T1DM after they tested positive with the celiac screening test. Ten (16%) were diagnosed with T1DM and CD in the same year. The rest of the sample had a positive screening test after being diagnosed with T1DM. There was no statistically significant difference between the CD positive and negative groups for HbA1C, DKA frequency, microvascular complications of diabetes or thyroid disorder. For histopathological confirmation of CD, only 37% (n=23) of the group with a positive screening test underwent endoscopy. In this group, 43% (n=10) had normal endoscopic biopsy findings, 21.7% (n=5) had partial villous atrophy and 34.7% (n=8) had total villous atrophy. CONCLUSIONS: This study highlights the importance of screening for CD in T1DM patients. CD prevalence is high in patients with T1DM, despite the high likelihood of underdiagnosis. Additional studies of different age groups and the use of different study methods are required. In addition, a unified national strategy to diagnose CD in T1DM patients is highly advisable. LIMITATIONS: Retrospective, single-center, few confirmations of CD by intestinal biopsy. CONFLICT OF INTEREST: None.

Sign in / Sign up

Export Citation Format

Share Document