التفاصيل البيبلوغرافية
| العنوان: |
A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY |
| المؤلفون: |
Kettunen, Jarno L. T., Rantala, Elina, Dwivedi, Om P., Isomaa, Bo, Sarelin, Leena, Kokko, Paula, Hakaste, Liisa, Miettinen, Päivi J., Groop, Leif C., Tuomi, Tiinamaija |
| المساهمون: |
Institute for Molecular Medicine Finland, HUS Abdominal Center, Endokrinologian yksikkö, CAMM - Research Program for Clinical and Molecular Metabolism, HUS Children and Adolescents, Clinicum, Research Programs Unit, Children's Hospital, STEMM - Stem Cells and Metabolism Research Program, Department of Medicine |
| بيانات النشر: |
Springer |
| سنة النشر: |
2022 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
Age at onset, Glucagon, HNF1A-MODY, Insulin deficiency, Lipolysis, Maturity-onset diabetes of the young (MODY), MODY3, Monogenic diabetes, NEFA, Polygenic risk score for type 2 diabetes, HEPATIC NUCLEAR FACTOR-1-ALPHA, HOMEOSTASIS MODEL ASSESSMENT, INSULIN SENSITIVITY, CELL DYSFUNCTION, ALPHA-GENE, YOUNG MODY, C-PEPTIDE, ONSET, GLUCOSE, MUTATION, Biomedicine |
| الوصف: |
Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m(2) units of BMI, p=2.2 x 10(-4), using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 mu mol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 mu mol/l, p=3.1 x 10(-5)). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than ... |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. The Botnia, FINNMODY and PPP-Botnia studies have been financially supported by grants from Folkhalsan Research Foundation, the Sigrid Juselius Foundation, the Academy of Finland (grants no. 263401, 267882, 312063, 336822 to LCG; 312072 and 336826 to TT), the University of Helsinki, the Nordic Center of Excellence in Disease Genetics, the EU (EXGENESIS, MOSAIC FP7-600914), the Ollqvist Foundation, the Swedish Cultural Foundation in Finland, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Signe and Ane Gyllenberg Foundation, the Finnish Medical Society, the Paavo Nurmi Foundation, State Research Funding via the Helsinki University Hospital, the Perklen Foundation, Narpes Health Care Foundation and the Ahokas Foundation. These studies have also been supported by the Ministry of Education in Finland, the Municipal Health Care Center and Hospital in Jakobstad, and Health Care Centers in Vasa, Narpes and Korsholm.; Kettunen , J L T , Rantala , E , Dwivedi , O P , Isomaa , B , Sarelin , L , Kokko , P , Hakaste , L , Miettinen , P J , Groop , L C & Tuomi , T 2022 , ' A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY ' , Diabetologia , vol. 65 , no. 4 , pp. 632–643 . https://doi.org/10.1007/s00125-021-05631-zTest; ORCID: /0000-0002-8306-6202/work/111173625; ORCID: /0000-0002-5184-9616/work/111175276; ORCID: /0000-0002-9995-698X/work/111175325; http://hdl.handle.net/10138/342495Test; 8c98c354-c157-42e1-b5a3-4d2086a40533; 000734005000001 |
| الإتاحة: |
http://hdl.handle.net/10138/342495Test |
| حقوق: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| رقم الانضمام: |
edsbas.15545652 |
| قاعدة البيانات: |
BASE |
