The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3

OBJECTIVE—The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS—We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS—Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10−4). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03). CONCLUSIONS—These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors

Clinical Characteristics and Diagnostic Criteria of Maturity-Onset Diabetes Of The Young (MODY) due to Molecular Anomalies of the HNF1A Gene

Context: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed.Objective: The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. Design, Setting, and Patients: This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). Results: In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. Conclusions: Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations

Mouse vanin-1 is cytoprotective for islet beta cells and regulates the development of type 1 diabetes.

International audienceAIMS/HYPOTHESIS: Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence. METHODS: Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments. RESULTS: The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo. CONCLUSIONS/INTERPRETATION: This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis

Ghréline et adiponectine sont associées aux taux de HDL-cholestérol dans l’obésité indépendamment de la résistance à l’insuline et de l’inflammation

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Pratique des endocrinologues français en lipidologie : évaluation lors des situations complexes à la frontière des recommandations

National audienceIl existe de nombreuses recommandations récentes sur le traitement des dyslipidémies (SFC-EAS/AHA-ACC/IAS), parfois contradictoires. Certaines situations cliniques se situant à la frontière du champ traité par les recommandations, nous avons souhaité évaluer le comportement des endocrinologues français face à ces situations. Cinq cent seize endocrinologues (289 femmes et 212 hommes) ont répondu à 6 cas cliniques soumis en ligne via un sondage effectué en juillet et septembre 2015. Selon la méthode Delphi, 10 experts ont attribué une note sur 10 à chaque item de chaque cas clinique appréciant la conformité escomptée par rapport aux recommandations thérapeutiques et l’agressivité thérapeutique. Les variables explicatives prises en compte en analyse univariée puis multivariée ont été : sexe, âge, inter-région d’exercice, lieu d’exercice, mode d’exercice et lecture régulière d’au moins une revue internationale. La conformité est en moyenne de 6,2 (± 2,0) et l’agressivité de 5,1 (± 1,7), proches des valeurs moyennes établies par les experts. Le score de conformité et celui de l’agressivité sont étroitement corrélés (r = 0,669, p < 10−3). Seuls l’âge (le score le plus bas étant observé chez les plus de 50 ans, p = 0,0038) et le mode d’exercice non libéral vs libéral (moyenne 6,5 ± 2,0 vs 5,8 ± 1,9, p = 0,0001) sont associés avec le score de conformité. En analyse multivariée, ces deux variables explicatives demeurent indépendantes mais le meilleur modèle explique moins de 10 % de la variabilité des scores. Les tranches d’âges extrêmes et l’exercice libéral sont des facteurs associés avec une moindre conformité aux recommandations, toutefois cette enquête suggère que de nombreux facteurs additionnels non explorés sont susceptibles d’interveni