scholarly journals A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Diabetologia ◽  
2021 ◽  
Author(s):  
Jarno L. T. Kettunen ◽  
Elina Rantala ◽  
Om P. Dwivedi ◽  
Bo Isomaa ◽  
Leena Sarelin ◽  
...  

Abstract 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/m2 units of BMI, p=2.2 × 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 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 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 C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes. Graphical abstract

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1645-P
Author(s):  
JOHANNE TREMBLAY ◽  
REDHA ATTAOUA ◽  
MOUNSIF HALOUI ◽  
RAMZAN TAHIR ◽  
CAROLE LONG ◽  
...  

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 304-OR
Author(s):  
MICHAEL L. MULTHAUP ◽  
RYOSUKE KITA ◽  
NICHOLAS ERIKSSON ◽  
STELLA ASLIBEKYAN ◽  
JANIE SHELTON ◽  
...  

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 1134-P
Author(s):  
SANGHYUK JUNG ◽  
DOKYOON KIM ◽  
MANU SHIVAKUMAR ◽  
HONG-HEE WON ◽  
JAE-SEUNG YUN

Author(s):  
HODA A. ALI ◽  
SAHAR H. MOHAMED ◽  
HEND F. ALHARBI ◽  
REHAM M. ALGHESHAIRY

Objective: This study aims to explore the adjuvant effect of multi-strain probiotics with either saffron, cardamom, ginger, or cinnamon herbs to achieve synergistic management for controlling type 2 diabetes (T2D). Methods: Eighty-eight adult male, Wistar rats were used. Eight rats were kept as healthy control. Eighty rats were used to induce type 2 diabetic rats (T2DR) and were randomly assigned to ten groups. One group was an offer to 0.2 ml multi-strain probiotics orally. The rest of T2DR were gavage with 100 mg/kg aqueous extract of saffron, cardamom, ginger, or cinnamon without or with 0.2 ml multi-strain probiotics orally. Bodyweight gain (BWG), and feed efficiency ratio (FER) were recorded. Determination of oral glucose tolerance test (OGTT), serum insulin, C-peptide, HDL, LDL, HDL/total cholesterol ratio were performed. Serum antioxidant activity, Th1and Th2 cytokines and histopathology of the pancreas were done. Results: Comparable with T2DR, solely multi-strain probiotics or with herbs caused a significant reduction in BWG (P<0.05). Groups fed saffron, cardamom, and ginger and enriched with multi-strain probiotic showed significant improvement in OGTT, serum insulin, C-peptide and lipid abnormalities (P<0.05) compared to T2DR. Besides, they had antioxidant and anti-inflammatory effects. The group received ginger alone exerted anti-hyperglycemia and anti-inflammatory effects. However, cinnamon had a moderate anti-diabetic effect and solely probiotics did not show a significant benefit for all parameters except BWG. Conclusion: Cardamom, saffron, and ginger enriched with multi-strain probiotics achieve a synergistic relationship for managing T2D. This finding exhibits a possible new hypothesis to manage diabetes that needs further study.


2021 ◽  
Vol 62 (8) ◽  
pp. 1123-1128
Author(s):  
Su-Min Yoon ◽  
Suk-Gyu Ha ◽  
Yeong-Woo Seo ◽  
Seung-Hyun Kim

Purpose: Clinical factors affecting the recovery period in patients with vascular or idiopathic paralytic strabismus were evaluated.Methods: This study involved a retrospective review of medical records of patients diagnosed with vascular and idiopathic acquired paralytic strabismus. Vascular paralysis was defined in cases of hypertension, diabetes mellitus, or cardiovascular disease. The angle of deviation and limitation of extraocular movement were evaluated at each visit. Recovery was defined as the absence of diplopia and complete resolution of limitation of extraocular movement. Factors affecting recovery success and recovery period were analyzed.Results: We retrospectively reviewed data of 145 patients consisting of 87 with vascular paralytic strabismus (cranial nerve [CN] III: 21, CN IV: 28, CN VI: 38) and 58 with idiopathic paralytic strabismus (CN IV: 20, CN VI: 24, CN III: 14). The recovery rate did not significantly differ between vascular (60.9%) and idiopathic (63.8%) groups (p = 0.15). The recovery period was longer in the vascular group (130.1 ± 145.1 days) than in the idiopathic group (92.6 ± 76.6) (p = 0.02). Age at onset was significantly associated with the recovery period in both vascular and idiopathic groups. In the vascular group, the recovery periods were 107.4 ± 74.8 days in CN III palsy, 97.2 ± 51.9 days in CN IV palsy, and 159.3 ± 194.1 days in CN VI palsy. The recovery period was significantly longer in patients with CN VI palsy (p = 0.03). Hypertension was significantly influencing the recovery period in patients with vascular CN VI palsy (odds ratio = 2.54, p = 0.01).Conclusions: The recovery period was longer in patients with vascular paralytic strabismus than in patients with idiopathic paralytic strabismus. Recovery rates were not significantly different between groups. In patients with vascular CN VI palsy, a history of hypertension was significantly associated with the recovery period.


2020 ◽  
Vol 21 (5) ◽  
pp. 1703 ◽  
Author(s):  
Felipe Padilla-Martínez ◽  
Francois Collin ◽  
Miroslaw Kwasniewski ◽  
Adam Kretowski

Recent studies have led to considerable advances in the identification of genetic variants associated with type 1 and type 2 diabetes. An approach for converting genetic data into a predictive measure of disease susceptibility is to add the risk effects of loci into a polygenic risk score. In order to summarize the recent findings, we conducted a systematic review of studies comparing the accuracy of polygenic risk scores developed during the last two decades. We selected 15 risk scores from three databases (Scopus, Web of Science and PubMed) enrolled in this systematic review. We identified three polygenic risk scores that discriminate between type 1 diabetes patients and healthy people, one that discriminate between type 1 and type 2 diabetes, two that discriminate between type 1 and monogenic diabetes and nine polygenic risk scores that discriminate between type 2 diabetes patients and healthy people. Prediction accuracy of polygenic risk scores was assessed by comparing the area under the curve. The actual benefits, potential obstacles and possible solutions for the implementation of polygenic risk scores in clinical practice were also discussed. Develop strategies to establish the clinical validity of polygenic risk scores by creating a framework for the interpretation of findings and their translation into actual evidence, are the way to demonstrate their utility in medical practice.


2021 ◽  
Author(s):  
Sam Hodgson ◽  
Qin Qin Huang ◽  
Neneh Sallah ◽  
Chris J Griffiths ◽  
William Newman ◽  
...  

Background: Type 2 diabetes is a heterogeneous condition highly prevalent in British Pakistanis and Bangladeshis (BPB). The Genes & Health (G&H) cohort offers means to explore genetic determinants of disease in BPBs, combining genetic and lifelong health record data. Methods: We assessed whether common genetic loci associated with type 2 diabetes in European-ancestry individuals (EUR) replicate in G&H. We constructed a type 2 diabetes polygenic risk score (PRS) and combined it with a clinical risk instrument (QDiabetes) to build a novel, integrated risk tool (IRT). We compared IRT performance using net reclassification index (NRI) versus QDiabetes alone. We assessed the ability of the PRS to predict type 2 diabetes following gestational diabetes (GDM). We compared PRS distribution between type 2 diabetes subgroups identified by clinical features at diagnosis. Findings: Accounting for power, we replicated fewer loci associated with type 2 diabetes in G&H (n = 76/338, 22%) than would be expected if all EUR-ascertained loci were transferable (n = 95, 28%) (binomial p value = 0.01). In 13,648 patients free from type 2 diabetes followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval 2.0 - 4.4%). IRT performance was best in reclassification of young adults deemed low risk by QDiabetes as high risk. PRS was independently associated with progression to type 2 diabetes after GDM (p = 0.028). Mean type 2 diabetes PRS differed between phenotypically-defined type 2 diabetes subgroups (p = 0.002). Interpretation: The type 2 diabetes PRS has broad potential clinical application in BPB, improving identification of type 2 diabetes risk (especially in the young), and characterisation of type 2 diabetes subgroups at diagnosis. Funding: Wellcome Trust, MRC, NIHR, and others. Full funding disclosed within.


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