Recently, we witnessed great progress in the discovery of genetic variants associated with obesity and type 2 diabetes (T2D), especially in adults. Much less is known regarding genetic variants associated with insulin resistance (IR). We hypothesized that novel IR genes could be efficiently detected in a population of obese children and adolescents who may not exhibit comorbidities and other confounding factors. This study aimed to determine whether a genome-wide association study (GWAS), using a DNA-pooling approach, could identify novel genes associated with IR. The pooled-DNA GWAS analysis included Slovenian obese children and adolescents with and without IR matched for body mass index, gender and age. A replication study was conducted in another independent cohort with or without IR. For the pooled-DNA GWAS, we used HumanOmni5-Quad SNP array (Illumina). Allele frequency distributions were compared with modified t-tests and χ2-tests and ranked using PLINK. Top single nucleotide polymorphisms (SNPs) were validated using individual genotyping by high-resolution melting analysis and TaqMan assay. We identified five top-ranking SNPs from the pooled-DNA GWAS analysis within the ECE1, IL1R2, GNPDA1, HLA-J and PYGB loci. All except SNP rs9261108 (HLA-J locus) were confirmed in the validation phase using individual genotyping. The SNP rs2258617 within PYGB remained statistically significant for both recessive and additive models in both cohorts and in a merged analysis of both cohorts and present the strongest novel candidate gene for IR. We report for the first time a pooled-DNA GWAS approach to identify five novel SNPs or genes for IR in a paediatric population. The four loci confirmed in the second validation phase study warrant further studies, especially the strongest SNP rs2258617 within PYGB, and provide targets for further basic research of IR mechanisms and for the development of potential new IR and T2D therapies.
COBISS.SI-ID: 4003720
Genetic variant c.-143T)C (rs7840156) was associated with a significant 2-fold decreased risk to present with IR, determined by HOMA-IR and WBISI. Of importance this association was not dependent on degree of overweight. Variant c.-143T)C was located in evolutionary highly conserved region in DEPTOR promoter region further proving the importance of the results. DEPTOR was therefore determined as a novel biomarker for the determination of prediabetes in obese children and adolescents.
COBISS.SI-ID: 2775980
The liver-specific miR-122 was proposed as biomarker for NAFLD in adults. Here, we investigated the relationship between miR-122 levels, parameters of liver metabolism and NAFLD in pre-pubertal obese children. Parameters of liver metabolism (ALT, AST and GGT) of three European cohorts were included (German cohort [n = 71; age: 11.53 ± 1.29 years; BMI z-score: 2.96 ± 0.64], Italian cohort [n = 45; age: 9.60 ± 2.11 years; BMI z-score: 3.57 ± 1.16], Slovenian cohort [n = 31; age: 7.53 ± 1.47 years; BMI z-score: 3.66 ± 0.88]). MiR-122 levels and CK18 concentrations were measured in fasting blood samples. In the German and Italian cohort, the diagnosis of NAFLD and grading of NAFLD was assessed by ultrasound. NAFLD was diagnosed in n = 50 patients of the German cohort (29.6%) and in n = 29 patients (72.5%) of the Italian cohort. In all three cohorts, miR-122 was positively correlated with ALT and AST as well as with CK18 concentrations. MiR-122 levels were higher in children with NAFLD compared with healthy controls. MiR-122 levels in pre-pubertal obese children could be a potential biomarker for paediatric NAFLD.
COBISS.SI-ID: 4637868
Aim of the study was to investigate whether predictive low glucose management of an insulin pump system reduces the rate of hypoglycemia compared with the sensor-augmented insulin pump in children with type 1 diabetes. The predictive low glucose management insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia
COBISS.SI-ID: 3683756
Study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes. Closed-loop insulin delivery was determined to be safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia.
COBISS.SI-ID: 4633772