Background. The role of the hormones in eating behavior in the regulation of appetite has been well studied, but their relationship with various types of eating behavior has not been established. Aims. To study the frequency of different types of eating behavior, hunger/satiety feeling estimated by the visual analog scale and levels of leptin and gastrointestinal tract hormones that are involved in appetite regulation, fat and carbohydrate metabolism (ghrelin and glucagon-like peptide 1) in patients with diabetes mellitus type 2 and obesity. Materials and methods. The study included 35 people with obesity (BMI35 kg/m2) and diabetes mellitus type 2 (T2DM) who received the stable sugar-lowering therapy, the median body mass index (BMI) was 40,1 [36,5; 49,6] kg/m2, the median age was 58 [52,5; 64] years. Blood tests for insulin, leptin, ghrelin, glucagon-like peptide-1, C-peptide, glucose, glycated hemoglobin and lipids profile were done in all cases, also HOMA-IR and HOMA- were calculated. All patients completed questionnaires determining eating behavior type and hunger/satiety feeling severity. Results. In patients with T2DM and obesity a high frequency of combination of different types of eating behavior were found, it was 54,3%. Among the isolated types, restrictive eating behavior was more common in 40%. In patients with different types of eating behavior the tendency to difference in the level of hormones regulating appetite was found, but it was not significant. High frequency of an appropriate reduction of postprandial ghrelin level was found in patients with restrictive type of eating behavior. Correlation between the level of hormones regulating appetite and hunger/satiety feeling was weak, it might reflect the resistance to these hormones in patients with severe obesity and T2DM. At the same time the relationship between the ghrelin level and the -cells functional state parameters was significant. Conclusions. The severity of leptin and ghrelin resistance correlated with each other in T2DM and obesity patients; the severity of ghrelin resistance was associated with the beta cells functional state; according to our data postprandial ghrelin level may have opposite changes in patients with T2DM and obesity and its adequate reduction is more common for patients with restrictive type of eating behavior.

Проект федеральных клинических рекомендаций по диагностике и лечению амиодарон-индуцированной дисфункции щитовидной железы

The adenomas in Cushing’s disease frequently exhibit mutations in exon 14, within a binding motif for the regulatory protein 14-3-3 located between the catalytic domain (DUB), responsible for ubiquitin hydrolysis, and the WW-like domain that mediates autoinhibition, resulting in constantly active USP8. The exact molecular mechanism of deubiquitinase activity disruption in Cushing’s disease remains unclear. To address this, Sanger sequencing of USP8 was performed to identify mutations in corticotropinomas. These mutations were subjected to computational screening, followed by molecular dynamics simulations to assess the structural alterations that might change the biological activity of USP8. Eight different variants of the USP8 gene were identified both within and outside the “hotspot” region. Six of these had previously been reported in Cushing’s disease, while two were detected for the first time in our patients with CD. One of the two new variants, initially classified as benign during screening, was found in the neighboring SH3 binding motif at a distance of 20 amino acids. This variant demonstrated pathogenicity patterns similar to those of known pathogenic variants. All USP8 variants identified in our patients caused conformational changes in the USP8 protein in a similar manner. The identified mutations, despite differences in annotation results—including evolutionary conservation assessments, automated predictor data, and variations in localization within exon 14—exhibit similar patterns of protein conformational change. This suggests a pathogenic effect that contributes to the development of CD.

In the current work, we aimed to evaluate the association of clinical data of Cushing’s disease (CD) patients with USP8 mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in USP8 revealed variants in eighteen adenomas, two of which were described for the first time in CD. USP8 variants were more common in women (94% vs. 76%; p = 0.001), and microadenomas and tumor recurrence were prevalent in the USP8-mutant group (44% vs. 29%; p = 0.04 and 44% vs. 22%; p = 0.0015). Preoperative ACTH and serum cortisol did not differ in the USP8-WT and USP8-mutant patients. All USP8-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of USP8-WT adenomas were double-negative (SST5−/SST2−), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine USP8-mutant and six USP8-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the USP8-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors’ trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring USP8 variants.

Persistent and recurrent hypercortisolism after transsphenoidal endoscopic surgery (TSS) is considered to be an urgent issue prompting the search for Cushing’s disease (CD) remission predictors. The goal was to find a combination of predictors that can forecast the remission of CD after TSS. A total of 101 patients with CD who had undergone TSS were included. One year after surgery, CD remission status was evaluated. Preoperative pituitary magnetic resonance imaging (MRI) data, preoperative results of a high-dose dexamethasone suppression test (HDDST) and morning serum cortisol level collected 24 h after TSS (24 h MSeC) were compared in patients with and without remission of hypercortisolism. Remission one year after TSS was confirmed in 63 patients. CD remission predictors one year after TSS were: adenoma size ≥ 3 mm in the absence of invasive growth and the suppression of serum cortisol ≥ 74% in the HDDST, 24 h MSeC ≤ 388 nmol/L. A total of 38 patients had three favorable values of detected predictors; all of them had CD remission one year after TSS. With long-term follow-up, 36 of them remained in remission. Patients who had no one favorable predictor had no remission of hypercortisolism one year after TSS. Our data confirmed the prospects of using a combination of selected predictors to forecast CD remission after TSS.