The role of Leu260Phe polymorphism of the receptor gene to GLP-1 incretin in the pathogenesis of diabetes type 2 diabetes with obesity

BACKGROUND: Glucagon-like peptide-1 (GLP-1) stimulates the proliferation of β-cells, enhances their resistance to apoptosis and increases glucose-dependent insulin secretion. AIMS: Study of the relationship of Leu260Phe polymorphism (rs1042044) of the GLP-1R gene with postprandial hormone production (C-peptide, insulin, ghrelin, GLP-1) in obese patients with type 2 diabetes. MATERIALS AND METHODS: A total of 174 patients, 82 patients with obesity with type 2 diabetes (BMI=40.4±14.3 kg/m2)and 92 conditionally healthy donors (BMI=22.6±2.7 kg/m2) were studied. The material for the study was venous blood taken on an empty stomach and 60 minutes after the test breakfast. Genotyping was performed by PCR using the sets for determining polymorphism (rs1042044) of the GLP-1R gene (Sintol) and the amplificator (CFX96 BioRad, USA). Plasma hormone levels were evaluated by flow fluorimetry (Bio-PlexProteinAssaySystem, Bio-Rad, USA) using commercial test systems (Bio-PlexProHumanDiabetes 10-Plex Assay, Bio-Rad, USA). Statistical analysis and graphs were obtained at R Statistical Software. RESULTS: A violation of postprandial production of GLP-1 and ghrelin after a test breakfast in obese patients with type 2 diabetes was found. A postprandial increase in C-peptide levels of 3.25[1.83;4.16] ng/ml and insulin 3048 [1978;4972] ng/ml in carriers of the CC genotype compared with carriers of the CA genotype in the group of patients with obesity with type 2 diabetes type In carriers of the CA genotype, there was a decrease in the C-peptide level of 2.21 [1.8;2.49] ng/ml and insulin 1462 [1146; 2304] ng/ml with a constant concentration of GLP-1. The postprandial level of ghrelin in carriers of the CA genotype of the Leu260Phe polymorphism increased to 118[96.1;157] ng/ml compared to carriers of the AA 98 genotype [86; 109] ng/ml. CONCLUSION: The presence of the CC genotype of the Leu260Phe polymorphism of the GLP-1 receptor gene is associated with an increase in postprandial plasma levels of C-peptide and insulin in obese patients with type 2 diabetes, and the CA genotype with a decrease in these indicators and an increase in ghrelin content

Adipokines in metabolic processes regulating during obesity treatment

Bariatric surgery serves as a model for the assessment of the relationship between body mass index (BMI) reduction and changes in adipokine production and for exploring the endocrine function of the pancreas in patients who do not have the proximal part of the small intestine. Aim.  of the study was to assess the biochemical parameters and plasma levels of adipokines [adiponectin, adipsin, leptin, plasminogen activator inhibitor (PAI-1), resistin and visfatin], insulin, C-peptide, ghrelin and incretins [glucose insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)] in patients with morbid obesity after surgery (gastric bypass) and therapeutic correction. Materials and methods. A total of 75 patients (34 men and 41 women; age range: 24?67 years) diagnosed as obese were divided into two groups according to the treatment they received. Biochemical analysis was performed to estimate carbohydrate and lipid metabolism rates and plasma levels of adipokines (adiponectin, adipsin, leptin, PAI-1, resistin, visfatin), insulin, C-peptide, ghrelin and incretins (GIP and GLP-1) using the flow fluorometry. Results. Surgical treatment of obesity resulted in a significant decrease in BMI (from 45.67?9.87 to 32.45?5.35 kg/m2,

Promising Directions in Atherosclerosis Treatment Based on Epigenetic Regulation Using MicroRNAs and Long Noncoding RNAs

Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and long noncoding RNA (lncRNA), was investigated for the treatment of atherosclerosis. Regulation of the expression of noncoding RNA targets the constituent element of the pathogenesis of atherosclerosis. Currently, miRNA therapy commonly employs miRNA antagonists and mimic compounds. In this review, attention is focused on approaches to correcting molecular disorders based on the genetic regulation of the transcription of key genes responsible for the development of atherosclerosis. Promising technologies were considered for the treatment of atherosclerosis, and examples are given for technologies that have been shown to be effective in clinical trials

The postprandial dynamics of gastroduodenal zone hormones in patients with metabolic obesity associated or not associated with type 2 diabetes

Background. The main aims of the conservative treatment of metabolic obesity (MО) are weight loss and the prevention of type 2 diabetes. Incretin-based drugs are considered to be effective and safe and stimulate insulin secretion via the β-cells of the pancreas, and are widely used to restore impaired glucose tolerance. Bariatric surgery not only significantly reduces BMI but also normalises carbohydrate metabolism in patients with MО over a short period after the operation by increasing the secretion of endogenous incretins. Aim. To investigate hormone secretion in the gastroduodenal zone in patients with MО after Roux-en-Y gastric bypass before and after a test meal. Material and methods. We studied the plasma levels of insulin, C-peptide, glucagon, ghrelin and incretins (GIP and GLP-1) using flow fluorometry in 28 patients with MO (12 males and 16 females aged 29–63 years). Patients were divided into two groups: those who did not undergo gastric bypass surgeries and those after treatment (18 months). Results. We found a postprandial increase in the plasma GIP levels with respect to the baseline values in all subject groups, regardless of whether or not they had type 2 diabetes. A analysis of the levels of postprandial GLP-1 secretion revealed the existence of multidirectional dynamics of this indicator regardless of the presence of type 2 diabetes: an increase, decrease, or no difference in GLP-1 secretion was found compared to the measurements on an empty stomach. Conclusions. The postprandial GIP levels increased compared with baseline levels in all groups. The dynamics of the changes in the postprandial GLP-1 levels were multidirectional in patients with MО regardless of the presence of impaired glucose tolerance after Roux-en-Y gastric bypass. A positive correlation was observed between the plasma ghrelin levels and glucagon in all groups

gp130 Activates Mitochondrial Dynamics for Hepatocyte Survival in a Model of Steatohepatitis

Obesity is the main cause of metabolic complications. Fatty liver infiltration is a companion of obesity. NAFLD is associated with impaired energy metabolism with an excess of nutrients. Mitochondrial dynamics are important for the regulation of energy balance, which regulates mitochondrial function, apoptosis, and mitophagy. The aim of this study was to investigate the effect of gp130 on the components of mitochondrial dynamics in a cellular model of steatohepatitis. Addition of IL-6/gp130 contributed to an increase in the percentage of live cells and a decrease in the percentage of dead and apoptotic cells. Addition of IL-6/gp130 increased the expression of NF-kB1 gene and mitochondrial dynamics markers (MFN2 and TFAM) in HepG2 with tBHP/Oleic. Addition of IL-6 or gp130 reduced the expression of cytoprotector genes (HSF1 and HSP70) in HepG2 cell cultures with tBHP/Oleic. Increased mitochondrial dynamics gene activity protected against HepG2 cell death in the steatohepatitis model. Trans-signaling resulted in increased TFAM and MAPLC3B, and decreased DNM1L gene expression in HepG2 with tBHP/Oleic

gp130 Activates Mitochondrial Dynamics for Hepatocyte Survival in a Model of Steatohepatitis

Obesity is the main cause of metabolic complications. Fatty liver infiltration is a companion of obesity. NAFLD is associated with impaired energy metabolism with an excess of nutrients. Mitochondrial dynamics are important for the regulation of energy balance, which regulates mitochondrial function, apoptosis, and mitophagy. The aim of this study was to investigate the effect of gp130 on the components of mitochondrial dynamics in a cellular model of steatohepatitis. Addition of IL-6/gp130 contributed to an increase in the percentage of live cells and a decrease in the percentage of dead and apoptotic cells. Addition of IL-6/gp130 increased the expression of NF-kB1 gene and mitochondrial dynamics markers (MFN2 and TFAM) in HepG2 with tBHP/Oleic. Addition of IL-6 or gp130 reduced the expression of cytoprotector genes (HSF1 and HSP70) in HepG2 cell cultures with tBHP/Oleic. Increased mitochondrial dynamics gene activity protected against HepG2 cell death in the steatohepatitis model. Trans-signaling resulted in increased TFAM and MAPLC3B, and decreased DNM1L gene expression in HepG2 with tBHP/Oleic

Pathogenetic significance of single nucleotide polymorphisms in the gastric inhibitory polypeptide receptor gene for the development of carbohydrate metabolism disorders in obesity

Aim. To investigate the association of the GIPR gene polymorphisms rs2302382 and rs8111428 with increased risk of type 2 diabetes mellitus and abdominal obesity. Materials and methods. The study involved 163 patients with abdominal obesity (BMI, 39.5 ± 8.3 kg/m2; age, 44.7 ± 8.9 years; men, 61; women, 102), 72 with type 2 diabetes mellitus (BMI, 43.70 ± 9.32 kg/m2; age, 46.5 ± 10.1 years; men, 29; women, 43) and 91 patients without carbohydrate metabolism disorders (BMI, 36.13 ± 6.72 kg/m2; age, 43.93 ± 8.35 years; men, 32; women 59). The control group comprised 109 relatively healthy volunteers (BMI, 22.6 ± 2.7 kg/m2; age, 39.5 ± 7.6 years; men, 66; women, 43). Genotypes were analysed by real-time PCR and serum insulin and C-peptide levels were evaluated by ELISA. Results. The AA genotype in the rs2302382 polymorphism of GIPR was associated with an increased risk for type 2 diabetes mellitus in abdominal obesity and the CA genotype was associated with a reduced risk. In individuals with abdominal obesity and type 2 diabetes mellitus carrying the CA genotype in rs2302382 polymorphism of GIPR, serum insulin and C-peptide levels were elevated to 56.27 mU/L (55.49–58.41 mU/L) and 2.04 ng/ml (1.37–2.85 ng/ml), respectively (p 0.05). In obese patients with the same genotype and without type 2 diabetes, serum insulin levels and C-peptide levels were 22.73 mU/L (19.07–25.76 mU/L) and 0.73 ng/ml (0.53–1.03 ng/ml), respectively (p 0.05). The GIPR rs8111428 polymorphism was not associated with increased risk of type 2 diabetes mellitus in obesity for any of the groups examined. Conclusion. Serum insulin and C-peptide levels were increased in patients with abdominal obesity who were carriers of the CA genotype in the rs2302382 polymorphism of GIPR, which is associated with a decreased risk of type 2 diabetes mellitus in obesity compared with the CC genotype

Gemostaz u detey i vzroslykh s sakharnym diabetom 1 tipa

Цель. Провести сравнительный анализ состояния коагуляционного и тромбоцитарно-сосудистого гемостаза у детей, подростков и взрослых при CД 1. Материалы и методы. Обследовано 335 человек, из них 117 здоровых лиц и 118 детей, подростков и взрослых с СД 1 в возрасте от 11 до 50 лет, которые были разделены на 5 возрастных групп. Дизайн исследования ? простое, сравнительное. Материалом для исследования служила венозная и капиллярная кровь. Оценивали тромбоцитарный гемостаз, коагуляционный гемостаз, антикоагулянтное звено. Результаты. Исследование антикоагулянтных свойств выявило повышение уровня антитромбина III у больных в возрасте от 19 до 25 лет по сравнению со здоровыми людьми соответствующего возраста. Изучение сосудисто-тромбоцитарного гемостаза у данной категории больных выявило снижение содержания тромбоцитов у обследуемых в возрасте от 19 до 25 лет по сравнению с контролем. Хроническая гипергликемия вызывает повышение активности свертывающей системы крови у больных СД 1, что диктует необходимость строгого контроля за показателями гемостаза и коррекции выявленных нарушений. Заключение. Развитие сосудисто-тромбоцитарной дисфункции при сахарном диабете 1 типа не зависит от возраста. Для детей и подростков, больных сахарным диабетом 1 типа, характерно компенсаторное повышение активности антикоагулянтной системы. Активность фибринолитической системы у детей, подростков и взрослых, больных сахарным диабетом, превышает таковую в норме

NGR4 and ERBB4 as Promising Diagnostic and Therapeutic Targets for Metabolic Disorders

Obese individuals are at high risk for developing type 2 diabetes mellitus, cardiovascular diseases, and nonalcoholic fatty liver disease. The aim of this review was to analyze the scientific literature and databases to reveal the fundamental role of neuregulin 4 (NRG4) and its receptors in the development of obesity-associated metabolic disorders. This review demonstrates that NRG4 and its receptors are promising therapeutic targets for the treatment of socially significant obesity-associated pathologies. The review contains nine chapters. Information on the structure of ERBB4 and NRG4 splice isoforms and subsequent activation of downstream targets is presented. The tissue-specific features of the NRG4 and ERBB4 genes and protein production are also highlighted. The role of NRG4 and ERBB3/4 in the pathophysiological mechanisms of the development of metabolic disorders in obesity is discussed in detail. The final chapter of the review is devoted to the miRNA-dependent regulation of NRG4 and ERBB4. Recent studies have shown that several miRNAs regulate ERBB4 expression, but no information was found on the interaction of NRG4 with miRNAs. We now demonstrate the putative relationships between NRG4 and let-7a-5p, let-7c-5p, miR-423-5p, miR-93-5p, miR-23a-3p, and miR-15b-5p for the first time. In addition, we found SNP mutations affecting the interaction of NRG4 and ERBB4 with miRNA in these genes as well as in miRNAs. In summary, this review provides a detailed and comprehensive overview of the role of NRG4 in obesity-associated metabolic disorders. The review summarizes all current studies on this topic and opens perspectives for future research