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,

The relationship between the mtDNA copy number in insulin-dependent tissues and markers of endothelial dysfunction and inflammation in obese patients

Abstract Background Mitochondria play a central role in the regulation of energy metabolism, and the biogenesis of mitochondria is enhanced by the action of nitric oxide (NO), which is the key signaling molecule in the regulation of vascular homeostasis. A disturbance in the regulation of energy metabolism can be a key reason for the formation of insulin resistance and type 2 diabetes mellitus. Moreover, mitochondrial dysfunction leads to oxidative stress, which increases the production of proinflammatory cytokines. In this regard, the aim of this study was to identify the relationship of the copy number of mtDNA in adipose tissue from different locations (subcutaneous adipose tissue (SAT), mesentery (Mes), greater omentum (GO)), liver biopsy samples and mononuclear blood cells (MNCs) with endothelial dysfunction markers (eNOS, ET-1, iCAM-1, vCAM-1, VEGF) and inflammatory mediators (TNF-α, IL-6, IL-8, CRP, leptin) in obese patients (body mass index (BMI) > 35 kg/m2) with and without type 2 diabetes. Methods The study included 88 obese patients (BMI > 35 kg/m2) treated at the Kaliningrad Region Hospital. The control group consisted of 20 healthy donors. To measure mtDNA copy number we used droplet digital PCR. The concentrations of molecules (TNF-α, IL-6, IL-8, VEGF, eNOS, ET-1, iCAM-1, vCAM-1, VEGF) were measured in plasma using the following sandwich enzyme-linked immunosorbent assays (ELISAs). Quantitative determination of leptin was evaluated by flow-fluorimetry on a «Bio-Plex Protein Assay System». Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1). Results The systemic character of chronic subclinical inflammation in obesity is established, and an increase in the level of endothelial dysfunction molecules was observed in the blood plasma. The levels of TNF-a, IL-6, and IL-8 were positively correlated with increases in BMI, serum glucose and cholesterol levels. Conclusions The copy number of mtDNA in various fat stores was higher in obese patients with type 2 diabetes than in obese patients without diabetes or in the control subjects and was related to the levels of leptin and proinflammatory cytokines

Interrelation of chemerin and TNF-α with mtDNA copy number in adipose tissues and blood cells in obese patients with and without type 2 diabetes

Abstract Background Inflammatory response plays a key role in the development of insulin resistance (IR) in obesity. Oxidative stress triggers the replication of the mitochondrial genome and division of the organelle. The purpose of this study was to identify the relationship of chemerin and TNF-α with mitochondrial DNA (mtDNA) copy number in subcutaneous adipose tissue (SAT) and visceral adipose tissue (mesentery of the small intestine (Mes), greater omentum (GO) and blood mononuclear cells (MNCs)) in patients with obesity with/without type 2 diabetes mellitus (T2DM). Methods The study included 142 obese patients and 34 healthy donors. The samples used for the study were peripheral venous blood (MNCs) and ATs (SAT, Mes and GO). The measurement of mtDNA copy number was done by droplet digital PCR. Quantitative determination of insulin, adiponectin, TNF-α and chemerin in serum/plasma was performed by flow-through fluorometry and commercial ELISA kit. Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1). Results The increase in body mass index (BMI) was accompanied by an increase in TNF-α production, an increase in mtDNA copy number in SAT and a decrease in mtDNA copy number in MNCs. The negative association between plasma chemerin and mtDNA copy number in the Mes, as well as between mtDNA copy number and chemerin expression in the Mes, in the group with BMI > 40 kg/m2 without T2DM demonstrates the protective effect of chemerin against the development of IR via the regulation of mtDNA copy number in adipose tissues. Conclusions We thus speculated the existence of a compensatory mechanism in which leads to the increased number of mtDNA copies under the influence of proinflammatory factors. Based on the obtained data, we propose that reducing mtDNA copy number in cases of morbid obesity without T2DM has a positive effect on carbohydrate metabolism, which may help maintain glucose levels within reference values. Obesity, type 2 diabetes, mtDNA, cytokines, TNF-a, chemerin

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

IL-6 Reduces Mitochondrial Replication, and IL-6 Receptors Reduce Chronic Inflammation in NAFLD and Type 2 Diabetes

Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the study aimed to investigate the role of the IL-6 cytokine family (sIL-6Ra, gp130/sIL-6Rb, and IL-11) in the regulation of mitochondrial dynamics in the liver in obese patients and to assess the contribution of these cytokines to the pathogenesis of type 2 diabetes mellitus (T2DM). We studied 134 obese patients with and without T2DM and 41 healthy donors. We found that increasing the concentration of sIL-6Ra and gp130/sIL-6Rb protected against carbohydrate disorders in obese patients and prevented non-alcoholic fatty liver disease (NAFLD) progression in obese patients. An increase in plasma IL-6 levels is associated with decreased, mitochondrial transcription factor A (TFAM) protein production in liver biopsies in obese patients with and without T2DM. Replication, transcription, and division processes in liver biopsy were reduced in patients with T2DM. Inflammatory processes stimulate liver cell apoptosis in obese patients with T2DM. The increase in IL-11 levels is associated with decreased pro-apoptotic Bcl-2-associated X protein (BAX) protein production in obese patients with and without T2DM

IL-6 Reduces Mitochondrial Replication, and IL-6 Receptors Reduce Chronic Inflammation in NAFLD and Type 2 Diabetes

Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the study aimed to investigate the role of the IL-6 cytokine family (sIL-6Ra, gp130/sIL-6Rb, and IL-11) in the regulation of mitochondrial dynamics in the liver in obese patients and to assess the contribution of these cytokines to the pathogenesis of type 2 diabetes mellitus (T2DM). We studied 134 obese patients with and without T2DM and 41 healthy donors. We found that increasing the concentration of sIL-6Ra and gp130/sIL-6Rb protected against carbohydrate disorders in obese patients and prevented non-alcoholic fatty liver disease (NAFLD) progression in obese patients. An increase in plasma IL-6 levels is associated with decreased, mitochondrial transcription factor A (TFAM) protein production in liver biopsies in obese patients with and without T2DM. Replication, transcription, and division processes in liver biopsy were reduced in patients with T2DM. Inflammatory processes stimulate liver cell apoptosis in obese patients with T2DM. The increase in IL-11 levels is associated with decreased pro-apoptotic Bcl-2-associated X protein (BAX) protein production in obese patients with and without T2DM

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