Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

Relationship between the Levels of lncRNA H19 in Plasma and Different Adipose Tissue Depots with Patients' Response to Bariatric Surgery.

Bariatric surgery represents a widespread approach to treating morbid obesity. The search for biomarkers to identify patients to whom this type of treatment will be most effective is needed. Our aim was to characterize the relationship of levels of lncRNA H19 in plasma and different adipose tissue depots with patients' response to bariatric surgery. The study includes control subjects, patients with obesity and patients with obesity accompanied by impaired carbohydrate metabolism (ICM). Quantitative analysis of lncRNA H19 levels has been performed using qPCR in plasma and subcutaneous (SAT) and visceral adipose tissue (VAT). Patients with obesity without ICM have higher levels of lncRNA H19 in VAT compared to SAT, and higher levels of lncRNA H19 in SAT compared to SAT of control individuals. One year after the intervention, levels of lncRNA H19 decreased in SAT of patients with obesity without ICM. The preoperative level of lncRNA H19 in VAT demonstrates a positive correlation with excess weight loss and a negative correlation with initial BMI. In conclusion, ICM affects expression of lncRNA H19 in SAT of patients with obesity. The preoperative level of lncRNA H19 in VAT can be used to predict excess weight loss in patients with obesity after bariatric surgery.

Metformin: Expanding the Scope of Application-Starting Earlier than Yesterday, Canceling Later.

Today the area of application of metformin is expanding, and a wealth of data point to its benefits in people without carbohydrate metabolism disorders. Already in the population of people leading an unhealthy lifestyle, before the formation of obesity and prediabetes metformin smooths out the adverse effects of a high-fat diet. Being prescribed at this stage, metformin will probably be able to, if not prevent, then significantly reduce the progression of all subsequent metabolic changes. To a large extent, this review will discuss the proofs of the evidence for this. Another recent important change is a removal of a number of restrictions on its use in patients with heart failure, acute coronary syndrome and chronic kidney disease. We will discuss the reasons for these changes and present a new perspective on the role of increasing lactate in metformin therapy.

Association between Markers of Fibrosis and Heart Failure Incidence in Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) and chronic heart failure (HF) have close association, and several biomarkers have been studied to better understand this association and improve prediction of HF in T2DM. Furthermore, in recent clinical trials, sodium glucose cotransporter 2 inhibitors (SGLT2i), glucose-lowering drugs, improved HF outcomes. The objective of the present study was to evaluate association between circulating biomarkers of fibrosis and incidence of HF with preserved ejection fraction (HFpEF) in patients with T2DM receiving sodium glucose cotransporter 2 inhibitors (SGLT2i). Materials and Methods. At baseline, transthoracic echocardiography and laboratory assessment of N-terminal fragment of the brain natriuretic peptide (Nt-proBNP), soluble suppression of tumorigenesis-2 (sST2), galectin-3 (Gal-3), C-terminal propeptide of procollagen type I (PICP), N-terminal propeptide of procollagen type III (PIIINP), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix proteinase-1 (TIMP-1) were done. After 3 years of follow-up, information about HF events (hospitalization for HF, established HF in outpatient department by a cardiologist) was obtained. Results. Seventy-two patients were included in the study. The mean age was 57 (49.7; 63.2) years; 44% were female. Most patients had T2DM for more than 4 years. All patients were overweight or had obesity, and 93% patients had arterial hypertension (AH). After 3 years of follow-up, HFpEF was established in 21% patients. Patients were divided into two groups according to the presence of HFpEF, and baseline characteristics were compared. Patients with HF were older and had longer diabetes and AH duration and higher Nt-proBNP, Gal-3, PIIINP, and PICP levels at baseline than patients without HF (all p < 0.05). Gal - 3 > 10 ng/ml (OR = 2.25; 95% CI, 1.88-5.66; p = 0.01) and NT - pro - BNP > 80 pg/ml (OR = 2.64; 95% CI, 1.56-4.44; p = 0.001) were associated with increased risk of HF incidence. Age > 60 years, diabetes duration > 10 years, and presence of abdominal obesity were independent predictors of HFpEF as well. Conclusions. T2DM patients treated with SLGT2i, who developed HFpEF after 3 years of follow-up, had higher PICP, PIIINP, Gal-3, and NT-proBNP serum concentrations at baseline, and Gal-3 level was an independent predictor of HFpEF.

Regulatory Action of Plasma from Patients with Obesity and Diabetes towards Muscle Cells Differentiation and Bioenergetics Revealed by the C2C12 Cell Model and MicroRNA Analysis.

Obesity and type 2 diabetes mellitus (T2DM) are often combined and pathologically affect many tissues due to changes in circulating bioactive molecules. In this work, we evaluated the effect of blood plasma from obese (OB) patients or from obese patients comorbid with diabetes (OBD) on skeletal muscle function and metabolic state. We employed the mouse myoblasts C2C12 differentiation model to test the regulatory effect of plasma exposure at several levels: (1) cell morphology; (2) functional activity of mitochondria; (3) expression levels of several mitochondria regulators, i.e., Atgl, Pgc1b, and miR-378a-3p. Existing databases were used to computationally predict and analyze mir-378a-3p potential targets. We show that short-term exposure to OB or OBD patients' plasma is sufficient to affect C2C12 properties. In fact, the expression of genes that regulate skeletal muscle differentiation and growth was downregulated in both OB- and OBD-treated cells, maximal mitochondrial respiration rate was downregulated in the OBD group, while in the OB group, a metabolic switch to glycolysis was detected. These alterations correlated with a decrease in ATGL and Pgc1b expression in the OB group and with an increase of miR-378a-3p levels in the OBD group.

Short-term renal and metabolic effects of low dose vildagliptin treatment added-on insulin therapy in non-proteinuric patients with type 2 diabetes: open-label randomized prospective study

ABSTRACT Objective The aim of this randomized comparative study was to assess renal and metabolic effects of vildagliptin in insulin-treated type 2 diabetes (T2DM) patients without overt chronic kidney disease. Subjects and methods We randomized 47 insulin-treated non-proteinuric patients with satisfactory controlled T2DM and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m 2 either to continue insulin therapy (control) or to receive combined insulin-vildagliptin treatment (VIG group). We assessed eGFR using serum creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys), and urinary creatinine-adjusted excretion of albumin (UACR), type IV collagen (uCol IV/Cr), and neutrophil gelatinase-associated lipocalin (uNGAL/Cr) at baseline and after 6 months of treatment. Results Study groups were comparable in terms of age and sex (60.1 ± 6.1 years and 42.9% men in control group vs. 60.8 ± 5.2 years and 39.1% in VIG group). After 6 months of treatment, there were no significant changes in main assessed parameters in control group. VIG group demonstrated significant decrease in HbA1c, diastolic blood pressure, frequency of hypoglycemia, and high-sensitivity C-reactive protein level as compared to the changes in control group. While eGFRcreat, UACR, and uNGAL/Cr showed no significant changes after vildagliptin addition, eGFRcys, eGFRcreat-cys, and uCol IV/Cr changed significantly in comparison with control group (+7.0% [3.7;13.3]; +5.1% [1.4;8.5]; -32,8% [-55.8;-24.4], respectively, p < 0.01 each). Correlation and regression analysis revealed glucose-independent pattern of these changes. Conclusion Addition of vildagliptin to ongoing insulin therapy in patients with T2DM was associated with a reduction in uCol IV/Cr and an increase in eGFRcys and eGFRcreat-cys, independent of T2DM control parameters.

Short-term renal and metabolic effects of low dose vildagliptin treatment added-on insulin therapy in non-proteinuric patients with type 2 diabetes: open-label randomized prospective study.

Objective The aim of this randomized comparative study was to assess renal and metabolic effects of vildagliptin in insulin-treated type 2 diabetes (T2DM) patients without overt chronic kidney disease. Subjects and methods We randomized 47 insulin-treated non-proteinuric patients with satisfactory controlled T2DM and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m 2 either to continue insulin therapy (control) or to receive combined insulin-vildagliptin treatment (VIG group). We assessed eGFR using serum creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys), and urinary creatinine-adjusted excretion of albumin (UACR), type IV collagen (uCol IV/Cr), and neutrophil gelatinase-associated lipocalin (uNGAL/Cr) at baseline and after 6 months of treatment. Results Study groups were comparable in terms of age and sex (60.1 ± 6.1 years and 42.9% men in control group vs. 60.8 ± 5.2 years and 39.1% in VIG group). After 6 months of treatment, there were no significant changes in main assessed parameters in control group. VIG group demonstrated significant decrease in HbA1c, diastolic blood pressure, frequency of hypoglycemia, and high-sensitivity C-reactive protein level as compared to the changes in control group. While eGFRcreat, UACR, and uNGAL/Cr showed no significant changes after vildagliptin addition, eGFRcys, eGFRcreat-cys, and uCol IV/Cr changed significantly in comparison with control group (+7.0% [3.7;13.3]; +5.1% [1.4;8.5]; -32,8% [-55.8;-24.4], respectively, p < 0.01 each). Correlation and regression analysis revealed glucose-independent pattern of these changes. Conclusion Addition of vildagliptin to ongoing insulin therapy in patients with T2DM was associated with a reduction in uCol IV/Cr and an increase in eGFRcys and eGFRcreat-cys, independent of T2DM control parameters.

Predictors of Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Patients with Type 2 Diabetes and Obesity.

RATIONALE: It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. PURPOSE: To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. METHODS: The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients' evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. RESULTS: Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI loss ≥ 5%, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. CONCLUSION: The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are useable for estimating the expected efficacy of aGLP-1.

Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes.

Type 2 diabetes (DM2) could be reproduced in rats with alimentary obesity by using low doses of streptozotocin (LD-STZ) as well as STZ in high doses with preliminary nicotinamide (NA) administration. However, STZ could induce tubulotoxicity. Aim. To develop rat model of DN in NA-STZ-induced DM2 and compare it with LD-STZ-model in order to choose the most relevant approach for reproducing renal glomerular and tubular morphofunctional diabetic changes. Starting at 3 weeks after uninephrectomy, adult male Wistar rats were fed five-week high-fat diet and then received intraperitoneally either LD-STZ (40 mg/kg) or NA (230 mg/kg) followed by STZ (65 mg/kg). Control uninephrectomized vehicle-injected rats received normal chow. At weeks 10, 20, and 30 (the end of the study), metabolic parameters, creatinine clearance, albuminuria, and urinary tubular injury markers (NGAL, KIM-1) were evaluated as well as renal ultrastructural and light microscopic changes at weeks 20 and 30. NA-STZ-group showed higher reproducibility and stability of metabolic parameters. By week 10, in NA-STZ-group NGAL level was significantly lower compared to LD-STZ-group. By week 30, diabetic groups showed early features of DN. However, morphofunctional changes in NA-STZ-group appeared to be more pronounced than those in STZ-group despite lower levels of KIM-1 and NGAL. We proposed a new rat model of DM2 with DN characterized by stable metabolic disorders, typical renal lesions, and lower levels of tubular injury markers as compared to LD-STZ-induced diabetes.