Association of insulin resistance and non-alcoholic fatty liver disease

BACKGROUND: The number of patients with chronic metabolic disorders such as obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease (NAFLD) is growing at an alarming rate worldwide in both developed and developing countries. In the world, the prevalence of NAFLD is approaching 25%. Among patients with T2D, 70–80% are diagnosed with NAFLD. Insulin resistance (IR) is recognized as one of the main pathogenetic factors in the development of the most common chronic liver disease — NAFLD.AIM: Our search work was aimed at determining the contribution of the degree of IR to the progression of NAFLD; compare the gold standard for the determination of IR (clamp) and the mathematical model (HOMA-IR).METHODS: An observational one-stage open comparative study was conducted on the basis of the case-control principle. The objects of the study were overweight and obese patients who had not previously been diagnosed carbohydrate metabolism disorders, without secondary causes of fat accumulation in the liver. During the examination, clinical and laboratory studies were carried out, IR indices (M-index, HOMA-IR index) were obtained, a diagnosis of carbohydrate metabolism disturbance (or its absence) was made, a liver biopsy was made, morphological and clinical diagnoses were made.RESULTS: The analysis included information about 60 patients, they are divided into 3 groups: without NAFLD (7 people), with steatosis (18 people), with non-alcoholic steatohepatitis (NASH) (35 people), groups are comparable by age, gender, and body mass index (BMI), glycated hemoglobin. When assessing the degree of IR using the hyperinsulinemic euglycemic clamp test, 19 showed a severe degree of IR, 28 had a moderate degree, 8 had a mild degree, and 5 had no IR. In the three studied groups, the median IR corresponded to an average degree and did not significantly differ. When comparing the gold standard for determining IR and the mathematical model (HOMA-IR) in the studied groups, an negative significant correlation was revealed (p = 0,0001).CONCLUSIONS: In the course of our study, no correlation was found between the degree of IR and the severity of NAFLD. This result allows us to think about other pathogenetic factors that affect the progression of NAFLD

Assessment the equivalence of the bioanalogue insulin lizpro biphasic 25 (Geropharm-bio, Russia) and Humalog® Mix 25 (Lilly France, France) using the euglycemic hyperinsulinum clamp method on healthy volonters

Background: Modern medicine requires use of effective antidiabetic drugs that can imitate the natural profile of insulin in the body of patients with diabetes mellitus. Examples of such preparations include biphasic insulin lispro, which is a mixture of insulin lispro ultra-short action and insulin lispro protamine suspension with prolonged effect. The clinical trials (CT) program for biosimilar insulins contains pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety studies. Aims: To demonstrate Biphasic Insulin Lispro 25, suspension for subcutaneous administration, 100 U/ml (GEROPHARM-Bio, Russia) and Humalog® Mix 25, suspension for subcutaneous administration, 100 U/ml (Lilly France, France) have comparable pharmacokinetic profiles under conditions of hyperinsulinemic euglycemic clamp (HEC) in healthy volunteers. Materials and methods: The study was conducted on 48 healthy men aged between 18 to 50 years. This was a double-blind, randomized, crossover study of comparative pharmacokinetics of drugs. The investigational products (IP) were administered before the clamp in a single dose of 0.4 U/kg subcutaneously in the abdominal wall. Regular blood sampling was performed during the study. The insulin concentrations in the samples were determined using an ELISA method. The results of the determination were used to calculate the PK parameters and construct the concentration-time curves. Adjust glucose infusion rates were based on blood glucose measurements. These data were used to calculate the PD parameters. Results: Our results demonstrated that Biphasic Insulin Lispro 25 and Humalog® Mix 25 have comparable PK and PD profiles under conditions of HEC in healthy volunteers. The confidence intervals for the ratio of the geometric mean for Cins.max and AUCins.0–12 were 87.75–99.90% and 83.76–96.98% respectively, which were well within 80–125% limits for establishing comparability. Conclusions: Biphasic Insulin Lispro 25 and Humalog® Mix 25 are equivalent based on this CT applying the HEC technique in healthy volunteers

Influence of hyperinsulinemic – hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von Willebrand factor in patients with type I diabetes

Background. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications. Aims. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemichypoglycaemic clamp. Materials and methods. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 5.6 years, A1C 9.7 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp. Results. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin23.9%, ADP30.6%, arachidonic acid30.9%, collagen69.4% and ristocetin70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly. Conclusions. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemichypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation

A look at new therapeutic opportunities in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis

Evaluation of biosimilarity of RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) using the euglycemic hyperinsulinemic clamp technique in patients with type 1 diabetes: double-blind randomized clinical trial

Background: Prevention of the development of micro-and macrovascular complications in patients with diabetes melli-tus (DM) encouraged the search for insulin analogues that allow imitating, as close as possible, a normal physiological insulin secretion in healthy people. Biosimilars (bioanalogues of reference products) play an important role in the full provision with high-quality insulin medications throughout patients. The program of clinical trials of insulin bioanalogues includes pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety research.Aims: To test whether RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) have similar PK and PD profiles in a hyperinsulinemic euglycaemic clamp (HEC) setting in patients with type 1 diabetes mellitus. Permission of the Ministry of Health of the Russian Federation No. 150 of 03/03/2016.Materials and methods: The study was conducted in 42 patients with type 1 diabetes aged 18 to 65 years. A doubleblind, randomized, crossover study of comparative PK and PD of drugs was chosen as a study design. The investigational products were injected after achieving a state of euglycemia before the HEC in a single dose of 0.6 U/kg subcutaneously into the subcutaneous fat of the anterior abdominal wall. During the study, regular blood sampling was performed, the amount of insulin glargine in the samples was determined by ELISA. The results are used to calculate the PK parameters and generate the concentration-time curves. The glucose infusion rate was corrected based on the measurement of glycemia. These data are used to calculate the PD parameters.Results: RinGlar® and Lantus® interventions have comparable PK and PD profiles in HEC setting in patients with type 1 diabetes. This is confirmed by the similarity of the main PK/PD parameters, PK/PD curves, and comparable safety. The confidence intervals of the geometric mean ratio were 81.02% - 120.62% for the PK parameter AUCins0-T, and 85.43% - 115.64% for the PD-parameter AUCGIR0_T, which fall within the specified limits of 80% - 125% to establish comparability between drugs.Conclusions: Results of the clinical trial demonstrate the biosimilarity of the products RinGlar® and Lantus®

Genetic Aspects of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most commonly diagnosed hepatopathy. There is an increase in the incidence of NAFLD in the structure of liver diseases in children and adolescents, which is directly related to the increasing prevalence of obesity. The spectrum of liver tissue changes in NAFLD ranges from benign hepatocellular steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis of the liver, and hepatocellular carcinoma. With the increasing prevalence of NAFLD in children, we can expect an increase in the incidence of adverse outcomes among people of working age. The key problem for NAFLD is the prediction of disease outcomes. In epidemiological and genetic studies, the relationship between the morphological stage of NAFLD and hereditary factors is shown. Currently, there are three genes associated with NAFLD (PNPLA3, TM6SF2, and GCKR), which, together with the genes responsible for insulin resistance, lipid deposition, inflammation and fibrogenesis in hepatocytes, determine the phenotype of fatty liver disease. The article considers the modern understanding of the issues of genetics, development of liver steatosis and progression of NASH. It is expected that this knowledge can transform our risk stratification strategies in patients with NAFLD and help identify new therapeutic goals

Farnesoid X receptor (FXR) as a potential therapeutic target in nonalcoholic fatty liver disease and associated syndromes

Nonalcoholic fatty liver disease (NAFLD) is a group of obesity-associated pathological changes characterized by abnormal accumulation of lipids in cells of the liver parenchyma. NAFLD and associated conditions, namely insulin resistance and type II diabetes mellitus (DM2), as well as the possible risks of developing fibrosis and cirrhosis with a potential outcome in hepatocellular carcinoma, represent the primary health problems in developed countries, gradually replacing the importance of similar pathologies caused by the regular use of hepatotoxic doses of alcoholic beverages. Recent fundamental and clinical studies demonstrated the important role of the farnesoid receptor (FXR, NR1H4) in the regulation of the metabolism of glucose, lipids and bile acids. This review focuses on the molecular aspects of the pathogenesis of NAFLD, the role of FXR (NR1H4) in the biology of this disease, and the prospects for using different FXR (NR1H4) modulators for therapy of NAFLD and associated conditions such as metabolic syndrome and DM2, as well as a number of other FXR (NR1H4) mediated diseases

Nonalcoholic fatty liver disease: cause or consequence of insulin resistance?

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are pathological conditions that are co-occurring, and have been reaching epidemic proportions. One of the most significant risk factors for the development of both T2DM and NAFLD is obesity, which increases existing insulin resistance (IR). IR thought to be one of the main pathogenic causes linking T2DM and NAFLD. In recent years, there has been increased interest in obtaining non-invasive methods for assessing fibrosis and determining indications for liver biopsy, such as the NAFLD fibrosis score, extended liver fibrosis panel, and transient elastography. However, liver biopsy remains the gold standard for diagnosing NAFLD. Given that patients with T2DM are at higher risk of NAFLD than the general population, and that the presence of diabetes is a risk factor for the progression of NAFLD, patients with T2DM should be more closely monitored by clinicians. The present review paper is devoted to the search for causeeffect relationships of concurrent diseases such as NAFLD and disorders of carbohydrate metabolism, and priority areas of diagnosis of NAFLD