Clinical Pharmacology of GP40321 (Insulin Glulisine Biosimilar): Pharmacokinetic and Pharmacodynamic Comparability in a Hyperinsulinemic-Euglycemic Clamp Procedure.

The aim of the study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T-glu (GP40321, test drug), and reference insulin glulisine in a hyperinsulinemic-euglycemic clamp procedure. During this study, 34 healthy male volunteers underwent the hyperinsulinemic-euglycemic clamp procedure following subcutaneous 0.3 U/kg injection of T-glu or reference insulin glulisine in a randomized, double-blind, crossover study. Plasma glucose levels were monitored every 5 minutes for 8 hours. Glucose infusion rate adjustment was based on the blood glucose measurements. Evaluation of PD was performed using the glucose infusion rate values, while PK was calculated using insulin concentrations measured via enzyme-linked immunosorbent assay. The study results showed that the 90% CI for the geometric mean ratios of primary PK and PD of T-glu and reference insulin glulisine were within 80%-125% comparability limits, and that the safety profiles were comparable. PK, PD, and safety similarity of T-glu and reference insulin glulisine was demonstrated.

Primary hyperparathyroidism in young patients is associated with metabolic disorders: a prospective comparative study.

BACKGROUND: Components of metabolic syndrome can be observed in patients with primary hyperparathyroidism (PHPT). The link between these disorders remains unclear due to the lack of relevant experimental models and the heterogeneity of examined groups. The effect of surgery on metabolic abnormalities is also controversial. We conducted a comprehensive assessment of metabolic parameters in young patients with PHPT. METHODS: One-center prospective comparative study was carried out. The participants underwent a complex biochemical and hormonal examination, a hyperinsulinemic euglycemic and hyperglycemic clamps, a bioelectrical impedance analysis of the body composition before and 13 months after parathyroidectomy compared to sex-, age- and body mass index matched healthy volunteers. RESULTS: 45.8% of patients (n = 24) had excessive visceral fat. Insulin resistance was detected in 54.2% of cases. PHPT patients had higher serum triglycerides, lower M-value and higher C-peptide and insulin levels in both phases of insulin secretion compared to the control group (p < 0.05 for all parameters). There were tendencies to decreased fasting glucose (p = 0.031), uric acid (p = 0.044) and insulin levels of the second secretion phase (p = 0.039) after surgery, but no statistically significant changes of lipid profile and M-value as well as body composition were revealed. We obtained negative correlations between percent body fat and osteocalcin and magnesium levels in patients before surgery. CONCLUSION: PHPT is associated with insulin resistance that is the main risk factor of serious metabolic disorders. Surgery may potentially improve carbohydrate and purine metabolism.

PKPD Modeling and Simulations to Support Biosimilar Development of Biphasic Insulin Aspart 30.

This paper presents an analysis of data from a comparative study of biosimilarity in terms of pharmacokinetics and pharmacodynamics in healthy volunteers using a hyperinsulinemic euglycemic clamp for reference and test biphasic insulin aspart 30 (BIAsp 30). As a result of the study, one of the secondary pharmacodynamic (PD) endpoints did not satisfy the classical criterion of 80%-125% (the lower limit for PD parameter area under the glucose infusion rate-time curve [ AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ ] turned out to be 79.5%). The main hypothesis explaining this result is that the sample size is insufficient to conduct a PD test with 90% statistical power, since the sample size has been calculated based on the coefficient of variation (CV) of pharmacokinetic (PK) parameters. To test this hypothesis, population PKPD (popPKPD) modeling and subsequent simulations of the required number of PD profiles were used. Two popPKPD models were constructed (a one-compartment double simultaneous absorption model for PK and an effect compartment Emax model for PD) to describe the PKPD data of reference and test insulins. As a result, using real data along with model-based simulation data, a biosimilarity test for PD was performed, and the lower limit for AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ became 82.6%, while the CV decreased from 31.7% to 24.1%. Thus, popPKPD modeling and simulations have been shown to be effective in interpreting and supporting the results of clinical biosimilarity trials.

Direct Effect of the Synthetic Analogue of Glucagon-Like Peptide Type 1, Liraglutide, on Mature Adipocytes Is Realized through Adenylate-Cyclase-Dependent Enhancing of Insulin Sensitivity.

Incretin hormones analogues, including glucagon-like peptide type 1 (GLP-1), exhibit complex glucose-lowering, anorexigenic, and cardioprotective properties. Mechanisms of action of GLP-1 and its analogues are well known for pancreatic ß-cells, hepatocytes, and other tissues. Nevertheless, local effects of GLP-1 and its analogues in adipose tissue remain unclear. In the present work effects of the GLP-1 synthetic analogue, liraglutide, on adipogenesis and insulin sensitivity of the 3T3-L1 adipocytes were examined. Enhancement of insulin sensitivity of mature adipocytes by the GLP-1 synthetic analogue liraglutide mediated by adenylate cyclase was demonstrated. The obtained results imply existence of the positive direct insulin-sensitizing effect of liraglutide on mature adipocytes.

The Effects of Glucagon-Like Peptide Type 1 (GLP-1) and its Analogues in Adipose Tissue: Is there a way to Thermogenesis?

Obesity is a global problem and the most common metabolic disorder leading to many associated diseases, such as arterial hypertension, ischemic heart disease, type 2 diabetes, certain types of cancer, impaired lipid and uric acid metabolism. The prevalence of obesity has risen globally in the past four decades in both children and adults, and it accounts for the rapid increase in the prevalence of diabetes. Currently, the study of thermogenic tissues, brown and beige adipose tissues, is of extreme value from the point of view of therapeutic potential for obesity and its associated diseases. An analogue of the glucagon-like peptide-1 (GLP-1) liraglutide, used in the treatment of type 2 diabetes, has been proven to have a positive effect on weight loss through appetite suppression. However, this mechanism of weight loss is not the only one involved. This article discusses the main molecular and cellular mechanisms of adipogenesis, as well as the effect of GLP-1 and its analogues, in particular liraglutide on this process through various transcription factors, signaling pathways, and hormones, including brown and beige adipose tissue. Also, the twincretins have had a positive effect on insulin resistance and fat beiging activation. The results of numerous studies have helped us to better understand the peripheral mechanisms of lipid metabolism regulation, and have demonstrated the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity.

Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population.

BACKGROUND: The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. METHODS: The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-ß were used to measure insulin resistance and ß-cell secretory function, respectively. RESULTS: The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired ß-cell function. CONCLUSION: In the Russian population, genes, which affect insulin synthesis and secretion in the ß-cells of the pancreas, play a central role in the development of T2DM.

A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance.

We report the case of a 12-year-old boy with a glucokinase (GCK) mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA1c) levels of 6.6%-7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in GCK (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day. One year later, his HbA1c level was 6.9%, postprandial glycemia at 120 min of oral glucose tolerance test was 15.4 mmol/L, hyperinsulinemia had increased to 508.9 mU/L, homeostasis model assessment index was 114.2 and the Matsuda index was 0.15. Insulin resistance was confirmed by a hyperinsulinemic euglycemic clamp test - M-index was 2.85 mg/kg/min. This observation is a rare case of one of the clinical variants of diabetes, which should be taken into account by a vigilant endocrinologist due to the need for nonstandard diagnostic and therapeutic approaches.

The Relationship Between Brown Adipose Tissue Content in Supraclavicular Fat Depots and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus and Prediabetes.

BACKGROUND: The evaluation of brown adipose tissue (BAT) and its role in metabolism and obesity remains an important topic in the recent literature. This study evaluated the influence of the BAT triglyceride content measured by proton magnetic resonance (MR) spectroscopy in patients with type 2 diabetes mellitus (DM2) and prediabetes on insulin sensitivity. METHODS: A total of 25 patients with DM2 and prediabetes (45.9 ± 10.1 years old, body mass index [BMI] of 31.6 ± 5.4 kg/m2) underwent anthropometric measurements (BMI), insulin sensitivity analysis (M value during euglycemic hyperinsulinemic clamp and homeostasis model assessment of insulin resistance), proton MR spectroscopy, and blood tests (total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides). The relationship between the triglyceride content in the supraclavicular fat depot and insulin sensitivity, anthropometric measurements, and blood test results was assessed. RESULTS: The triglyceride content in the supraclavicular fat depot varied between 79.2% and 97.1% (mean: 92.6% ± 4.2%). The triglyceride content in the subcutaneous white adipose tissue of the neck was significantly higher (85.3%-99.3%; mean: 95.5% ± 2.9%; P = 0.0007). The triglyceride content in the supraclavicular fat depot exhibited a significantly moderate correlation with the BMI (r = 0.64; P = 0.0009). A significant weak negative correlation between the supraclavicular fat content and M value was revealed (r = -0.44; P = 0.002). Patients with high insulin resistance (IR) had a higher triglyceride content in the supraclavicular fat depot than patients with normal and lower IR (94.3% ± 2.0% vs. 90.4% ± 5.2%; P = 0.02). CONCLUSIONS: Reducing the BAT content in the supraclavicular fat depot can influence the development of IR in patients with DM2 and prediabetes.