Application of Clinical Blood Metabogram to Type 2 Diabetes Mellitus.

The clinical blood metabogram (CBM) was developed to match a tailored analysis of the blood metabolome to the time, cost, and reproducibility constraints of clinical laboratory testing. By analyzing the main blood metabolite groups, CBM offers clinically relevant information about the intake of low-molecular substances into the organism, humoral regulation, liver function, amino acid level, and the lipid and carbohydrate metabolism. The purpose of this work was to investigate the relevance of using the CBM in patients with diabetes mellitus. For this, a CBM was obtained for 18 healthy individuals, 12 individuals with prediabetes, and 64 individuals with type 2 diabetes mellitus, separated into groups according to fasting blood glucose and oral glucose tolerance tests. The results showed that the CBM reveals diabetes-associated metabolic alterations in the blood, including changes in the levels of carbohydrates, ketone bodies, eicosanoids, phospholipids, and amino acids, which are consistent with the scientific data available to date. The CBM enabled the separation of diabetic patients according to their metabolic metabotypes, providing both a general overview of their metabolic alterations and detailing their individual metabolic characteristics. It was concluded that the CBM is a precise and clinically applicable test for assessing an individual's metabolic status in diabetes mellitus for diagnostic and treatment purposes.

Shear Stress and the AMP-Activated Protein Kinase Independently Protect the Vascular Endothelium from Palmitate Lipotoxicity.

Saturated free fatty acids are thought to play a critical role in metabolic disorders associated with obesity, insulin resistance, type 2 diabetes (T2D), and their vascular complications via effects on the vascular endothelium. The most abundant saturated free fatty acid, palmitate, exerts lipotoxic effects on the vascular endothelium, eventually leading to cell death. Shear stress activates the endothelial AMP-activated protein kinase (AMPK), a cellular energy sensor, and protects endothelial cells from lipotoxicity, however their relationship is uncertain. Here, we used isoform-specific shRNA-mediated silencing of AMPK to explore its involvement in the long-term protection of macrovascular human umbilical vein endothelial cells (HUVECs) against palmitate lipotoxicity and to relate it to the effects of shear stress. We demonstrated that it is the α1 catalytic subunit of AMPK that is critical for HUVEC protection under static conditions, whereas AMPK-α2 autocompensated a substantial loss of AMPK-α1, but failed to protect the cells from palmitate. Shear stress equally protected the wild type HUVECs and those lacking either α1, or α2, or both AMPK-α isoforms; however, the protective effect of AMPK reappeared after returning to static conditions. Moreover, in human adipose microvascular endothelial cells isolated from obese diabetic individuals, shear stress was a strong protector from palmitate lipotoxicity, thus highlighting the importance of circulation that is often obstructed in obesity/T2D. Altogether, these results indicate that AMPK is important for vascular endothelial cell protection against lipotoxicity in the static environment, however it may be dispensable for persistent and more effective protection exerted by shear stress.

[Specific features of the use of alogliptin in various groups of patients with type 2 diabetes mellitus: additional results of the ENTIRE study].

BACKGROUND: Since the obtaining of data on the effect of Alogliptin towards the lipid profile, body weight and blood pressure (BP) of patients, the additional analysis of the results of the ENTIRE study, completed in the Russian Federation in 2018, was conducted. AIMS: Assess the dynamics of HbA1c, body weight, fats indices, blood pressure (BP), and characterize the profile of the patient who received the maximum clinical benefit on treatment of Alogliptin therapy in the ENTIRE study. MATERIALS AND METHODS: A prospective non-interventional observational study that included patients aged 18 years and older with first-onset type 2 diabetes mellitus (T2DM) or patients with T2DM who did not achieve their glycemic targets during the previous therapy. RESULTS: A decrease in glycated hemoglobin (HbA1c) by more than 0.5% was detected in 73.5% of patients. The most significant absolute decrease of HbA1c was noticed in patients with initially higher values. Younger patients with a shorter duration of T2DM showed the more often compensation of carbohydrate metabolism. The average loss of weight was -2.6±4.2 kg. 76.6% of patients showed the loss of weight. The most significant decrease in body weight was noticed in patients with a large initial body mass index and a shorter duration of the disease. 74.7% of patients showed a decrease of the level of low-density lipoproteins (LDL). The most significant absolute decrease in LDL was noticed in patients with initially higher values and more often in younger people with a shorter duration of T2DM. The average decrease in systolic blood pressure (BP) was 5.9±0.3 mm Hg; the average decrease in diastolic blood pressure (BP) was 2.7±0.2 mm Hg. 59% of patients showed decrease of blood pressure during the group analyzing. The most frequent BP reduction was observed in younger patients with shorter duration of T2DM. At the same time, a more significant absolute decrease in blood pressure was noticed in patients with initially higher indicators, and an increase, on the contrary, was observed in patients with initially lower indicators. CONCLUSIONS: The intensification of Alogliptin therapy allowed to achieve the compensation of carbohydrate metabolism, moderate decrease of body weight, blood pressure and LDL indices within the majority of patients with T2DM. The most frequent achievement of HbA1c targets was noticed in young patients with a shorter duration of T2DM.

Low AS160 and high SGK basal phosphorylation associates with impaired incretin profile and type 2 diabetes in adipose tissue of obese patients.

OBJECTIVE: To compare basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT), and correlate it with clinical parameters of carbohydrate metabolism and incretin secretion profiles. METHODS: Recruited were 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and analyzed by western blots. RESULTS: As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 was significantly lower and that of serum and glucocorticoid-induced kinase (SGK) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1. CONCLUSION: Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype.

Diagnosing impaired glucose tolerance using direct infusion mass spectrometry of blood plasma.

The goal of this study was to evaluate the capacity for mass spectrometry of blood plasma to diagnose impaired glucose tolerance (IGT). For this study, blood plasma samples from control subjects (n = 30) and patients with IGT (n = 20) were treated with methanol and low molecular weight fraction were then analyzed by direct infusion mass spectrometry. A total of 51 metabolite ions strongly associated with IGT were detected. The area under a receiver operating characteristic (ROC) curve (AUC) for diagnosing IGT that was based on an analysis of all these metabolites was 0.93 (accuracy 90%, specificity 90%, and sensitivity 90%). The associated reproducibility was 85%. The metabolites identified were also consistent with risk factors previously associated with the development of diabetes. Thus, direct infusion mass spectrometry of blood plasma metabolites represents a rapid, single-step, and reproducible method for the analysis of metabolites. Moreover, this method has the potential to serve as a prototype for clinical analyses that could replace the currently used glucose tolerance test with a more patient-friendly assay.