Obesity is a high-risk factor for such comorbidities as cardiovascular disease, several types of cancer, and type 2 diabetes; however not all individuals with obesity have such complications. Approximately 20% of individuals with obesity are metabolically healthy. This study focused on differences between obese individuals with and without type 2 diabetes (T2D+ and T2D–, respectively) on the transcriptome level. Subjects included were 35 T2D– patients with obesity and 35 T2D+ patients with obesity with the same body mass index (BMI). The study was based on the transcription analysis of mRNA and microRNAs (miRs) by RNAseq. In the first step, we performed RNAseq of miRs, in the second step, we analyzed only those mRNA, which appeared targets for significant miRs from the first step. All RNAseq results were validated by qPCR. There were seven miRs differently expressed with adjusted p-value <0.1, which were confirmed by qPCR. Five among them: miR-204-5p, miR125b-5p, miR-125a-5p, miR320a, miR-99b—were upregulated in T2D+ patients with obesity, while only two miRs, miR-23b-3p, and miR197-3p, were increased in T2D– patients with obesity. These seven miRs target two groups of genes: matrix metalloproteinases and TGFβ signal pathway genes. According to the results of transcriptome analysis, the main difference between T2D+ and T2D– patients with obesity was in adipogenesis and fibrosis regulation by matrix metalloproteinases and SMAD4-RUNX2 signal cascade. Based on the data about transcription profiles of both groups, we suggested that the process of fibrosis in T2D+ patients with obesity is more pronounced than in T2D– patients with obesity.
Background: At present a lot of attention is paid to the so-called “metabolically healthy obesity”. More than a half of patients with prolonged history of obesity lack any carbohydrate metabolism disorders. Unfortunately, physiological factors forming the foundation of a favorable metabolic profile in such patients are not sufficiently defined. Aims: Evaluation of insulin resistance (IR) degree, the level of insulin secretion by pancreatic β-cells, and the contribution of both these mechanisms to the maintenance of normal carbohydrate metabolism in patients with prolonged history of obesity. Methods: An observational cross-sectional non-blinded selective comparative case-control study was performed. Patients with prolonged history of obesity without carbohydrate metabolism disorders and with type 2 diabetes mellitus (DM2) were included into the study. The following parameters were analyzed: IR parameters (М-index, HOMA-IR); insulin secretion parameters (НОМА-%β and insulinogenic index, glucose disposition index, GDI); body composition indices (total body fat and visceral fat area). Results: 68 patients participated in the study: 34 patients with obesity and normal carbohydrate metabolism («Obesity and NCM» group), and 34 patients with obesity and DM2 («Obesity and DM2» group); both groups were matched by body mass index, known obesity duration, and sex ratio (males/females) in each group. «Obesity and NCM» groups significantly differed from «Obesity and DM2» group by the following parameters: lower IR level (М-index median 4.13 vs 1.52 mg/kg/min, p0.001; HOMA-IR median 4.84 vs 9.94, p0.001); better insulin secretion (insulinogenic index median 28.15 vs 15.24, p0.002; HOMA-%β median 115.63 vs 25.94, p0.001); higher GDI (median 115.63 vs 25.94, p0.001); lower visceral fat area (median 170.00 vs 230.00 cm2, p0.001). Differences in total body fat (%) were not statistically significant. Conclusions: Patients with obesity and NCM compared to patients with DM2 have a less significant IR and a more preserved basal stimulated insulin secretion, which allows to maintain normal carbohydrate metabolism. Low visceral fat grade also contributes to this. Most likely, the most important factor contributing to the “maintenance” of normal carbohydrate metabolism in patients with obesity is preserved insulin secretion, which is confirmed by the high glucose disposal index (almost 4.5-fold higher than that in patients with DM2) characterizing the ability of β-cells to secrete the amount of insulin required to overcome IR.
Aim.Obese patients without diabetes present an interesting phenotype to explore protective mechanisms against type 2 diabetes (T2D) development. In our study we looked for specific hormonal features of obese patients without T2D. Materials and methods.We included 6 groups of patients with different metabolic profiles (n=212): controls with BMI25 kg/m2, HbA1c6%, age 30 years; patients with 25BMI30 kg/m2and HbA1c6%; patients with 25BMI30 kg/m2and HbA1c6%; patients with BMI30 kg/m2and HbA1c6% (+ Obesity - T2D) obese patients without T2D or prediabetes; patients with BMI30 kg/m2and newly-diagnosed T2D/prediabetes, HbA1c6%; patients with known history of T2D on glucose-lowering drugs with BMI30 kg/m2. Insulin, GLP-1, GIP were measured during glucose-tolerance test at 0, 30 and 120 minutes; insulin resistance (IR) was assessed by HOMA-IR. Results.Waist circumference was bigger in patients with obesity despite their metabolic profile comparing to patients without obesity (p0.001). Waist-to-hip ratio was similar in patients with different metabolic status. According to IR + Obesity - T2D group had intermediate position: IR was higher in that group comparing to people without obesity, but was less that in patients with obesity and HbA1c6% (p0.001). + Obesity - T2D group had the most potent baseline insulin secretion, assessed by НОМА-%band the highest postprandial secretion, measured by insulinogenic index among all patient groups with obesity (p0.001). There was no significant difference in GLP-1 secretion; GIP secretion was higher in patients with BMI30 kg/m2comparing to people with BMI30 kg/m2(p0.01).
Background Obesity, remaining a topical issue of modern medicine, leads to development of latent inflammation and insulin resistance in adipose tissue with subsequent development of type 2 diabetes mellitus (T2DM). Among patients with obesity, patients with obesity and normal glucose tolerance (NGT) are often encountered. In our study we have tested the hypothesis that low proliferative potential of adipose derived stromal cells (ADSC) associates with reduced formation of new fat depots, excess accumulation of fat in the functional adipocytes and their hypertrophy, resulting in fat inflammation and insulin resistance. Methods We screened two groups of obese patients with or without T2DM, matched for BMI, age, and duration of obesity to test the hypothesis that hypertrophy and decreased renewal of adipocytes may underlie transition from obesity to T2DM. All patients were matched for carbohydrate metabolism (fasting blood glucose level, glycated hemoglobin, HOMA-IR index and M-index). The subcutaneous and omental fat tissue biopsies were obtained during bariatric surgery from obese individuals with or without T2DM. The morphology and immunophenotype of subcutaneous and omental fat was assessed in frozen tissue sections. ADSC were isolated from both types of fat tissue biopsies and screened for morphology, proliferative potential and inflammatory status. Results The non-diabetic patients had normal carbohydratemetabolism andmoderate insulin resistancemeasured byHOMA-IR and hyperinsulinemic clamp (M-index),while T2DM patientswere extremely insulin resistant by both indexes. The average size of diabetic adipocytes was higher than that of non-diabetic in both subcutaneous and omental fat tissues, indicating adipocyte hypertrophy in T2DM. We have shown that ADSC from T2DM patients had significantly higher level of inflammation. According to measurement of p62 expression and LC3 modification we can say that ADSC from T2DM patients have less autophagy level compare with ADSC from NGT patients. Immunohistochemistry have shown that patients with T2DM have much more infiltration of CD68+-cells in subcutaneous and omental adipose tissue and immunophenotype (balance of M1-M2 macrophages) of adipose tissue at this patients shift toward inflammatory state. Conclusion These results suggest that decreased proliferation and increased hypertrophy of diabetic ADSC may lead to reduced insulin sensitivity via increased inflammation mediated by M1-macrophages and JNK1/2 pathway. Acknowledgement/Funding This work was supported by RSF grant #17-15-01435
ЦЕЛЬ: феномен сохранения нормальной толерантности к глюкозе при длительном анамнезе ожирения обнаруживается у 20-30% пациентов с ИМТ≥30 кг/м 2 . Причины сохранения нормогликемии у ряда пациентов с ожирением остаются неясными. Цель настоящей работы -охарактеризовать гормональный профиль и степень инсулинорезистентности (ИР) у пациентов с наличием или отсутствием сахарного диабета (СД) 2 типа при равной длительности ожирения. МАТЕРИАЛЫ И МЕТОДЫ: в исследование включено 86 пациентов с анамнезом ожирения более 15 лет: 44 -без нарушений углеводного обмена, 42 -с СД 2 типа. Всем пациентам проведено определение базального и постпрандиального уровня гормонов ЖКТ, вовлеченных в регуляцию углеводного обмена и веса: инсулина, глюкагона, грелина, ГПП-1, ГИП. Для расчета ИР был выполнен гиперинсулинемический эугликемический клэмп-тест, в ходе которого рассчитан М-индекс -показатель, отражающий количество поглощаемой глюкозы одним килограммом тела пациента в минуту (мг/кг в минуту) и определяющий степень тяжести ИР. Для статистических расчетов использовалась программа SPSS v.23. Для определения межгруппового различия использовался тест Манна-Уитни. РЕЗУЛЬТАТЫ: группы пациентов с нормальным углеводным обменом (НУО) и СД 2 типа были сопоставимы по возрасту, ИМТ, отношению ОТ/ОБ, длительности анамнеза ожирения. Медиана длительности СД 2 типа в соответствующей группе составила 9,0 лет [6,0; 12,0]. Гликированный гемоглобин в группе НУО составил 5,5% [5,3; 5,8], у пациентов с СД 2 типа -8% [7,2; 8,7]. Стимулированная секреция инсулина, глюкагона и гормонов инкретинового ряда у пациентов без анамнеза СД 2 определялась в ходе перорального глюкозотолерантного теста, у пациентов с СД 2 типа -в ходе теста со смешанной пищей. В группе пациентов с СД 2 по сравнению с группой НУО в ходе пищевой нагрузки отмечались следующие значимые различия (данные представлены в виде площади под кривой):
Active development of the "anti-aging medicine", attempts to slow down biological (including vascular) aging led to the creation of new pharmaceuticals including menopausal hormone therapy. The vascular wall protective mechanism of the hormones is not completely clear, but it was shown that natural estrogens are able to control the condition of the vascular wall, prevent platelet adhesion, control a range of metabolic and trophic and energy processes in the endothelium of the vascular wall, producing antithrombogenic factors, namely their inhibition contributes to the development of atherosclerosis. It is known that standard and low-dose estrogen may restore the impaired antithrombogenic potential of the vascular wall, provided its initial reduction does not exceed 20%. The issue of the role and possibilities of correction of the antithrombogenic activity of the vascular wall with ultra-low dose estradiol remained unresolved. As a "clinical model" for the study of this issue, we formed 2 groups of patients: in the study group patients received ultra-low dose estradiol plus dydrogesterone, subjects from the control group received beta-alanine. Three-year follow-up showed a decrease in antithrombogenic activity of the vascular wall in control subjects after 2 and 3 years of follow-up according to the M.V. Baluda's test versus subjects treated with ultra-low dose estrogen plus dydrogesterone. The decrease of the relative risk of reduction of the antithrombogenic activity of the vascular wall with the use of ultra-low dose estrogen plus dydrogesterone during the first two years was 2.3 times, and during the 3 years of follow-up 3.8 times versus control. Thus, prescribing only ultra-low dose estradiol plus dydrogesterone for patients with normal antithrombogenic activity of the vessel wall at baseline reliably lowers the risk of long-term reduction of antithrombogenic potential of the vascular wall.
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