[Clinical features and complication rates in type 2 diabetes mellitus clusters on five variables: glycated hemoglobin, age at diagnosis, body mass index, HOMA-IR, HOMA-B].

BACKGROUND: Diabetes mellitus (T2DM) is a serious medical and social problem. Now they are studying the possibility of a new stratification of diabetes. The possibility of cluster analysis for different durations of diabetes, in different cohorts to identify phenotypic clusters of T2DM and validation by reproducing clusters is relevant. AIM: Identify clusters of type 2 diabetes mellitus in patients with different disease duration based on five variables: HbA1c, age at diagnosis, BMI, HOMA-IR, HOMA-B and study the clinical features and complication rates in each cluster in the Novosibirsk region. MATERIALS AND METHODS: Cluster analysis of K-means was performed in 2131 patients with T2DM, aged 44 to 70 years, with a duration of diabetes of 6.42±5.66 years, living in the Novosibirsk region based on 5 variables - HbA1c, age at -diagnosis, BMI, HOMA-IR, HOMA-B. All patients a complete clinical and laboratory examination. The insulin resistance index in the HOMA (HOMA-IR, u) and the ß-cell function assessment index (HOMA-B) were calculated using the calculator -version 2.2.3 at www.dtu.ox.ac.uk. RESULTS: Cluster analysis revealed: Cluster 1 included 455 patients with preserved ß-cell function (HOMA-B 82.97±23.28%), moderate insulin resistance (HOMA-IR 5.57±4.72) and higher diastolic BP; Cluster 2 in 1658 patients with reduced function of ß-cells (HOMA-B 21.71±12.51%), the lowest indices of insulin resistance (HOMA-IR 3.50±2.48) and was characterized by a longer duration of diabetes, high fasting glycemia , HbA1c, higher eGFR and MAU, men compared with women had a 31% higher risk of developing diabetic neuropathy and 28% more diabetic nephropathy; Cluster 3 in 18 patients with high function of ß-cells (HOMA-B 228.53±63.32%), severe insulin resistance (HOMA-IR 6.92±4.77), features were high incidence of men, shorter duration of diabetes, lower fasting glycemia and HbA1c, lower diastolic BP and eGFR, high incidence of early development of diabetic retinopathy after 4.00±3.6 years. CONCLUSION: Cluster analysis in patients with different durations of diabetes mellitus confirmed the possibility of using cluster analysis to identify T2DM phenotypes in the Russian population. The clusters differed in the clinical characteristics of patients, the frequency and risk of diabetic complications. These results have potential value for early stratification of therapy.

Hypoglycemic syndrome in hepatic epithelioid hemangioendothelioma, successful treatment - liver transplantation from a living related donor.

Hypoglycemic syndrome occurs not only in endocrine diseases but can complicate the course of many somatic diseases and tumors of pancreatic and extra-pancreatic localization. Development of hypoglycemia in liver tumors is associated with a decrease in the volume of functioning liver tissue, increased consumption, and utilization of glucose by the tumor tissue, inhibition of gluconeogenesis and glycogenolysis, and secretion of insulin-like peptides. Hypoglycemia in liver tumors is rarely the first symptom of the disease and usually occurs in patients with large tumor sizes and symptoms of tumor intoxication. Epithelioid hemangiendothelioma of the liver is the primary malignant neoplasm from the group of mesenchymal tumors, it occurs less than in 1% of cases of all malignant neoplasms of the liver. The clinical course of epithelioid hemangiendothelioma of the liver is highly variable. There are slowly and rapidly progressing variants. The diagnosis is based on the results of histological and immunohistochemical examination of the postoperative material. In the literature there is no description of hypoglycemia in epithelioid hemangiendothelioma. We report a patient with severe hypoglycemic syndrome, which was due to an epithelioid hemangioendothelioma of the liver. Pharmacological treatment of hypoglycemia was ineffective. The presence of massive bilobar tumor made it impossible to use a liver resection. Hepatectomy with living related liver transplantation was life-saving procedure and made it possible to eliminate hypoglycemia.

[Primary hyperparathyroidism in Russia according to the registry].

BACKGROUND: There are no large-scale epidemiological studies on primary hyperparathyroidism (PHPT) in Russia. The high prevalence of the disease, the high risk of disability and death in this cohort of patients requires the study of the epidemiological and clinical structure of PHPT to determine the extent of medical care. AIM: Evaluate the frequency of PHPT detection and characterize its clinical forms in Russia using an online registry. METHODS: The object of the study is the database of the State Register of Patients with PHPT 1914 patients from 71 regions of the Russian Federation. New cases of the disease, as well as dynamic indicators are recorded when patients visit outpatient clinics or medical institutions. The analysis of data made at the end of December 2017 was carried out. The following parameters were evaluated: demographic and clinical indicators; indicators of phosphorus-calcium metabolism, the main forms of PHPT and its course, the primary characteristic of PHPT in hereditary syndromes and parathyroid carcinoma. Results are presented as mean and standard deviations, or medians and quartiles; descriptive statistics of qualitative attributes absolute and relative frequencies. RESULTS: the total number of patients with PHPT in the registry on 31 of December 2017 was 1914 cases (0.001% of the population of the Russian Federation). Identification of PHPT was 1.3 cases per 100 thousand of the population in Russia, 7.6 cases in Moscow, 6.1 cases per 100 thousand in the Moscow region. The average age of patients at the time of diagnosis was 55.6 10 years. The active phase of the disease was registered in 84.6% of patients (1620/1914), most of whom had a symptomatic PHPT 67.1% (1087/1620), and 32.9% a asymptomatic disease (533/1620). Symptomatic disease with visceral complications was detected in 15.8% cases (172/1087), with bone complications in 48.4% (526/1087). The mixed form of the disease was detected in 35.8% of patients with manifest form (389/1087). Normocalcemic variant PHPT (nPHPT) was registered in 14.5% cases (234/1620). Sporadic PHPT occurs in 83% of cases (1592/1914). 326 patients (17%) had a suspicion for hereditary form of the disease: average age was 31.2 12.3 years. A genetic analysis was conducted in 61 patients (3.2%): showed the mutation in the MEN1 gene in 2.9% of cases (55/1914) and the mutation in the CDC73 gene in 0.3% of cases (6/1914) (HPT-JT syndrome). Parathyroid carcinoma was confirmed in 1.8% of all patients (35/1914). Surgical treatment was performed in 64.5% of patients (1234/1914). Remission was achieved in 94% of cases (1160/1234), in 6% of cases relapse after surgical treatment or persistence of PHPT was recorded. CONCLUSION: detection of PHPT in the Russian Federation raised in comparison to 2016, which is associated with an active start of registration of patients in the regions. At this stage, it is necessary to modify the principles of registration and control, to make a platform for gathering information and calculating the necessary volumes of medical care for PHPT patients.

[Urinary excretion of fibrogenic and antifibrotic growth factors in type 1 diabetic patients: the interrelationship with diabetic nephropathy].

AIM: To assess the relation between urinary excretion of profibrotic and antifibrotic growth factors, albuminuria and glomerular fibrosis in type 1 diabetic patients. MATERIALS AND METHODS: 64 patients with diabetes were examined, including 25 ones with normal albumin excretion rate (AER), 30 microalbuminuric and 9 macroalbuminuric patients. Urinary excretion of type IV collagen, transforming growth factor-beta 1] (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha), fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF) and bone morphogenetic protein-7 (BMP-7) was determined by ELISA and compared to control (10 healthy subjects). Renal biopsy specimens were assessed in 7 patients with normal AER and in 14 microalbuminuric patients. RESULTS: Type IV collagen, TGF-beta1 and TNF-alpha excretion was increased significantly in patients with micro- and macroalbuminuria as compared to control (all p<0.05). Excretion of FGF-2 was increased in macroalbuminuric patients only (p=0.003). No marked changes in excretion of antifibrotic growth factors (HGF and BMP-7) were observed. TNF-alpha and FGF-2 correlated positively with urinary type IV collagen (r=0.37 and r=0.31, respectively). The presence of glomerular fibrosis in renal biopsy specimens was associated with higher excretion of TGF-beta1, TNF-alpha and FGF-2 (all p<0.05). CONCLUSION: The results suggest that unbalance between profibrotic and antifibrotic growth factors in the kidneys plays an important role in pathogenesis of diabetic nephropathy. Urinary TGF-beta1, TNF-alpha and FGF-2 may offer new possibilities for detection of renal fibrosis in diabetic patients.

[Obesity and chronic kidney disease].

Obesity and overweight are now characterized as epidemics. It is shown that body overweight is associated with functional and structural changes in the kidneys. The results of epidemiological studies indicate that obesity can be the risk factor of chronic kidney disease (CKD) irrespective of the presence or absence of diabetes, arterial hypertension and other comorbidities. Manifestations of renal pathology in obese persons include microalbuminuria and proteinuria, hyperfiltration or impaired renal function. Glomerulomegaly and focal segmental glomerulosclerosis are the most typical structural signs of obesity-related nephropathy. More evidence is accumulated on the link between CKD in obesity and abnormalities in adypokine secretion (hyperleptinemia, lack of adiponectin), activation of rennin-angiotensin system, chronic inflammation, endothelial dysfunction, lipid accumulation, impaired renal hemodynamics and diminished nephron number related to body mass. A decrease of body weight following lifestyle modification or bariatric surgery leads to reduction in albuminuria and eliminates hyperfiltration in obese subjects. Thus, prevention and treatment of obesity may reduce CKD incidence in general population.

[Treatment of diabetes mellitus in dialysis patients].

Diabetes mellitus is a key cause of chronic kidney disease (CKD) in developed contries. Disorders of glucose metabolism regulation in CKD are explained by insulin resistance, decreased insulin clearance, weak hormonal response to hypoglycemia. These disturbances appear in inhibition of glomerular filtration rate under 60 ml/min. Hemodialysis treatment raises the risk of hypoglycemic conditions due to glucose elimination from blood circulation during the sessions and improvement of sensitivity to insulin. Use of glucose-containing solutions for dialysis, step-by-step achievement of normoglycemia, monitoring of blood glucose during dialysis sessions are recommended for reducing the risk of hypoglycemic conditions in DM patients on dialysis. Insulin is the most common preparation in the treatment with use of hemodialysis in diabetics. Tiasolidindions (pioglitason, rosiglitason) and analogues of dipeptidilpeptidase of type IV (sitagliptin, saxagliptin) can be administered in type 2 diabetics without insulin insufficiency. As solutions for peritoneal dialysis contain glucose, such dialysis may entail such metabolic complications as fat accumulation, metabolic syndrome. Intraperitoneal introduction of insulin allows avoiding hyperinsulinemia and in some cases to decrease the risk of hypoglycemia. Side effects of intraperitoneal insulin administration are significant absorption of insulin on the surface of the systems for intraperitoneal dialysis, higher rate of peritonitis, subcapsular hepatic steatosis. In the absence of controlled studies the mode of insulin administration in patients on peritoneal dialysis should be chosen individually basing on potential risk and benefit for the patient and experience of the dialysis center. It should be remembered that adequate sugar-reducing treatment is necessary for prevention of complications and prolongation of survival of diabetics on dialysis.

[Clinical and metabolic risk factors for cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus].

AIM: to study clinical and metabolic risk factors for cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: One hundred and fifty-seven patients were examined. According to the results of ECG tests and cardiointervalography, the patients were divided into 2 groups: 1) 45 patients without cardiovascular autonomic neuropathy; 2) 112 patients with this condition. RESULTS: The T2DM patients with cardiovascular autonomic neuropathy significantly differed from those without autonomic disorders in DM duration, insulin level, insulin resistance indices (HOMA-IR, FIRI), atherogenicity coefficient, and high-density lipoprotein levels. The glycated hemoglobin level of more than 9% affected the values of autonomic ECG tests. CONCLUSION: In patients with T2DM, the development of cardiovascular autonomic neuropathy is affected by not only the duration of DM and the decompensation of carbohydrate metabolism, but also by hyperinsulinemia and insulin resistance, the low level of high-density lipoproteins, and the high coefficient of atherogenicity.

[The antioxidant Dibicor in the treatment of vascular complications of type 2 diabetes].

The effects of Dibicor (taurine) were studied in 20 patients with type 2 diabetes (T2D) with a disease duration of 1 to 9 years and a mean body weight of 93.8±16 kg who received concomitant therapy (monotherapy with sulfonylurea (n = 7), novonorm (n = 1), sulfonylurea with metformin (n = 7); one patient was on diet therapy). Addition of Dibicor to the therapy following 3 months caused a statistically significant reduction in fasting and postprandial glycemia (from 7.9 to 6.3 mmol/l and from 7.9 to 6.9 mmol/l, respectively). Glycated hemoglobin decreased from 7.8 to 7.05% (p = 0.062). Lipid metabolic parameters improved after 3-month course of therapy. There was also a statistically significant fall in microalbuminuria from 0.082 to 0.054 g/day (p = 0.042). The administration of Dibicor can significantly improve T2D compensation.

[Urinary excretion of proinflammatory cytokines and transforming growth factor beta at early stages of diabetic nephropathy].

AIM: To examine correlations between urine excretion of proinflammatory cytokines, transforming growth factor beta (TGF-b) and changes in renal structure and function, quality of glycemia control in patients with type 1 diabetes mellitus. MATERIAL AND METHODS: Urinary excretion of interleukine 1-beta (IL-1b), monocytic chemoattractive protein-1 (MCP-1), RANTES and TGF-b was measured with enzyme immunoassay in 57 patients including 22 patients with normal albuminuria, 23--with microalbuminuria, 12--with macroalbuminuria. Creatinine clearance was subnormal in 8 patients with macroalbuminuria. The control group consisted of 10 healthy persons. Morphological examination of renal biopsies was performed in 8 patients with normoalbuminuria and 10 patients with microalbuminuria. RESULTS: Patients with normoalbuminuria had excretion of MCP-1 significantly higher than in controls. Microalbuminuria patients showed high excretion of IL-1b, MCP-1 and TGF-b. Excretion of IL-1b, MCP-1, RANTES and TGF-b in patients with macroalbuminuria was higher than in controls and other groups of patients. Excretion of cytokines and TGFb correlated inversely with glomerular filtration rate and hemoglobin level. Positive correlations were detected between excretion of IL-1b, MCP-1, TGFb and glycated hemoglobin A(1c). In patients with normo- and microalbuminuria cytokine and TGFb excretion correlated with thickness of glomerular and glomerular basal membrane. CD68-positive macrophages were detected in the intersticium of 1 patient with normoalbuminuria and 6 patients with microalbuminuria. CONCLUSION: Urinary excretion of proinflammatory cytokines and TGF-b was elevated in patients with DM-1 having micro- and macroalbuminuria suggesting participation of inflammation in development of diabetic nephropathy.

[Hyperhomocysteinemia in coronary artery disease and hemostasis disorders in patients with type 2 diabetes mellitus].

The purpose of the study was to evaluate the effects of hyperhomocysteinemia (HHC) on vascular-thrombocyte and coagulation hemostasis and the development of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM2). DM 2 patients with or without CAD were examined; high incidence of HHC (40.3%) was revealed. The level of homocysteine was significantly higher in DM2 patients with CAD vs. non-CAD subjects. Among patients with DM2 and CAD the level of the amino acid was elevated in 77.1% of cases with a history of myocardial infarction. In patients with DM2, CAD, and HHC, vascular-thrombocyte hemostasis factors were found to be hyperactive, while anticoagulatory ones were suppressed. These changes in the hemostatic system in HHC increase the probability of thrombus formation and CAD progress.

[Renal excretion of insulin-like growth factor 1 and vascular endothelial growth factor in patients with type 1 diabetes with nephropathy].

Thе aim of the investigation was to study the urinary excretion of insulin-like growth factor 1 (ICF-1) and vascular endothelial growth factor (VEGF) at different stages of nephropathy in 57 patients with type 1 diabetes, including 22 patients with normal albuminuria, 23 with microalbuminuria, and 12 with proteinuria. The excretion of IGF-1 and VEGF was increased in the microalbu-minuric and proteinuric patients as compared with the controls (1GF-1: p = 0.004 and p = 0.00005; VEGF: p = 0.06 and p = 0.02). That of growth factors inversely correlated with glomerular filtration rates and hemoglobin levels (IGF-1: r = -0.43 and r = -0.41; VEGF: r = -0.14 and r - -0.27). In the normo- and microalbuminuric patients, IGF-1 excretion was associated with the thickness of glomerular and tubular basement membranes (r = 0.59 and r = 0.53, respectively) and with the number of podocytic foot processes (r = -0.69). VEGF correlated with the volume of the mesangium (r = 0.69) and the thickness of the glomerular basement membrane (r = 0.53). IGF-1 rather than VEGF positively correlated with HbA1c (r = 0.47 and r = 0.02). It has been concluded that in patients with type I diabetes, the increased urinary excretion of IGF-1 and VEGF is associated with the development of nephropathy and may be used for the early diagnosis of this complication.

[Immune inflammatory mechanisms in the development of diabetic nephropathy].

Diabetic nephropathy has long been attributed to non-immune and non-inflammatory lesions of the kidneys, considering metabolic and hemodynamic factors to be the main reason for its development. However, in recent years, the effect of inflammation on the development of diabetic nephrosclerosis has been established. This served as the basis for the further development of the concept of the pathogenesis of diabetic nephropathy, the development of methods for its diagnosis and treatment.

[Early renal changes in type 1 diabetes].

The relationships between renal structural abnormalities, metabolic, and hemodynamic changes were studied in 35 type diabetic patients with normal creatinine clearance. Sixteen patients had normal urinary albumin excretion (UAE) rates, 17 were microalbuminuric and 2 had proteinuria (0.68 and 0.8 g/day). Light and electron microscopy revealed the early stages of diffuse glomerulosclerosis, tubular dystrophy and atrophy, intestinal and arteriolar sclerosis in the renal biopsy specimens of the examinees. Increased UAE was associated with the reduced percent of glomerular podocytes, the thickening and fusion of small podocytic processes, the increased thickness of the glomerular and tubular basement membrane, the reduced number of endothelial fenestrae, the increased fractional volume of the mesangium, perioglomerular sclerosis, global sclerosis of some glomeruli, tubular endothelial atrophy, and intestinal and arteriolar sclerosis. Clycemic control, diabetes duration, albumin excretion rate, and blood pressure are the predictors of early renal structural changes.

[Urinary hydroxyproline excretion and glomerular location of collagen III, IV, and VI in patients with type 1 diabetes mellitus concurrent with nephropathy].

The study was undertaken to investigate the metabolism of collagen and the accumulation of collagens III, IV, and VI in the glomeruli in patients with type 1 diabetes mellitus (DM) and early-stage nephropathies. The urinary excretion of peptide-bound and free hydroxyproline was determined in 57 patients with DM and 15 healthy individuals. Immunohistochemical investigations of their renal biopsy specimens were performed in 17 patients, by using monoclonal antibodies to collagens III, IV, and VI. The kidneys from 70 healthy individuals who had died due accidents served as a control. A significantly increased urinary excretion of peptide-bound hydroxyproline was found in patients with DM and micro- and macroalbuminuria. There was an excessive glomerular accumulation of collagens IV and VI in 8 and 7 patients, respectively. Interstitial collagen HI was detected in the glomeruli of 9 patients while it was absent in the controls. The findings show the high rates of collagen metabolism and collagens III, IV, and VI accumulation in the glomeruli of patients with type 1 DM and early-stage diabetic nephropathy.

[Collagen metabolic changes in diabetic nephropathy].

Diabetic nephropathy is one of the most severe and prognostically unfavorable complications of diabetes. The mechanisms of development of diabetic nephropathy remain the subject of intensive study. Currently, the leading role in the development of this complication is assigned to hyperglycemia and its associated metabolic disorders. The latter include collagen metabolic disorders.

[The diurnal blood pressure and the EchoCG parameters of the left ventricle in patients with diabetic nephropathy]. / Sutochnyi profil' arterial'nogo davleniia i EkhoKG-parametry levogo zheludochka u bol'nykh diabeticheskoi nefropatiei.

The purpose of the study was to examine the geometry of the left ventricle (LV) in patients with type 1 diabetes mellitus (DM) in relation to the 24-hour profile of blood pressure (BP) and urinary albumin excretion. The study covered 60 patients with type 1 DM and normal creatinine clearance, including 20 patients with normal albuminuria, 23 with microalbuminuria, and 17 with proteinuria. 24-hour BP monitoring was performed oscillometrically; myocardial structural parameters were studied by echoCG. LV hypertrophy (LVH) was found in 1 patient with normal albuminuria and in 8 with proteinuria (5, 30.4, and 47%, respectively; chi2 = 9.3; p = 0.09). The frequency of concentric and eccentric types of LVH was equal. In patients with a lower nocturnal BP decrease, the LV myocardial mass index (LVMMI) and relative posterior wall thickness (RPWT) were higher than those in other patients (LVMMI, 120.8 +/- 24.6 and 95.0 +/- 23.1 g/m2, respectively; p < 0.001; RPWT, 0.35 +/- 0.06 and 0.31 +/- 0.06, respectively, p = 0.013). Multifactorial stepwise regression analysis has indicated that age, male sex, and proneinuria directly affected LVMMI (R2 = 0.70; p < 0.001). Diastolic BP, autonomic neuropathy, and hemoglobin levels were found to be independent predictors of RPWT (R2 = 0.70; p < 0.009). The findings suggest that there is a close relationship between diabetic neuropathy and LV remodeling in patients with type 1 DM. This relationship may be operative via factors, such as arterial hypertension, altered diurnal BP profile, autonomic neuropathy, and anemia.

[The interferon status in diabetes mellitus]. / Interferonovyi status pri sakharnom diabete.

The investigation of interferon status in 54 diabetes mellitus patients gave evidence for high levels of blood serum interferon, leukocyte inhibition of alpha-interferon production against moderate synthesis of gamma interferon. More marked alterations in the interferon status were registered in severe insulin-dependent diabetes mellitus complicated by angiopathies and running more than 5 years. Compensation of metabolic processes was not relevant to interferon status. Variations in the levels of alpha- and gamma-interferons in the course ob observation occurred in 30% of the patients.

[The effect of various inducers on interferon-synthesizing activity of leukocytes in patients with diabetes mellitus]. / Vliianie razlichnykh induktorov na interferonsinteziruiushchuiu aktivnost' leikotsitov bol'nykh sakharnym diabetom.

The results of the study of interferon response of leukocytes in patients with diabetes mellitus (DM) with three inducers: Newcastle disease virus (NDV), poludan, and dipyridamole are presented. Different patterns of interferon production in patients with DM and normal subjects were shown. Dipyridamole and NDV induced high interferon levels in patients with DM which allow it to be recommended as an additional therapeutic means.