According to the International Diabetes Federation, 10.9 million people have diabetes mellitus (DM) in Russia; however, only up to 4 million are registered. In addition, 11.9 million people have impaired glucose tolerance and impaired fasting glucose levels [1].
One of the significant risk factors for type 2 DM (T2DM) is obesity, which increases insulin resistance (IR). IR is the major pathogenetic link to T2DM.
According to current concepts, there are three types of adipose tissue: white adipose tissue (WAT), brown adipose tissue (BAT) and ?beige?, of which the last two types have a thermogenic function. Some research results have revealed the main stages in the development of adipocytes; however, there is no general consensus regarding the development of ?beige? adipocytes. Furthermore, the biology of BAT and ?beige? adipose tissue is currently being intensively investigated, and some key transcription factors, signalling pathways and hormones that promote the development and activation of these tissues have been identified. The most discussed hormones are irisin and fibroblast growth factor 21, which have established positive effects on BAT and ?beige? adipose tissue with regard to carbohydrate, lipid and energy metabolism. The primary imaging techniques used to investigate BAT are PET-CT with 18F-fluorodeoxyglucose and magnetic resonance spectroscopy.
With respect to the current obesity epidemic and associated diseases, including T2DM, there is a growing interest in investigating adipogenesis and the possibility of altering this process. BAT and ?beige? adipose tissue may be targets for developing drugs directed against obesity and T2DM.

Adhesive capsulitis (АС) has an incidence of 20% in diabetic patients. The tightening of the shoulder capsule ("freezing") can cause gradually increasing limitation in active and passive range of motion (ROM) of shoulder. Consequences of the increasing limitations are reduced quality of life and patient disability. It is thought that AC is a self-limiting disorder that resolves in 1?2.5 years in most cases. However, new clinical data indicate both long-term persistent pain and residual loss of motion in 10% of patients without diabetes and in 85% of patients with diabetes. In this review, we summarize the results from different clinical trials in which risk factors and pathogenesis of AC in diabetic patients as well as the diagnosis and efficacy of various methods for the treatment of AC were examined.

Coronary artery bypass grafting (CABG) is the main method used for myocardial revascularisation in patients with diabetes mellitus (DM), and determining the factors affecting the outcomes of CABG in these patients is important.
Objective.
To identify risk factors for in-hospital mortality after coronary artery surgery (CABG) for patients with and without type 2 diabetes mellitus (T2DM).
Methods.
A retrospective analysis of the medical records of patients who underwent CABG from 2006 to 2009 was conducted. From these, 317 patients with T2DM were selected (median age: 59,0 years). As a control group, 350 patients (median age: 58,0 years) without diabetes or pre-diabetes, who were matched by sex, age and CABG characteristics, were selected. Logistic regression models were used to identify factors possibly associated with in-hospital mortality.
Results.
There were no group differences for the frequency of postoperative complications and in-hospital mortality (p >0,05). During the early postoperative period, 5 (1,6%) diabetic and 7 (2,0%) non-diabetic patients died (p=0,682). By the logistic regression analysis, T2DM did not predict patient mortality (p=0,458). Among the patients with T2DM, a risk of death was associated with a stroke history (OR 21,661; 95% CI 1,701-76,521; р=0,013), and a decreased glomerular filtration rate (GFR) as estimated by the CKD-EPI equation (OR 1,512 per 5 ml/min/1,73m2.
 decrease; 95% CI 1,017-2,257; р=0,048), independent of gender, age or triple-vessel and left-main disease. By multivariate analysis for the non-diabetic patients, the risk of death increased by more than 10 times because of reinfarction (OR=10,272; 95% CI: 1,258?56,163; p=0,029) and increased by 6,8 times with an increase in preoperative fibrinogen levels of 1 g/l (OR=6,802; 95% CI: 1,283?35,714; p=0,024), independent of gender, age, smoking or mitral valve regurgitation.
Conclusions.
T2DM was not a predictor of death during the early period after CABG. For the diabetic patients, independent predictors of in-hospital mortality after CABG were stroke history and reduced GFR. For the patients without T2DM, the independent predictors were reinfarction and preoperative fibrinogen levels.

Aim.
To investigate the mobilisation of endothelial progenitor cells (EPC) in patients with type 2 diabetes mellitus (T2DM) after endovascular interventions for coronary and peripheral arteries.
Materials and Methods.
The levels of EPC in peripheral blood were determined by flow cytometry in 42 patients prior to endovascular intervention and 2?4 days after surgery. EPC were defined as CD34+ VEGFR2+ CD45- and CD34+ CD133+CD45- cells. Twenty-three patients with T2DM were included in group 1, and 19 patients without metabolic disorders were included in group 2.
Results.
The levels of EPC in the peripheral blood of patients with T2DM before and after endovascular interventions were not significantly different. In the subgroup of patients without TDM2, the levels of CD34+VEGFR2 +CD45- cells increased after surgery to 55,5% (p <0,01), and the levels of CD34 + CD133 + CD45- cells increased to 27,7% (p <0,05). After endovascular intervention for the subgroup of patients with T2DM and with the levels of HbA_1c ?7,5%, the levels of CD34+VEGFR2+CD45- cells increased to 46,6% (p=0,01), and the levels of CD34+CD133+CD45- cells increased to 40,3 % (p=0,006) compared with the subgroup of patients with T2DM and with HbA_1c levels of?7,5%.
Conclusion.
The patients with T2DM displayed alterations in EPC mobilisation after endovascular interventions. In addition, the EPC level changes were dependent on glycaemic control. Thus, in the subgroup of patients with T2DM and with good glycaemic control (HbA_1c ?7,5%), the EPC levels were significantly higher after endovascular interventions.

Aims.
The aim of the present study was to investigate the role of chronic low-grade inflammation in the development of the diabetic neuropathy and the possibility of its medical treatment with fenofibrate (145 mg/day).
Materials and Methods.
This trial included 60 patients with type 2 diabetes mellitus. The serum levels of several factors were measured: tumour necrosis factor-? (TNF-?), interleukin-1? (IL-1?), interleukin-6 (IL-6), C-reactive protein (CRP), markers of oxidative stress (malondialdehyde levels), haemostasis, uric acid, glycaemic and lipid profile and the peripheral status (electromyography, total symptom score [TSS] and neuropathy impairment score in the lower limbs [NIS-LL]). Follow-up was at 24 weeks.
Results.
A significant negative correlation was found between the excitation rate of the sural nerve and levels of TNF, IL-6 and CRP (p <0.05). A number of changes were observed in the group of patients treated with fenofibrate (145 mg, daily) for 24 weeks: Levels of TNF decreased from 9.6?3.68 to 8.1?3.02 pg/ml (p <0.05), IL-6 decreased from 3.3?1.69 to 2.7?1.28 pg/ml (p <0.05), CRP decreased from 5.6?3.63 to 3.1?2.34 mg/l (p <0.05), thiobarbituric acid (TBARS) decreased from 3.1?089 to 2.6?1.21 mmol/l (p >0.05), uric acid decreased from 364?69.85 to 296.8?87.3 mmol/l (p <0.05) and fibrinogen decreased from 4.1?0.59 to 3.4?0.71 g/l (p <0.05). Improved levels of total cholesterol, triglycerides, HDL, VLDL and atherogenic index (p <0.05) were observed. Significantly increased M-wave in extensor digitorum brevis muscle was observed, from 5.25?2.31 to 6.3?3.14 mV (p <0.05). In addition, TSS changed from 9.55?1.53 to 7.28?1.26 (p <0.005) and NIS-LL changed from 10.12?2.05 to 8.24?1.68 (p <0.05).
Conclusion.
A correlation was found between EMG parameters and serum levels of inflammatory markers. Fenofibrate significantly reduced levels of inflammatory cytokines and improved lipid and purine metabolism as well as the function of the peripheral nervous system.

Diabetic macular oedema (DMO) is the leading cause of vision loss and disability in working-age people with diabetes mellitus.
This literature review describes pathogenetic mechanisms, concepts, diagnostic techniques and capabilities of novel laser technologies in the treatment of DMO. In recent years, the role of cytokines and growth factors in retinal neurodegeneration has been actively investigated. Modern diagnostic techniques for the treatment of diabetic macular oedema, in addition to conventional techniques, include optical coherence tomography, autofluorescence and microperimetry. These techniques allow the visualization of retinal structures and its functional condition, and they can be used to detect DMO at early stages and to provide the most effective treatment. The evolution of laser technology resulted in the formation of new approaches to DMO treatment. Subthreshold micropulse laser (SML) treatment, in conjunction with conventional photocoagulation, has pronounced therapeutic effects. SML shows high selectivity towards retinal pigment epithelium while avoiding neurosensory retina injury. Owing to the chronic nature of DMO and pathogenetic mechanisms recently discovered, further elaboration of the SML technique appears to be a very promising treatment.

Long-term offloading is the key factor in the treatment of the acute stage of Charcot foot. The indication for remobilization and transition of the affected foot to weight-bearing activities is believed to be based on two factors: the absence of the clinical signs of inflammation and results of the objective diagnostic tests. At the present time, consensus about appropriate methods sufficient for initiating weight-bearing activities after immobilization is absent. This paper discusses current data on clinical and laboratory tests and methods and describes their advantages and disadvantages.

Aim.
The purpose of this study was to assess the clinical efficacy, safety and consumer properties of ankle-foot pneumoorthosis with a HAS-337 TM Orlett compared with non-removable total contact cast (TCC) immobilization.
Materials and methods.
Our study included 40 patients with diabetes mellitus type 1 (DM1) and type 2 (DM2) with neuropathic diabetic foot syndrome and chronic uninfected wounds of the plantar surface of the forefoot, with wound duration of at least 3 weeks, wound areas not less than 1 cm2 and wound depths not more than stage II based on Wagner?s classification. We excluded patients with infected wounds, osteomyelitis, Charcot osteoarthropathy or peripheral vascular disease. Our test group included 20 patients who received pressure off-load using ankle-foot pneumoorthosis with a HAS-337 TM Orlett. For a control group (n = 20), pressure off-load was achieved using TCC immobilization. Both groups were comparable with regard to age, gender, duration and degree of diabetes compensation and by original wound defect sizes (p >0.05). The study duration was 6 months. Plantar pressure was measured inside the orthosis or TCC and was compared with test shoe measurements. Our major criteria for pressure relief were reduced pressures in the wound area and the whole foot and the rate of wound healing.
Results.
At the end of the 6-month period, complete healing of all ulcers was achieved. The average healing time was 46.1?19.0 days for the test group and was 48.3?20.5 days for the control group (p >0.05). Two patients who wore pneumoorthosis with HAS-337 were discontinued upon patient request.
With pneumoorthosis, the maximum peak pressure on the foot and wound defect areas was reduced by 26% and 57%, respectively. The pressure/time integral decreased on average by 41% (p >0.05). Furthermore, in the midfoot area with pneumoorthosis, the maximum pressure increased by 48% and the pressure/time integral increased by 47%.
Conclusions.
Using pneumoorthosis with HAS-337 was an effective and safe method for pressure off-load, resulting in 100% healing of uninfected neuropathic ulcers of the plantar surface of the forefoot. However, pneumoorthosis with HAS-337 is not recommended for those patients with wound defects in the midfoot and heel areas.

Optimizing treatments for type 2 diabetes mellitus (T2DM) remains an urgent issue. In addition to T2DM treatment strategies, such as glycaemic goals (glucose and glycated haemoglobin ? HbА_1c) among different patient populations, the influence of glycaemic variability (GV) on the prognosis of patients with T2DM is also important. According to recent data, GV is associated with cardiovascular complications arising from T2DM. However, although the influence of GV on the development of vascular complications arising from diabetes and underlying mechanisms has been extensively investigated, few studies have investigated the effects of different glucose-lowering medications on GV, and there are even fewer reviews of this topic. This type of analysis is highly relevant, particularly because new classes of antidiabetic medications with potent glucose-dependent insulinotropic effects have been developed. These include groups of drugs that mimic or enhance incretin activity, such as glucagon-like peptide (GLP)-1 analogues/mimetics and dipeptidyl peptidase (DPP)-4 inhibitors. A glucose-dependent mechanism suggests that these groups of antidiabetic medications have beneficial effects on GV. Thus, the current study focusses on the comparative analysis of drugs based on their incretin effects (GLP-1 analogues/mimetics and DPP-4 inhibitors) and оther antidiabetic medications with regard to GV in the patients with T2DM.

Current treatment strategies for type 2 diabetes mellitus (T2DM) are based on using safe and effective hypoglycaemic agents for preventing diabetic vascular complications and reducing the risks associated with weight gain and hypoglycaemia. These goals may be achieved using new agents with a fundamentally new mechanism of action: inhibitors of dipeptidyl peptidase-4 (DPP-4i). However, the wide distribution of this enzyme in the body is associated with extraglycaemic DPP-4i effects, both positive and negative. Thus, it is important to develop and implement new DPP-4i agents for clinical practice.
Aim.
To investigate the efficacy and safety of a novel DPP-4i, gosogliptin, for use as monotherapy and in combination with metformin vs. vildagliptin as monotherapy and in combination with metformin for patients with drug-naive type 2 diabetes in a multicentre, open, randomized clinical trial.
Materials and methods.
We enrolled 299 drug-naive type 2 diabetes patients; 149 patients were randomized to receive gosogliptin and 150 patients received tovildagliptin. These groups had similar baseline characteristics. After randomization, 12 weeks of monotherapy was administered to both groups. Further, it was decided to continue the monotherapy or in combination with metformin, depending on each patient. The results after the first 12 weeks are presented in this paper.
Results.
After 12 weeks of monotherapy, HbA_1c levels decreased significantly from 8.61% to 7.41% (p <0.05) in the gosogliptin group and from 8.7% to 7.34% (p <0.05) in the vildagliptin group; these changes were not significantly different between these groups. Target HbA_1c of ?7.0% was achieved for 59 patients (41%) who took gosogliptin and 66 patients (44%) who took vildagliptin (p=0.53). After 12 weeks of monotherapy, 11 episodes of mild hypoglycaemia occurred (7 on gosogliptin and 4 on vildagliptin), without clinical manifestations of blood glucose levels of <3.9 mmol/l based on metre readings. Only 14 adverse events (7 patients in each group) were assessed as ?related to? or ?probably related to? gosogliptin or vildagliptin.
Conclusion.
Our preliminary monotherapy study showed comparable efficacy and safety profiles for gosogliptin and vildagliptin.

Aim.
Glucose variability (GV) and hypoglycaemia frequency and duration, depending on cardiovascular autonomic dysfunction, in children and adolescents with type 1 diabetes mellitus (T1DM) were evaluated.
Materials and methods.
One hundred and thirty T1DM patients, aged 6?18 years, were included in this study. The study included 3 tests:.

1. continuous glucose monitoring (CGM) with GV evaluation, frequency and duration of hypoglycaemia;
2. 24-h ECG monitoring with automatic calculation of QTc interval and heart rate variability (HRV) parameters;
3. cardiovascular autonomic tests.

Results.
The estimated prevalence of cardiovascular autonomic neuropathy (CAN) was 19.2%. CAN positive (CAN+) patients had lower values from cardiovascular autonomic tests and HRV and longer QTc intervals compared with CAN negative (CAN-) patients (p <0.05). The median of glucose levels was independent of CAN. GV as well as time spent in hypoglycaemia (<3.9 mmol/l) were increased in CAN+ patients, but not the duration of hyperglycaemia (>10 mmol/l) (p <0.05). In CAN+ patients, the frequency and duration of hypoglycaemia were higher compared with CAN- patients (p <0.05). GV and hypoglycaemia were positively associated with autonomic dysfunction in multiple regression models (p <0.05).
Conclusion.
In this study, the presence of CAN was associated with increased GV and higher hypoglycaemia frequency and duration. This data suggest that GV and/or hypoglycaemia may contribute to impaired cardiovascular autonomic function. This can have an impact on the determination of individual blood glucose targets in patients with T1DM and CAN.

Aim.
We evaluated the clinical and functional characteristics of gastroesophageal reflux disease (GERD) in adolescents with a cardiac form of diabetic autonomic neuropathy.
Patients and methods.
Fifty-two adolescents, aged 12?17 years, with type 1 diabetes were studied. Patients were divided into two groups according to the results of two autonomic tests (cardiointervalography and Valsalva test). Group 1 included 14 adolescents with a cardiac form of diabetic autonomic neuropathy. Group 2 included 38 controls. Oesophageal pH parameters were monitored over 24 h using a Gastroscan-24. The 24-h period was divided into day-time (08:00?22:00) and night-time (22:00?08:00) periods to eliminate the influence of exogenous factors (such as eating, physical activity and change of body position) on the oesophageal kinetic function.
Results.
Pathological gastroesophageal reflux occurred more frequently in Group 1 (78.5%) than in Group 2 (36.8%; p=0.018). Heartburn was experienced by 14.3% of the patients in Group 1 and generally occurred with similar frequency in the two groups (p=0.91). The daily amount of pathological acid reflux in Group 1 (86 [62?141]) was higher versus Group 2 (52.5 [24?108]; p=0.047) that was associated with night-time reflux in Group 1. A correlation analysis demonstrated the increase of frequency and intensity of the acid reflux due to development of parasympathetic insufficiency.
Conclusion.
Diabetic autonomic neuropathy in adolescents with type 1 diabetes appears to be a significant risk factor for the development of pathological subclinical GERD with altered daily pattern.

Glargine became the first long-acting insulin analogue. Glargine was designed to meet basal insulin requirements throughout the day with a single injection. Pharmacokinetics of insulin glargine is characterized by biotransformation into metabolites M1 and M2 that transforms the B chain of glargine so it is similar to the B chain of human insulin. Plasma concentrations of active M1 and M2 metabolites have no pronounced peaks during the day, resulting in lower glucose variability and hypoglycaemia risk when compared with NPH insulin. The metabolic activities of M1 and M2 metabolites are similar to the effect of glargine, whereas the mitogenic effects of these metabolites do not exceed the effect of human insulin. Insulin glargine shows a higher affinity for the insulin-like growth factor-1 (IGF-1) receptor when compared with human insulin. Glargine has no proliferative effect in vivo owing to its rapid conversion into metabolites. Pharmacokinetic and pharmacodynamic variability of glargine is comparable to other insulins. These characteristics are important for the clinical efficacy and safety of glargine.

Achievement of glycemic control is the major therapeutic aim to prevent or delay the onset and progression of diabetes related complications. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. The aim for insulin therapy is to mimic the physiological profile of insulin secretion seen in nondiabetic patients. Development of the insulin analogs has offered new opportunities in the diabetes management to achieve greater safety and tolerability of diabetes treatment. Insulin degludec/insulin aspart(IDegAsp) (Ryzodeg?, Novo Nordisk, Denmark) is the first soluble co-formulation of 70% ultra-long acting insulin degludec and 30% rapid-acting prandial insulin aspart, providing both basal insulin coverage and a prandial insulin bolus in a single injection. This review discusses data regarding the efficacy, safety, tolerability and clinical benefits of IDegAsp. According to the clinical development program IDegAspprovides an achievement of similar glycemic control with superiority in lowering FPG with using less number of injections and lower daily insulin dose, and also associated with numerically lower rates of confirmed and nocturnal confirmed hypoglycaemia in comparison with premixed or basal insulin analogues, as well as a basal component for basal?bolus therapy with supplementary mealtime insulin aspart.Trial results suggest that IDegAspQD or BID maybe an appropriate and reasonable option for initiating insulin therapy in type 1 and type 2 diabetic patients inadequately controlled on maximal doses of oral antidiabetic drugs,and also a simple alternative to basal?bolus treatment in patients who require intensification of insulin therapy, especially when adherence to more complex regimens is challenging.

One hundred and five years ago was born a prominent Russian clinician, scientist and professor Vitaly Klyachko (1909-1977). For eleven years he headed the Department of Diabetology at the Institution for Experimental Endocrinology and Chemistry of Hormones (now Endocrinology Research Centre) and made an enormous contribution to the development of national endocrinology.