Diabetes mellitus (DM) dominates the chronic disease pandemics by its exceptionally rapid expansion into communities all over the world. DM is a disorder of complex nature that urges further dedicated studies and ingenuity in the search for novel therapeutic approaches. Nowadays, the blooming development of life sciences gives birth to some prodigious possibilities in treatment, diagnostics and prevention of this disease.

Patients with diabetes mellitus suffer either from destruction of pancreatic beta-cells or progressive deterioration of their function. Thus, transplantation of an intact beta-cell population fully capable of insulin secretion is the only means to cure this disease. Despite glycemic benefits and decrease in risks for late complications, islet transplantation or complete pancreatic grafting in humans remains a challenge due to necessity of lifetime immunosuppression and increasingly sparse donor resources. Current paper presents a review of modern endeavours to obtain a limitless source for glucose-sensitive insulin secreting cells. We discuss, in particular, complex aspects of beta-cell proliferation and/or neogenesis in vivo, issues with xenogenous pancreatic islets, and latest advances in controlled differentiation of embryonic and induced polypotent stem cells ? the most promising and relevant source of beta-cells.

Aims.
To evaluate key epidemiology trends for type 1 diabetes mellitus (T1DM) in children and adolescents of Russian Federation during 2001?2011 yy.
Materials and Methods.
Dynamics of incidence, prevalence and mortality from T1DM were assessed for national population and, separately, for all federal regions over the 2001?2011 yy. based on the questionnaires developed in the Institute of Paediatric Endocrinology (Endocrinology Research Centre) and data from the State Register of Diabetes Mellitus.
Results.
18,392 children aged 0 to 14 years and 8934 adolescents with T1DM were registered in Russian Federation by 01.01.2012. T1DM incidence in 2011 was estimated at 2407 among children and 1276 among adolescents. Mean T1DM prevalence across the Federation reached 72.8, incidence 12.43 (3.39?14.06) and mortality 0.07 (0.0?0.26) per 100,000 of relevant population (r.p.). Incidence rate for 2001?2011 indicates a 30% increase for past 11 years with average annual increase of 2.82%. According to the prognosis developed from these data, in 5 years T1DM incidence among children will reach 13.61 per 100,000 of r.p. Highest incidence was registered in Ural Federal Region (17.43 per 100,000 of r.p.) that assumed this position from North-Western federal region with 15.42 per 100,000 of r.p. as of 01.01.2010). T1DM incidence in adolescents is estimated at 15.26 per 100,000 r.p. with prevalence of 92.6 per 100,000 r.p. Incidence rate increased by 10.5% during past 6 years with average annual increase of 0.97%.
Conclusion.
This survey indicates that key epidemiological trends for T1DM in children and adolescents of Russian Federation correspond to average world parameters.

Aims.
to investigate the influence of environmental pollution on epidemiology of type 1 diabetes mellitus (T1DM) in children and adolescents of Krasnodar Region.
Materials and Methos.
Epidemiologic study was based on regional T1DM register data and official reports by medical facilities (form #112). Environmental survey was conducted according to the method of Shashel et al.
Results.
Epidemiologic study revealed increasing prevalence of T1DM among children and adolescents of Krasnodar Region for the period from 2000 to 2012 yy. Average prevalence of T1DM was estimated at 68.08 (children) and 135.78 (adolescents), and incidence at 10.08 and 17.01 per 100 000 inhabitants, respectively. Epidemiologic trend quantitatively correlates with ecological disturbance in resident areas of the population in question. Areas recognized as adverse environment reported a 2.8?3.2-fold increase in T1DM appealability as measured against neighboring areas with favourable ecologic environment. 
Conclusion.
Higher levels of environmental pollution drive both incidence and prevalence of T1DM in children and adolescents of Krasnodar Region, plausibly through induction of autoimmune process in the pancreas.

For the past several years, a number of studies addressed glucagon and its role in glycemic homeostasis and the development of diabetes mellitus. Current review discusses basic developmental stages of pancreatic islets with special regard for the role of beta-cells and basic mechanisms of glucagon function. We also highlight promising approaches to diabetes compensation based on adjustment of glucagon secretion.

Aim.
To evaluate the influence of metformin on nitric oxide bioavailability in patients with type 2 diabetes mellitus (T2DM) regarding glycemic homeostasis, and to investigate a correlation between metformin dosage and NO levels in vivo.
Materials and Methods.
Two groups ? primary and control ? were assembled for the clinical section of this study. Patients with newly diagnosed T2DM on metformin therapy were included to the primary group, while drug-naive T2DM patients were enrolled as control subjects. Glycemic parameters and NO bioavailability was tested in both groups prior to and after the follow-up period. Experimental section was dedicated to the elucidation of potential dose-dependent effects of metformin on NO bioavailability. Mice were intraperitoneally infused with metformin at 0.5; 1.1; 5.6 mg per subject. Tissue detection of NO was performed with diethyldithiocarbamate (DETC) iron complexes to form mononitrosyl iron compounds (MIC) with paramagnetic properties. Control rodents were intraperitoneally infused with metformin without spin trapping.
Results.
We found nitrite and methaemoglobin (a marker for NO bioavailability) to increase in parallel along with glycemic compensation in the primary but not control group. In vivo rodent models showed linear correlation between accumulation of DETC/MIC and dose of metformin, as well as formation of dinitrosyl iron complexes, known as endogenous NO transporters.
Conclusion.
Our data suggests that metformin benefits glycemic homeostasis in T2DM as an NO donor via formation of dinitrosyl iron complexes.

Aim.
To assess the prevalence of fear of hypoglycemia, its clinical features and influence on diabetes compensation.
Materials and Methods.
A cross-sectional study was conducted with 200 sequentially enrolled participants with type 2 diabetes mellitus (T2DM; n=139) and type 1 diabetes mellitus (T1DM; n=61). Patients were screened for psychiatric disorders with appropriate inventory and examined by a psychiatrist. Subjects identified as those with fear of hypoglycemia (n=12) formed the study group, while control group was assembled of individuals without phobic signs, matched for gender, age, type and duration of diabetes and concomitant psychiatric disorders.
Results.
Prevalence of fear of hypoglycemia was estimated at 6%, being consistently higher in patients with T1DM (16.1%) vs. T2DM (1%; p=0.0002). Fear of hypoglycemia was associated with higher median HbA_1c (9.4% [8.6 ; 9.9] vs. 8.2% [6.8 ; 9.3], p<0.05). These findings are in agreement with considerably higher prevalence of proliferative retinopathy (33%) observed in study group (0% in control group, p<0.05). Phobic patients with T1DM had higher occurrence of ketoacidosis (41.7% of subjects, 7 cases) than control subjects (16.6% of subjects, 2 cases). Similar trend was observed for severe hypoglycemic events. There was no significant difference between the groups in sensitivity to hypoglycemia, cognitive functions, educational level or social status. Patients with fear of hypoglycemia tend to regard hypoglycemia as primary, highly hazardous challenge of diabetes mellitus and perceive its symptoms as ?extremely unpleasant?. However, in this study phobic patients maintained the same level of self-monitoring as their control counterparts and demonstrated comparable knowledge of the causes of hypoglycemia. None of the participants reported a habit of carrying carbohydrates for hypoglycemia management.
Conclusion.
Fear of hypoglycemia is highly prevalent among patients with T1DM and is often associated with poor diabetes compensation, glycemic instability and higher risk for diabetic macroangiopathy. Attitude to hypoglycemia in such patients resembles idee fixe phenomenon with pathologically accentuated somatic perception of hypoglycemia and exaggeration of associated health hazards. Patients with fear of hypoglycemia tend to develop avoidance behaviour regarding diabetes mellitus that, combined with lower compliance for prevention of hypoglycemia, worsens clinical prognosis.

Aim.
To estimate clinical significance of nonverbal behaviour analysis and ethological method in diagnostics of emotional disorders in children and adolescents with type 1 diabetes mellitus (T1DM).
Material and Methods.
87 patients with T1DM aged 12.34?4.6 years were enrolled in this study. Ethological analysis was based on Glossary of Human Nonverbal Behaviour; behavioural characteristics were formalized according to Human Ethological Signs Scale (HESS).
Results.
Nonverbal signs of anxiety in children with long experience of T1DM were more diverse and prominent. Average occurrence of complete ethological repertoire was 80.6% and 76.4%, respectively. Children with clinical history of T1DM greater than 3 years demonstrated complete repertoire in 86.6% of cases, with that of only 76.4% of more recently diagnosed.
Conclusion.
Ethological analysis of nonverbal behaviour in children and adolescents with T1DM improves informative value of clinical examination and complements verification of psychopathological data on emotional disorders in this category of patients.

Cardiovascular intervention for myocardial revascularization dominates modern treatment of ischaemic heart disease (IHD). Current efficiency and safety of this method could never be achieved without the development of antiplatelet agents that provide indispensable protection for endovascular interventions. However, antithrombotic therapy is generally less effective in diabetes mellitus (DM), affecting prognosis for transcutaneous intervention. This trend is probably due to alteration of cellular homeostasis during hyperglycemia and correlates with its severity and persistence. This paper addresses modern understanding of factors affecting thrombogenesis in patients with DM.

Aims.
To evaluate plasma levels of transforming growth factor beta (TGFbeta1), basic fibroblast growth factor (bFGF), markers for nonspecific inflammatory process (interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP)) and their putative correlation with advanced glycation end-products relative to diabetes compensation in patients with ischemic heart disease (IHD).
Materials and Methods.
87 patients with IHD were enrolled in this study. All subjects underwent standard clinical examination, including laboratory assessment of glycemic parameters, lipid panel and renal function, with echocardiography, supplemented with coronary angiography. Analyses for study parameters were performed on samples obtained from aorta and, separately, from cubital vein during coronary angiography.
Results.
Diabetes mellitus in patients with IHD is firmly associated with TGFbeta1, IL-6 and CRP elevation in both arterial and venous plasma. TGFbeta1 positively correlates with lipid profile parameters. Plasma concentration of inflammatory markers and advanced glycation end-products positively correlates with the extent of coronary lesions in relation to the presence of diabetes mellitus.
Conclusion.
Our data suggests the interplay between connective tissue growth factors and lipid metabolism in the atherosclerotic process.

Diabetic foot syndrome (DFS) is one of the most prevalent and financially demanding complications of diabetes mellitus (DM). According to a number of expert analyses, DFS counts for 15% to 25% of total diabetes spendings by the developed economies. The Advanced Medical Care Program in Russian Federation covers expanses for patients with DFS. However, DFS patient profile has no dedicated budgeting quotation as yet, and that of ?general endocrinology? does not meet specific clinical requirements. An expenditure analysis was performed to facilitate the development of budgetary recommendations. The survey included two major steps: a systematic analysis of the data available from periodic literature, followed by an assessment of routine clinical practice in a federal healthcare institution (using the example of Moscow Endocrinology Research Centre).

Aim.
To determine risk factors for diabetic autonomic cardiovascular neuropathy (DACN) and to optimize diagnostic procedures for children and adolescents with type 1 diabetes mellitus.
Materials and methods.
Heart rate variability (HRV) was assessed in 101 subjects with type 1 diabetes mellitus aged 5?17 y.o. in 4 functional tests. Subjects with 3 positive tests out 4 were considered positive for DACN.
Results.
Increased glycemic variability (9+ mmol/l per day), regular hypoglycemic events and late diabetes complications were found to be DACN risk factors in children and adolescents.
Conclusions.
A diagnostic algorithm for DACN in children and adolescents with type 1 diabetes mellitus based on orthostatic HRV variability assessment shows high sensitivity and efficiency.

AIM: Combination of cardiovascular and renal disease is currently viewed as a unified cardiorenal syndrome (CRS). The aim of our study was to assess the CRS prevalence and risk factors associated with left ventricular hypertrophy (LVH) in patients with pre-dialysis stages of chronic kidney disease (CKD) of various etiology.

MATERIALS AND METHODS: We enrolled 172 patients with CKD to participate in this study. First group consisted of 83 patients with nondiabetic CKD at 2nd through 4th stage (mean age 46-15 years, 51% male and 29% female). Mean glomerular filtration rate (GFR) was 37.2 ml/min (33.9-41.4 with 95% CI); creatinine plasma clearance was 2.9 mg/dl (2.6-3.2). Second group consisted of 89 patients with type 2 diabetes mellitus (T2DM) and CKD at 1st?2nd stage (40% male and 60% female) with albuminuria (mean age 57.3-7.1 years). Duration of diabetes in this sampling was 10.4-7.1 years. All patients underwent standard clinical examination, supplemented with echocardiography to evaluate the influence of general and CKD-related risk factors for LVH.

RESULTS: LVH was diagnosed in 37.3% of non-diabetic patients with CKD at 2nd through 4th stage. Aside from classic cardiovascular risk factors (including age, gender, arterial hypertension, family history of cardiovascular diseases, hypercholesterolemia), we observed the impact of kidney-related factors (anemia, plasma creatinine, disturbance of calcium-phosphorus metabolism). CKD progression was associated with elevation in the incidence of concentric and eccentric LVH). Patients with T2DM were diagnosed with LVH in 36% of cases. Increased myocardial mass correlated with plasma levels of uric acid, HbA_1c, obesity and albuminuria. There was also a firm association between diabetic nephropathy, left ventricular myocardial remodelling and a history of cardiovascular events.

CONCLUSION: In patients with diabetes mellitus and CKD cardiorenal syndrome develops at pre-dialysis stages due to both classic and kidney-related cardiovascular risk factors.

Expansion of diabetic population (predominantly due to type 2 diabetes mellitus) with chronic kidney disease (CKD) comorbidity constitutes one of the major challenges in modern medicine.
Throughout the course of diabetes nephropathy development, from its debut to the terminal stage, survival rate and quality of life are lower than those of other categories of patients. This indicates crucial role of hyperglycemia in accelerated metabolic degradation typical of CKD.
Renal disease severely narrows the spectrum of available glucose-lowering agents. Concurrent treatment for hypertension and dyslipidemia, as well as anti-platelet therapy and stimulation of erythropoiesis becomes a complex issue. A creative and patient-oriented approach with clear metabolic and cardiovascular goals should be instrumental in its solution.

Climacteric syndrome in women with glycemic disorders is known to have several unique features, including earlier onset in women with type 1 diabetes mellitus (usually at the age of 46?48 years). However, diabetes mellitus is not a contraindication for hormone replacement therapy (HRT), though the appropriate age for its introduction should be determined on a case-by-case basis.

AIM: This study was aimed at investigation of daily glycemic variations in children and adolescents with type 1 diabetes mellitus (T1DM) on continuous subcutaneous insulin infusion (CSII) in order to define in greater detail the correlation of said parameters with periods of age to the end of improving current recommendations for pump settings adjustment.

MATERIALS AND METHODS: 138 children and adolescents aged 1?18 years on CSII therapy took part in this study. Patients were subdivided into three groups according to their age: preschool children (n=23), prepubertal children aged <12 years (n=39) and teenagers up to 18 years old (n=76). CSII regimens were analyzed in every group, including average daily insulin dose, basal-to-bolus ratio, daily basal profiles, carbohydrate ratio (CR) and insulin sensitivity factor (ISF).

RESULTS: Daily requirement for both basal and bolus insulin does differ between ages. Youngest children require higher basal infusion rate during evening hours and first half of the nighttime while demonstrating least requirement at daytime. Instead, prepubertal children and adolescents require higher basal infusion rate during early morning hours. We also show CR and ISF to be dependent of daytime in all studied age grades.

CONCLUSIONS: Basal-to-bolus ratio along with circadian variability in requirement for insulin are clearly governed by patient's age. Importantly, the ratios for bolus calculations, developed from our data, significantly differ from those provided by popular formulas, suggesting the latter be modified into taking regard of the age grade for proper individual adjustment of pump settings.

Some of the glucose-lowering drugs are biopharmaceuticals. This letter states the official position of the Russian Association of Endocrinologists about the treatment with biopharmaceuticals of patients with endocrine disorders. This topic has not yet been
adequately reflected in the legal regulation of the drug market in the Russian Federation .

We remember Harry Keene. He was one of the outstanding representatives of the world scientific community. His innovative research were landmarks in the diagnosis, prevention and treatment of complications of diabetes.