Vol 21, No 5 (2018)

Original Studies
Effectiveness prediction of Evogliptin treatment in type 2 diabetes mellitus in russian-korean population
Mosikian A.A., Babenko A.Y., Sevastyanova Y.A., Drai R.V., Shlyakhto E.V.


Background: Individualized treatment has already become a part of a routine clinical care. Many data on the effectiveness prediction of commercially available DPP-4 inhibitors had been published, but not on the effectiveness prediction of evogliptin.

Aim: To reveal the clinical characteristics and metabolic predictors of better hypoglycemic response to evogliptin. Matherials and methods: We have conducted a retrospective study, based on the data of a randomized clinical trial comparing effectiveness and safety of evogliptin and sitagliptin in Russian and Korean subpopulations. We provide univariate linear regression models for separate subpopulations and a multivariate stepwise regression model for the combined subpopulation. HbA1c change after 24 weeks of evogliptin treatment was a primary endpoint and a dependent variable in the analysis.

Results: The decrease of HbA1c after 24 weeks of treatment with evogliptin in Russian subpopulation negatively correlates with triglycerides/HDL level (p = 0,046). In South Korean subpopulation it correlates positively with HbA1c level at baseline (p < 0,0001). In order to increase the statistical power of the analysis the data of both populations were combined. According to the combined data, the decrease of HbA1c after 24 weeks of treatment with evogliptin positively correlates with HbA1c level at baseline (p<0.0001) and log(HOMA-B) (p=0.0042), and it negatively correlates with log(triglycerides/HDL) (p=0.0057), blood phosphorous concentration (p=0.014) and statin treatment (p=0.044). No correlation of HbA1c change at week 24 was observed with body mass index, diabetes duration and blood C-peptide concentration. Patients able to achieve HbA1c<7,0 % had higher HOMA-B (53.22 ± 36.95 и 39.67 ± 24.74, respectively, р=0.033) and were tend to have higher HDL concentration (1.36 ± 0.28 и 1.26 ± 0.26 mmol/l, respectively, р=0.076) and lower triglycerides to HDL ratio (0.87 ± 0.70 и 1.48 ± 0.95, respectively, р=0.079).

Conclusion: A patient, who benefits more when treated with evogliptin, has higher HOMA-B, lower triglycerides to HDL ratio and phosphorous concentration in the 1-2 quartiles of the normal range. Triglycerides to HDL ratio is, probably, a specific effectiveness predictor for Russian, but not for Korean subpopulation. These data prove the difference in effectiveness prediction for different drugs of DPP-4 inhibitors group and reveal the need of further investigation.

Diabetes mellitus. 2018;21(5):333-343
The role of newly diagnosed diabetes mellitus for poor in-hospital prognosis of coronary artery bypass grafting
Sumin A.N., Bezdenezhnykh N.A., Bezdenezhnykh A.V., Osokina A.V., Gruzdevа O.V., Belik E.V., Barbarash O.L.


Background: The management of coronary artery disease in patients with type 2 diabetes (T2DM) who need myocardial revascularization is a great challenge.

Aims: To study the role of newly diagnosed T2DM in the development of in-hospital adverse outcomes after coronary artery surgery (CABG).

Methods: 708 consecutive patients underwent CABG were included. All patients without history of T2DM and with border fasting hyperglycemia underwent an oral glucose tolerance test.

Results: The screening allowed to diagnose T2DM in 8.9% and prediabetes in 10.4% of the study population. The the number of patients with T2DM increased from 15.2% to 24.1%, and with prediabetes from 3.0% to 13.4%. The total number of patients with carbohydrate metabolism disorders increased from 18.2% to 37.5%. The trend towards higher rate of in-hospital complications after CABG was defined among patients with newly diagnosed and previously diagnosed T2DM. The regression analysis demonstrated the presence of the relationships between the previously diagnosed T2DM and the total number of significant complications (odds ratio (OR) 1.350, 95% confidence interval (CI): 1.057–1.723, p=0.020) and prolonged in-hospital stay (OR 1.609, 95%CI 1.202–2.155, p=0.001). The significance of these relationships increased with the addition of newly diagnosed T2DM to the regression model (for in-hospital complications: OR 1.731, 95% CI 1.131–2.626, p=0.012; for prolonged in-hospital stay: OR 2.229, 95%CI 1.412–3.519, p<0.001). Moreover, additional associations between T2DM and the risk of developing multiple organ dysfunction (OR 2.911, 95% CI 1.072–7.901, p=0.039), urgent lower extremity surgery (OR 1.638, 95%CI 1.009–15.213, p=0.020) and the need for extracorporeal correction of hemostasis (OR 3.472, 95%CI 1.042–11.556, p=0.044) have been defined. Importantly, the presence of these associations would not have been identified without including newly diagnosed DM in the regression model.

Conclusion: The newly diagnosed T2DM affects the prognosis of CABG as well as the previously diagnosed T2DM. The obtained results suggest the importance of active preoperative T2DM screening.

Diabetes mellitus. 2018;21(5):344-355
Electrical activity in rat retina in a streptozotocin-induced diabetes model
Klochihina E.M., Erdyakov A.K., Morozova M.P., Gavrilova S.A., Akhapkina E.S., Ivanov E.V., Dzhemilova Z.N., Artemova E.V., Tokmakova A.Y., Koshelev V.B., Galstyan G.R.


Objectives: Diabetic retinopathy remains the major cause of blindness among the working-age population of developed countries. Considering this, experimental models of diabetes involving laboratory animals are important for assessing clinically significant methods to determine early pathologic alterations of the retina. The early detection of diabetic retinopathy in combination with a search for new pathogenetic targets will enable focusing on new strategies to limit the development of critical changes in the retina and to prolong retinal functioning during the development of diabetes mellitus.

Aim: This study aimed to define parameters of electroretinography test that identifies changes due to retinal impairment in diabetes.

Methods: Experimental diabetes was induced in Wistar rats by intraperitoneally injecting streptozocin (65 mg/kg; group ‘DM’). The control group (‘CB’) received intraperitoneal injections of the vehicle, i.e. citric buffer. On each consecutive day of the experiment, all rats received insulin detemir (2 u/kg). Ophthalmoscopy and electroretinography were conducted before initiating the experiment and after 50, 58 and 66 days of injectin sptreptozocin.

Results: Amid 2u\kg insulin injection the glucose level in venous blood in «DM» group amounted to 30-40 mM. The ophthalmoscopy showed that the optic nerve disk paled by the 50th day, with its line erasing. During electroretinography, wave amplitude in oscillatory potential test tended to decrease. β-wave latency of photopic system increased with α-wave latency of photopic system and α- and β-waves latency of scotopic system not altering. In addition, the amplitude of rhythmic stimulation of 8 and 12 Hz decreased.

Conclusion: The most apparent parameters of electroretinography for modelling streptozocin-induced diabetes are wave amplitude during the oscillatory potential test, photopic B-wave latency and the amplitude of rhythmic stimulation. These results suggest that in diabetes, ischaemic injury is an important cause of early dysfunction of inner retinal layers.

Diabetes mellitus. 2018;21(5):356-363
Type 2 diabetes and metabolic syndrome: identification of the molecular mechanisms, key signaling pathways and transcription factors aimed to reveal new therapeutical targets
Dedov I.I., Tkachuk V.A., Gusev N.B., Shirinsky V.P., Vorotnikov A.V., Kochegura T.N., Mayorov A.Y., Shestakova M.V.


Type 2 diabetes mellitus (T2DM) is a socially important disease with only symptomatic therapy developed due to lack of knowledge about its pathogenesis and underlying mechanism. Insulin resistance (IR) is the first link of T2DM pathogenesis and results in decrease of ability of insulin to stimulate glucose uptake by target cells. Development of IR involves genetic predisposition, excessive nutrition, stress, obesity or chronic inflammation due to disruption of insulin signaling within cells. Molecular mechanisms and markers of IR are characterized rather poorly, which prevents early diagnosis and creation of preventive therapy. Euglycemic clamp test is still a golden standard for IR diagnosis in clinic. Hyperglycemia is a distant consequence of IR in which damaging effect of oxidative and carbonyl stress is realized and diagnosis of T2DM is stipulated. Molecular chaperones and small heat-shock proteins have a protective effect at the early stages of T2DM pathogenesis, preventing development of reticulum stress and apoptosis. Endothelial dysfunction is related to T2DM and its cardiovascular complications, however, it is unknown on which stage of pathogenesis these changes occur and what are their molecular inductors. Finally, transcriptional activity and adipogenic differentiation play an important role in formation of new fat depots from predecessor cells and activation of brown and “beige” fat demonstrating hypolipidemic and hypoglycemic properties. The aim of this study was investigation of pathophysiological mechanisms of development of IR and endothelial dysfunction, role of transcription factor Prep1 and small heat shock proteins, evaluation of novel methods of diagnostics of IR and therapeutic potential of brown and “beige” fat, determination of biotargets for new antidiabetic drugs.

Diabetes mellitus. 2018;21(5):364-375
Mechanisms of cardiovascular protection of non-insulin antidiabetic medications
Avogaro A.


Patients with type 2 diabetes mellitus die most frequently from cardiovascular disease (CVD). Metabolic control is a cornerstone of both primary and secondary prevention of CVD: its important is two-fold since the normalization of HbA1c not only counteracts the onset, and the progression of microvascular complication, but has also important and positive role in reducing the risk of major adverse cardiovascular events (MACE). However, among the available glucose-lowering medications, some exert a direct CV protection independently from their ability to normalize metabolic control. In this review I will highlight the pathophysiological mechanisms underlying the claimed cardiovascular protection of the different glucose-lowering drugs, the available evidence-based data for their protection, the potential adverse effects, and the different phenotypes of patients eligible for a specific treatment. The knowledge of pathophysiological mechanisms for CV protection of each glucose-lowering medication, and the constraints of their use supports the health care professionals to individualize the normalization of metabolic control in patients with type 2 diabetes mellitus.

Diabetes mellitus. 2018;21(5):376-385
Type 2 Diabetes Mellitus. From the start – combination therapy
Indovina F., Falcetta P., Del Prato S.


Modern treatment of T2DM requires a shift in paradigm with appropriate intensification of therapy from the very first time of diabetes diagnosis. This is supported by data showing how even a moderate delay in achieving good glycemic control can translate into a later increased risk of developing diabetic complications. The recognition of the complexity of the pathogenesis of T2DM leads to the appreciation of the importance of attacking the disease from different angles, i.e. simultaneous tackling of multiple mechanisms contributing to hyperglycemia. From the turn of century a growing number of new anti-hyperglycemic agents have been made available. As compared to the older ones, these new medicines have a more targeted mechanism of action as they act at the level of the specific pathophysiologic disturbances accounting the development and progression of hyperglycemia. Because of that drugs can be use in combination taking advantage of their complementary mechanisms of action and synergistic. If introduced earlier in the natural history of the disease combination therapy may contribute avoiding undesirable exposure to even mild chronic hyperglycemia and provide early benefits. With respect to that in this review we will discuss advantages, disadvantages and still unanswered questions related to the use of early combination therapy in type 2 diabetes.

Diabetes mellitus. 2018;21(5):386-394
Role of incretin based therapies in the treatment of diabetic kidney disease
Fioretto P., Frascati A.


Diabetic kidney disease (DKD), a serious microvascular complication of diabetes mellitus is a leading cause of end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Despite advancements in blood glucose and blood pressure (BP) control, ~20% to 40% of patients with diabetes mellitus develop DKD. Intensive glycaemic and BP control positively influence decline in estimated glomerular filtration rate and albuminuria, thereby delaying the onset and progression of diabetic nephropathy. Incretin based therapies namely glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used glucose lowering agents and have shown favorable renal outcomes in DKD. This article discusses the extra-glycaemic properties of incretin based therapies and their renoprotective effects on components of the metabolic syndrome, including obesity, hypertension and dyslipidaemia; reduction in oxidative stress and inflammation; and increase in natriuresis.

Diabetes mellitus. 2018;21(5):395-398
Heart failure in diabetes: From an increased risk to a treatment target
Standl E.


Heart failure (HF) is one of the most common comorbidities of type 2 diabetes mellitus (T2DM) and poor glycaemic control can worsen the HF outcomes and increase the risk of hospitalisations. With the entry of several antihyperglycaemic agents for the management of T2DM over the last decade, there has been an increasing concern regarding the cardiovascular (CV) safety profile of these agents. In view of this, FDA mandated the demonstration of cardiovascular risk-benefit profile of these agents through specifically designed CV outcome trials. Although we have several findings from these trials, none of them included HF as a primary endpoint indicating the need of trials focusing on HF. Here, we briefly discuss the results of the CV outcome trials in the context of HF.

Diabetes mellitus. 2018;21(5):399-403
Autoimmune gastritis: comorbid pathology in type 1 diabetes
Derevyanko O.S., Ibragimova L.I., Ragimov M.R., Nikonova T.V.


In recent years noted an increased number of patients with autoimmune diseases (AID), and the special attention deserves combination of several autoimmune pathologies collected in one patient, because such patients requires special tactics of management. Autoimmune diseases of the gastrointestinal tract are less researched and, nevertheless, prognostically unfavorable. Autoimmune gastritis (AIG) has a special place in other stomach diseases, which develops in the aggregate with type 1 diabetes. AIG is a chronic inflammation of the mucous membrane of the body of the stomach, leading to the appearance of atrophy and hypoxecretion. AIG is found in 5–10% of individuals in general population, with a higher incidence of AIG in patients with diabetes and other established autoimmune pathology.

AIG is asymptomatic at the early stage of the disease and clinical manifestations appear after the atrophic changes in the mucous membrane of the stomach develop. Since autoimmune gastritis does not have pathognomonic signs, it can manifest itself in hematological and oncological complications at later stages. This is why screening, early diagnosis, prevention and treatment are very important. Early diagnosis and prevention of AIG and its complications play the main role. This article provides an overview of the worldwide data dedicated to this issue.

Diabetes mellitus. 2018;21(5):404-408
Vaccination and diabetes mellitus type 1 in children
Vitebskaya A.V., Malahov A.B., Rtishchev A.Y.


Influence of vaccination on the risk of developing diabetes mellitus type 1 (DM1) has been studied by different researchers for several decades. In rodents, vaccination can prevent development of DM1. This review summarises existing literature and discusses the results of a 2016 meta-analysis, pertaining to vaccination and DM1. No vaccines appear to increase the risk of DM1. Additional investigations are needed to determine if vaccines can be considered protective against DM1.

Patients with DM1 are at increased risk of morbidities from controllable infections. Children with DM1 should receive regularly-scheduled vaccinations; choice of vaccines and inoculation with non-regular vaccines should be determined on an individual basis. We present basic principles surrounding vaccination in patients with DM1 and analyse the role of the paediatric endocrinologist in increasing vaccination uptake in children with DM1.

Diabetes mellitus. 2018;21(5):409-418
The role of proper insulin injection technique training FOR achieving of good glycaemic control
Misnikova I.V., Gubkina V.A., Dreval A.V.


Inappropriate injection technique leads to incorrect insulin dosing, increased pain and impaired glucose control in patients with diabetes. This review examines in detail the results of two clinical studies, the Glycemic Impact of Insulin Injection Technique (GIIIT) and the UK Lipo Study (UKLS) that examined the effect of teaching patients proper injection techniques to achieve good glycemic control.

The GIIIT study included patients with type 1 and type 2 diabetes (18–70 years) who were on a regimen of multiple daily insulin injections. They were categorised into three groups: those that received structured injection technique training using 4-mm injection needles (TN), those that received injection technique training (T) and control (C). The UKLS study included 75 patients who received structured training to reduce the risk of developing lipohypertrophy.

Initially, deviations from proper insulin injection technique were observed in a majority of patients in both the studies. In the GIIIT study, 6 months after training under TN and T conditions, HbA1c decreased by 1%, with no observable changes under the C condition. The daily insulin dose was increased by 6 IU in all conditions. Overall, the use of 4-mm short needles reduced post-injective pain in all patients. In the UKLS study, for 6 months, the variability of glycemia and frequency of unexplained hypoglycaemia decreased as the daily dose of insulin decreased by an average 6 IU; in addition, HbA1c level decreased from 8.6% to 8.2%. Six months after the training, both studies noted a decrease in or disappearance of lipohypertrophy in the patients.

These results indicate that proper injection technique training improves glycemic control in patients with diabetes.

Diabetes mellitus. 2018;21(5):419-424
Case report
In vitro fertilization as a method of infertility treatment in women with type 1 diabetes mellitus
Misharina E.V., Tiselko A.V., Yarmolinskaya M.I., Kogan I.U., Abashova E.I., Borovik N.V.


Some patients with type 1 diabetes have anovulation, tubal occlusion, male factor and other causes of infertility which require IVF procedure.

We examined 20 women with type 1 diabetes, in which pregnancy occurred as a result of ART, at the stage IVF protocol planning, during pregnancy course and delivery. One of the patients underwent IVF procedure twice. Mean age of the patients who applied to the Department of assisted reproductive technologies was 33±6 years, duration of infertility varied from 3 to 15 years. Two patients were performed donor oocytes transfer (patients with Turner Syndrome and Swyer Syndrome). In 70% of patients the method of CSII was used. Assessment of carbohydrate metabolism was based on the level of glycated hemoglobin A1c (HbA1c), plasma glucose level measured at least 8 times a day and results of continuous glucose monitoring (CGM).

18 singleton pregnancies and three multiple gestations (dichorionic diamniotic twins) occurred as a result of IVF. In 12 women delivery occurred on the 37–39th weeks of gestation, in 9 patients pregnancy was terminated on the 34–36th weeks. In all the cases it was live birth. Birth weight above the 90th percentile had 6 newborns.

Diabetes mellitus. 2018;21(5):425-430

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