Vol 21, No 6 (2018)

Original Studies
Epidemiology of acute diabetes complications (coma) according to the Federal Diabetes register of the Russian Federation (2013–2016)
Mayorov A.Y., Vikulova O.K., Zheleznyakova A.V., Isakov M.А., Melnikova O.G., Kononenko I.V., Shestakova M.V., Dedov I.I.

Abstract

Background: Despite the improvement in the quality of diabetes care in the Russian Federation (RF), coma remain one of the causes of death in patients with diabetes.

Aim: To assess dynamic of epidemiological characteristic of acute complications in adult patients with T1D and T2D in 2013–16.

Materials and methods: The database of the Russian Federal Diabetes register (81 regions). The indicators of coma for 2013–16 were estimated for 10000 adult patients with diabetes (>18 years).

Results: In 2016, the prevalence of coma in RF was 225.9 with T1D and 11.6/10000 adults with T2D. For the period from 2007 the prevalence of ketoacidotic coma decrease three times in T1D, 4 times for T2D.Totally in 2016, 165 new cases of coma for both types of diabetes were registered, an average of 0.4/10000 adults. Interregional differences in the prevalence of coma were observed 0–4.2/10000 adults. The frequency of new cases of coma has a tendency to decrease: 0,9→0,4/10000 adults: T1D 5.7→3.4, T2D 0.6→0.2/10000 adults. When evaluating the structure of coma, redistribution is evident in their form. So in 2016 the proportion of hypoglycemic coma increased to 40.7%, and ketoacidotic coma decreased to 56.6% in T1D. With T2D, the difference expressed in a lesser degree. The mean duration of diabetes at the time of coma development increased with T1D from 3.8→9.1 years, with T2D 3.5→7.0 years. The maximum frequency of development of coma is recorded with the diabetes duration more than 30 years, regardless of the type. The patients’ age at the time of coma development in T1D increased to 27.5 years old, and in T2D it was 60.4 years, it didn’t change significantly. The assessment of glycemic control showed a significant improvement: a decrease in the proportion of patients with HbA1c≥ 9.0% (23% with T1D, 8.8% with T2D), an increase with HbA1c <7% (32.4% and 51.7%, respectively). The average value of HbA1c in 2016 with T1D – 8.21%, with T2D – 7.48%.

Conclusions: It is established that the dynamics of the frequency of development of coma in 2013–16 in adult patients with diabetes in the RF has a stable tendency to decrease: 1.5 times with T1D and more than 3 times with T2D. It can be assumed that this is due to the improvement in the quality of diabetes care and glycemic control in general, as well as the use of modern medicines. Attention is required to draw to the high frequency of coma in T1D, the development of coma with a longer duration of diabetes, an increase in the proportion of patients with hypoglycemic coma. Significant interregional differences in the frequency of coma registration require additional analysis.

Diabetes mellitus. 2018;21(6):444-454
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Type 2 diabetes mellitus and multiple chronic diseases
Asfandiyarova N.S., Dashkevich O.V., Doroshina N.V., Suchkova E.I.

Abstract

Background: Recently, there has been an increase in the number of patients with multiple chronic diseases (MCD), particularly due to obesity and ageing. The role of type 2 diabetes mellitus (T2DM) in the development of MCD, however, is still unclear.

Aims: This study aimed to determine the incidence of T2DM in the structure of polymorbidity considering sex and age-related characteristics.

Materials and methods: Patients with MCD (n = 2,254; 769 men/1,485 women; aged, 18–99 years) were examined. The incidence of type 2 diabetes among patients with MCD considering age and sex was determined.

Results: Type 2 DM was detected in 407 patients with MCD (18.1%; male:female, 1:2.53). The polymorbidity index in male patients with type 2 diabetes was 1.5–2.0 times higher than that in male patients without diabetes. The rate of polymorbidity index increase was similar in both groups; however, its high initial value in patients with diabetes at a young age determined the burden of the comorbidity at a later age. In type 2 diabetes, hypertension was the predominant comorbidity at 18–59 years of age (p<0.05), whereas other cardiovascular diseases and liver and kidney diseases were predominant at 45–74 years of age (p<0.001) and hemiplegia at 45–89 years of age (p<0.05). Between 60 and 74 years, oncological diseases were found to be more common in patients without diabetes (p<0.001). Obesity, regardless of the presence of diabetes, was associated with a greater disease burden (p<0.05). Sex-related difference considering MCD in patients with type 2 DM was only observed for the higher incidence of myocardial infarction (p<0.001) and peptic ulcer disease in males (p<0.01). Females were more likely to have obesity, liver steatosis at a young age, or osteoarthritis than males in the general group (p<0.05); no differences were noted with respect to other diseases.

Conclusions: In this study, type 2 diabetes was present in 18.1% of patients with MCD; moreover, a high initial polymorbidity index in patients with T2DM at young age was associated with a higher incidence of chronic diseases later in life than that in patients without diabetes. Based on these results, type 2 diabetes, along with ageing and obesity, can be considered as a risk factor in the development of MCD.

Diabetes mellitus. 2018;21(6):455-461
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Assessment the equivalence of the bioanalogue insulin lizpro biphasic 25 (Geropharm-bio, Russia) and Humalog® Mix 25 (Lilly France, France) using the euglycemic hyperinsulinum clamp method on healthy volonters
Mayorov A.Y., Koksharova E.O., Mishina E.E., Drai R.V., Avdeeva O.I., Makarenko I.E.

Abstract

Background: Modern medicine requires use of effective antidiabetic drugs that can imitate the natural profile of insulin in the body of patients with diabetes mellitus. Examples of such preparations include biphasic insulin lispro, which is a mixture of insulin lispro ultra-short action and insulin lispro protamine suspension with prolonged effect. The clinical trials (CT) program for biosimilar insulins contains pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety studies.

Aims: To demonstrate Biphasic Insulin Lispro 25, suspension for subcutaneous administration, 100 U/ml (GEROPHARM-Bio, Russia) and Humalog® Mix 25, suspension for subcutaneous administration, 100 U/ml (Lilly France, France) have comparable pharmacokinetic profiles under conditions of hyperinsulinemic euglycemic clamp (HEC) in healthy volunteers.

Materials and methods: The study was conducted on 48 healthy men aged between 18 to 50 years. This was a double-blind, randomized, crossover study of comparative pharmacokinetics of drugs. The investigational products (IP) were administered before the clamp in a single dose of 0.4 U/kg subcutaneously in the abdominal wall. Regular blood sampling was performed during the study. The insulin concentrations in the samples were determined using an ELISA method. The results of the determination were used to calculate the PK parameters and construct the concentration-time curves. Adjust glucose infusion rates were based on blood glucose measurements. These data were used to calculate the PD parameters.

Results: Our results demonstrated that Biphasic Insulin Lispro 25 and Humalog® Mix 25 have comparable PK and PD profiles under conditions of HEC in healthy volunteers. The confidence intervals for the ratio of the geometric mean for Cins.max and AUCins.0–12 were 87.75–99.90% and 83.76–96.98% respectively, which were well within 80–125% limits for establishing comparability.

Conclusions: Biphasic Insulin Lispro 25 and Humalog® Mix 25 are equivalent based on this CT applying the HEC technique in healthy volunteers.

Diabetes mellitus. 2018;21(6):462-471
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Patient education: interpretation of medical terms as a key part of diabetes mellitus treatment
Novoselova N.S., Mosikian A.A., Martyanova O.Y., Patrakeeva E.M., Zalevskaya A.G.

Abstract

Background: Only a little percent of chronically ill patients was found to follow physicians’ prescriptions. One of the reasons for this issue is misunderstanding of recommendations due to inappropriate interpretation of medical terms, contained in medical advice.

Aims: The study is aimed to evaluate the quality of patient interpretation of the most frequently used medical terms in diabetes mellitus field (DM) and to evaluate the impact of misunderstanding on diabetes control.

Materials and methods: 13 endocrinologists composed 2 lists of the most frequently used terms – one list for DM type 1 and one for DM type 2. We selected 10 terms for DM type 1 and 10 terms for DM type 2, mentioned by the most of participated doctors, and created 2 kinds of questionnaire for patients. Patients were to explain the terms in written if they were aware of terms’ meaning. Three independent researchers evaluated every answer according to a 0 to 10 scale, where 0 was for totally incorrect or no answer, and 10 was for a completely correct answer. Patients also filled in the forms about their social and demographic parameters. Statistical analysis was conducted with the use of Wilcoxon Test and linear regression model.

Results: 89 patients with DM type 1 (27% men, HbA1c (mean±SD) 7,95±1,77%) and 86 patients with DM type 2 (27% men, HbA1c (mean±SD) 8,11±1,91%) were included into the study. Patients with type 1 DM received a greater overall score for understanding the terms than those with type 2 DM (p <0.0001) – 57.84±22.66 and 39.33±22.02 from 100, respectively. 38 (42.7%) participants with DM type 1 reported that they know all 10 terms, but only 15 (16.8%) respondents understand terms correctly. In the group of type 2 DM patients 9 (10.5%) of all answered yes for all the terms, but really know terms only 2 (2.3%) participants. In both groups, the total score of the terms knowledge did not correlate with the HbA1c level (р=0.698 and р=0.319 for type 1 and type 2 DM groups, respectively).

Conclusion: The most of patients with DM do not understand relevant medical terms properly. Some patients are in the wrong belief that they have no misunderstandings with their consulting doctors. However, terms understanding does not influence on glycemic control (HbA1c level). During the medical consultation, endocrinologists should check if a patient understands their advice properly to improve understanding and compliance of patients.

Diabetes mellitus. 2018;21(6):472-479
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Dysfunction of respiratory system in patients with diabetes mellitus and coronary artery disease
Bazdyrev E.D., Polikutina O.M., Slepynina Y.S., Barbarash O.L.

Abstract

Aims: we aimed to estimate the main parameters characterizing respiratory pulmonary function in patients with isolated type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), as well as with their combination.

Materials and methods: the study included 198 patients divided into 3 groups: I – with isolated CAD [94 (47.5%)], II – with T2DM without the signs of CAD [64 (32.3%)], III – with combined CAD and T2DM [40 (20.2%)]. The assessment of carbohydrate and lipid metabolism, as well as the measurement of inflammatory markers were performed using unified clinical and biochemical methods. Respiratory pulmonary function and diffusion lung capacity (Dlco) were assessed using Elite Dl-220v body plethysmograph.

Results: the parameters reflecting the respiratory pulmonary function and the level of gas diffusion through alveolar-capillary membrane (ACM) in patients with CAD both with and without diabetes was within the normal values. The exception was the level of residual volume, which was below the prognostic values in all the studied groups. At the same time, in diabetic patients with CAD the values of forced and slow vital lung capacity, forced expiratory volume for 1-second, as well as the level of diffusion were significantly lower as compared to the corresponding values in patients with isolated CAD and didn’t differ in comparison with the values of diabetic patients except for the level of diffusion. It should be noted that a number of respiratory parameters had a correlation relationships with glycemic level, inflammatory markers and with the indicators characterizing dyslipidemia and myocardial dysfunction.

Conclusions: in the course of the study it was found out that the diabetic patients had respiratory system dysfunction in comparison to the patients with isolated CAD. The presence of diabetes in patients with CAD worsens not only the somatic background but probably contributes to the respiratory dysfunction in the form of lower velocity and volumetric parameters, but also in the indicator showing respiratory metabolism.

Diabetes mellitus. 2018;21(6):480-489
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Clinical, pathomorphological and immunohistochemical evaluation of tissue repair in diabetic foot ulcers
Tokmakova A.Y., Zaitseva E.L., Voronkova I.A., Shestakova M.V.

Abstract

Background: It is known that wound healing is Impaired in diabetes mellitus. Possible reasons are widely being searched. However, despite all the available data, reliable markers of reparative processes in diabetes mellitus are needed to be found.

Aim: To study morphological and some immunohistochemical markers of tissue repair in patients with diabetic foot ulcers after local treatment.

Materials and methods: 70 patients with diabetic foot ulcers before and after surgical debridement were included. Histological (light microscopy) and immunohistochemical (CD68, MMP-9, TIMP-1) characteristics of tissue repair processes in soft tissues of the lower extremities in patients with diabetes mellitus were analyzed. Histological and immunohistochemical examination of soft tissues were performed in 63 patients before and after surgical debridement and 10 days after local treatment.

Results: After the surgical debridement a significant reduction in the area of wounds was registered by 23.4% (p <0.05), wound depth by 29.4% (p <0.05). Based on the results of the morphological study, the presence of mature granulation tissue in the wounds was confirmed. Immunohistochemical study of wound biopsies demonstrated a significant decrease in proteolytic activity in the wound as a decrease in MMP-9 expression (p <0.05). Statistically significant changes in the number of macrophages against the initial data were not found, as well as increased expression of TIMP-1 was observed (p> 0.05 and <0.05, respectively).

Conclusion: According to the data, there was a significant decrease in the area and depth of wounds during local treatment. The intensity of tissue repair was confirmed by the results of histological and immunohistochemical studies. However, the absence of a statistically significant change in the amount of macrophages on the background of treatment suggests that this repair link is disrupted in diabetes mellitus, which is the reason for the "chronic" wounds and requires further studies.

Diabetes mellitus. 2018;21(6):490-496
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Increased apoptosis, but not pancreatic duodenal homeobox-1 expression in pancreatic islets is associated with intermittent glucose loads in mice
Herawati L., Wigati K., Rejeki P., Widjiati W., Irawan R.

Abstract

Background: Several caloric restriction studies revealed good for diabetes prevention. However, prevalence of it seems rising yearly. It needs alternative technique thus people can choose suitable way for them.

Aim: To determine the effect of glucose diet intermittently on pancreatic duodenal homeobox-1 (PDX-1), apoptosis in pancreatic islets, and pancreatic islets area.

Materials and methods: Balb/c mice were divided into five groups. Control group was given standard diet. The Continuous group was given standard diet and added with 7.4% calories continuously. The 1x, 2x, and 3x intermittent groups were given standard diet and added 7.4% calories for 1x, 2x, and 3x/week respectively. The 7.4% calorie addition was a glucose solution by oral galvage and ad libitum for 8 weeks.

Results: There was a significantly difference on apoptosis density (p=0.043), but not in PDX-1. The islets Int2x and Int3x groups showed a significant decrease than control group (p=0.048). Insulin serum levels increased significantly in Continuous group compared to control group (p=0.04). In addition, the insulin serum level of 1x and 3x intermittent groups were significantly lower than Continuous group (p<0.05). Pre-post blood glucose levels on treatment groups decreased significantly compared to control group (p=0.012).

Conclusions: Continuous and 1-3x/week intermittent addition of 7.4% calories of glucose for 8 weeks indicate a compensation mechanism for maintaining homeostasis, such as increase insulin serum level and seem to initiate the changes of morphologic-biomolecular (mainly apoptosis density in islets). The better mode is 1x/week of additional calories. However it needs further exploration to find out other influenced factors for these mechanism discovery.

Diabetes mellitus. 2018;21(6):497-505
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Review
Pathogenetic aspects of hepcidin metabolism and ferrocinetics dysregulation in carbohydrate metabolism disorders
Saprina T.V., Zima A.P., Musina N.N., Prokhorenko T.S., Latypova A.V., Shakhmanova N.S., Budeeva S.V.

Abstract

Hepcidin, a hormone regulating iron metabolism, has received attention for its role in the pathogenesis of dysregulations in carbohydrate metabolism. Hepcidin disorders in patients with diabetes mellitus are bi-directional: manifesting as iron overload syndrome in cases of decreased hepcidin production and as anaemia of chronic disease in cases of hepcidin hypersecretion. However, till date, detailed analyses of mechanisms underlying hepcidin dysregulation have not been conducted nor have the interactions of ferrocinetic and carbohydrate-metabolic disorders been examined. An association between diabetes mellitus and neurodegenerative diseases as well as the role of iron metabolism in Alzheimer or Parkinson diseases is a subject of ongoing research. This review provides a summary of the current understanding of hepcidin regulation and its disorders in various diseases, including diabetes mellitus and neurodegenerative diseases. In addition, we provide an overview of the available therapies that address ferrocinetic disorders resulting from the dysregulation of hepcidin.

Diabetes mellitus. 2018;21(6):506-512
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Impaired hypoglycemia awareness in diabetes: epidemiology, mechanisms and therapeutic approaches
Klimontov V.V.

Abstract

Impaired awareness of hypoglycemia (IAH) is a frequent complication of insulin therapy. Up to half insulin-treated individuals with type 1 and type 2 diabetes report the problems with hypoglycemia awareness, and 15–25% of patients have a permanent IAH.

A recurrent hypoglycemia is a cornerstone in IAH formation. The repeated episodes of hypoglycemia impair neurohumoral response to hypoglycemia, reduce its symptoms and induce inadequate brain adaptation to low glucose levels. In this regard, the IAH phenomenon can be considered as an example of "metabolic memory" in diabetes.

The IAH is associated with episodes of severe hypoglycemia, fear of hypoglycemia and cognitive dysfunction. These associates can be combined into IAH syndrome. Development of IAH becomes a serious barrier in diabetes management.

A growing body of evidence indicates that IAH is a reversible condition. If the syndrome is present, the hypoglycemia avoidance should be primary goal of the treatment. Structured training under specialized programs with psychological support is the most reasonable therapeutic approach to IAH amending. Technological approaches, including continuous subcutaneous insulin infusion, real-time continuous glucose monitoring, closed-loop insulin delivery systems ("artificial pancreas"), and islet transplantation also showed efficacy in hypoglycemia awareness improvement in some clinical studies.

The diabetes management in patients with IAH is time-consuming and expensive. Therefore, step-by-step approach, from insulin personalization and therapeutic training to advanced medical technologies, should be recommended for these patients.

Diabetes mellitus. 2018;21(6):513-523
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Injectable therapy in type 2 diabetes mellitus: strategies to improve therapeutic adherence
Gurova O.Y., Fadeev V.V., Maloletkina E.S.

Abstract

In recent years, the options in treatment of diabetes mellitus type 2 have substantially expanded (currently more than 40 molecules are approved), however, the number of patients with decompensation of diabetes for the period from 2003 to 2014 remains unchanged. In clinical guidelines injecting drugs are given the «final» role as the most effective drugs. However in clinical trials injecting drugs showed a lower adherence compared to oral drugs. Currently injectable glucose lowering drugs include not only insulin but also analogues of glucagon-like peptide-1 (aGLP-1). However, majority of studies of treatment compliance in type 2 diabetes mellitus considered only insulin. Reasons of low compliance are: 1) offering comprehensive programmes for education, monitoring and patient support by primary care physicians; 2) addressing cost and availability issues; 3) prescribing current insulin, also in combination with GLP-1 agonists; 4) use of more simple and convenient devices for injecting insulin.

Diabetes mellitus. 2018;21(6):524-533
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