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Summary Background FTO, a gene recently discovered in genomewide associated studies for type 2 diabetes mellitus (T2D), play an important role in the management of energy homeostasis, nucleic acid demethylation and regulation of body fat mass by lipolysis. The aim of this study was to analyze the association of FTO rs8050136 A>C genetic variant with clinical and biochemical parameters of T2D in the population of West Balkan region (Bosnians and Herzegovinians and Kosovars). Methods The study included 638 patients with T2D and prediabetes and 360 healthy controls of both genders, aged from 40 to 65 years. Patients were recruited at the Clinical Centre University of Sarajevo, University Hospital of Clinical Centre in Banja Luka, General Hospital in Tešanj and Health Centre in Prizren. Genotyping of analyzed FTO polymorphism rs8050136 A>C was performed by qPCR allelic discrimination. Results Genotype frequencies of the analyzed polymorphism were comparable between patients with T2D, prediabetic patients, and healthy population. Logistic regression analyses didn’t show significant association of FTO rs8050136 A allele with increased risk of T2D. However, risk A allele was significantly associated with higher levels of HbA1c, insulin, HOMA-IR index, diastolic blood pressure, and inflammatory markers (fibrinogen and leukocytes) as well as showed tendency of association with increased values of obesity markers (BMI, waist and hip circumference). Conclusions Results of our study showed a significant association of FTO genetic variant rs8050136 A>C with the major markers of insulin resistance, obesity and inflammation, opening new avenues for solving many unclear questions in the pathogenesis of T2D.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7-like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study, we explored the effects of the TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA(1c), total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of the TCF7L2 rs7903146 was performed by the Sequenom MassARRAY(®) iPLEX(®) platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9–38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1–44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1–12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in the TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0–25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that the TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

Previous studies reported conflicting results regarding association of insulin receptor substrate 1 (IRS1) gene variation with type 2 diabetes (T2D) and insulin resistance (IR) in different ethnic groups. We examined the association of rs7578326, rs2943641, and rs4675095 in the IRS1 gene with T2D and related traits in a population from Bosnia and Herzegovina, which is one of the European countries with the highest T2D prevalence of 12.5%. Our study included 390 T2D patients and 252 control subjects. Biochemical parameters, including fasting glucose (FG), fasting insulin (FI), homeostasis model assessment insulin resistance index (HOMA-IR), and HbA 1c were measured in all participants. Genotyping analysis was performed by Mass Array Sequenom iPlex platform. Our results demonstrated that rs7578326 and rs4675095 variants were associated with increased FG levels. The rs7578326 was also associated with higher FI, HOMA-IR (B = 0.08, 95% CI [0.01, 0.15], p add = 0.025; B = 0.079, 95% CI [0.006, 0.150], p add = 0.033, respectively) in T2D, and with HbA 1c (B = 0.034, 95% CI [0.003, 0.065], p dom = 0.035) in non-drug-treated T2D. In contrast, rs2943641 C allele was associated with lower FG levels in control subjects (B = -0.17, 95% CI [-0.03, -0.002], p add = 0.030) and HbA 1c (B = 0.03, 95% CI [0.002, 0.06], p dom = 0.040) in non-drug-treated T2D. We report the association between common variants in IRS1 gene with insulin resistance, glucose, and HbA 1c levels in Bosnia and Herzegovina's population.

Aims Metformin is the most widely used oral anti‐diabetes agent and has considerable benefits over other therapies, yet 20–30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter‐individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced‐function polymorphisms with common metformin‐induced gastrointestinal side effects in Type 2 diabetes. Methods This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss‐of‐function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced‐function alleles with gastrointestinal side effects was analysed using logistic regression. Results Forty‐three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced‐function alleles was significantly associated with over two‐fold higher odds of the common metformin‐induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07–5.01, P = 0.034). Conclusions In conclusion, we showed for the first time the association between OCT1 variants and common metformin‐induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter‐individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment., What's new? The mechanism of high inter‐individual variability in gastrointestinal side effects associated with metformin treatment is unknown.We show for the first time the association between organic cation transporter 1 reduced‐function variants and common metformin‐induced gastrointestinal side effects.These results might contribute to more personalized and safer treatment with metformin.

To improve the quality of patient treatment by improving the functionality of medical devices in healthcare institutions. To present the results of the safety and performance inspection of patient-relevant output parameters of anesthesia machines and defibrillators defined by legal metrology. This study covered 130 anesthesia machines and 161 defibrillators used in public and private healthcare institutions, during a period of two years. Testing procedures were carried out according to international standards and legal metrology legislative procedures in Bosnia and Herzegovina. The results show that in 13.84% of tested anesthesia machine and 14.91% of defibrillators device performance is not in accordance with requirements and should either have its results be verified, or the device removed from use or scheduled for corrective maintenance. Research emphasizes importance of independent safety and performance inspections, and gives recommendations for the frequency of inspection based on measurements. Results offer implications for adequacy of preventive and corrective maintenance performed in healthcare institutions. Based on collected data, the first digital electronical database of anesthesia machines and defibrillators used in healthcare institutions in Bosnia and Herzegovina is created. This database is a useful tool for tracking each device's performance over time.

In this paper development of Artificial Neural Network for classification of prediabetes and type 2 diabetes (T2D) is presented. For development of this system 310 samples consisting of information about Fasting Plasma Glucose (FPG) and blood test called HbA1c were used. All samples were obtained from several healthcare institutions in Bosnia and Herzegovina, and diagnosis of prediabetes, T2D and healthy patients in this dataset were established by medical professionals. Two-layer feedforward backpropagation network with 15 neurons in hidden layer and sigmoid transfer function, used for classification of prediabetes and T2D in this paper, was trained with 190 samples.

Background: Acute respiratory distress syndrome (ARDS) is life treating condition, with intensive general inflammation. Objective: Inflammation can be present with infection or without. Septic embolism, according to our previous experience, is more often multiple, than single. General hypoxia of hall body cause damage of all tissue, and generalinflammationintensifies. A vicious circle was formed and inflammation runs its course in what is very often irrelevant how it was begun.How often pulmonary embolism causes ARDS and what are the main features of this disease, is the goal of the study. Methods: Patients with ARDS, treated in pulmonary intensive care unit were analyzed. Chest X-ray, microbiological analysis of sputum or bronchoalveolar lavage specimen, chest CT scan, blood culture, CRP (mg/dl), deep-dimmer and blood cell count, were performed for all cases. Results: In three years period 53 patients with ARDS were treated. Out of all 19 with septic pulmonary embolism (14 multiple), (CRP 198±28). In only 12 patients origin of venous thrombus was found. Out of all 6 patients have massive non septic embolism (CRP 28±7), 18 heavy pneumonia (CRP 166±28), 4 with interstitial pneumonia (CRP 76±19), 5 with massive TB with caverns (CRP 35±13) and 6 with not well defined cause. Blood culture was positive in 14 cases with septic embolism and in 11 cases with pneumonia. CRP was elevated in all cases but highest was in septic embolism (Mann-Whitney test p=0,024). Conclusion: Septic pulmonary embolism was common cause of ARDS, mostly as multiple, and should be considered even if origin of thrombus was found or not.

Objective: Tobacco cigarette smoking is one of the major leading causes of death throughout the world. Smoking has both acute and chronic effect on haematological parameters. The aim of the present study was to assess the extent of adverse effects of cigarette smoking on biochemical characteristics in healthy smokers. Subjects and Method: One hundred and fifty six subjects participated in this study, 56 smokers and 100 non-smokers. The smokers were regularly consuming 10-20 cigarettes per day for at least 3 years. Complete blood cell count was analyzed by CELL-DYN 3700 fully automatic haematological analyzer. Results: The smokers had significantly higher levels of white blood cell (p

Contemporary inhabitants of the Balkan Peninsula belong to several ethnic groups of diverse cultural background. In this study, three ethnic groups from Bosnia and Herzegovina - Bosniacs, Bosnian Croats and Bosnian Serbs - as well as the populations of Serbians, Croatians, Macedonians from the former Yugoslav Republic of Macedonia, Montenegrins and Kosovars have been characterized for the genetic variation of 660 000 genome-wide autosomal single nucleotide polymorphisms and for haploid markers. New autosomal data of the 70 individuals together with previously published data of 20 individuals from the populations of the Western Balkan region in a context of 695 samples of global range have been analysed. Comparison of the variation data of autosomal and haploid lineages of the studied Western Balkan populations reveals a concordance of the data in both sets and the genetic uniformity of the studied populations, especially of Western South-Slavic speakers. The genetic variation of Western Balkan populations reveals the continuity between the Middle East and Europe via the Balkan region and supports the scenario that one of the major routes of ancient gene flows and admixture went through the Balkan Peninsula.

Introduction: Because of increasing prevalence of T2MD worldwide, it’s very important to recognize risk factors for diabetic complications, as soon as possible. Symptoms of complications appear a few or many years after tissue damage. So, it’s imperative to establish surveillance of diabetics with laboratory and other diagnostic procedures for early recognition of diabetic complications. Follow up of clinical curs of diabetes, by using databases of patients, provide possibility for permanent analysis of important laboratory parameters and any changes could be registered. Although an emerging evidence suggests a strong association of ALT (alanine aminotransferase) and γGT (gamma glutamyl transferase) activity with type 2 diabetes mellitus (T2DM), only a limited number of studies have analyzed the association of AST (aspartate aminotransferase), ALT, γGT, and ALP (alkaline phosphatase) activities in controlled T2DM. Material and Methods: Gender differences are of special interest in trying to follow diabetes progression and development of its complications. Here the activities of ALT, AST, γGT, ALP were analyzed as well as levels of glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) in 40 T2DM patients and 40 age-matched healthy subjects. Blood samples were collected from all participants in regular 3-months intervals up to 6 months period. Standard IFCC enzyme protocols were used to determine enzyme activities. Results and discussion: In first measured interval, significantly higher activities of ALT (p= 0,050) and glucose levels (p=0,045) were shown in male. A significant correlation was shown between ALT and AST activity with FPG and HbA1c levels in first and third measured interval. ALT activity was much higher in the group of patients with poor glycemia control. Average levels of activities of enzymes stay nearly in normal limits, but changes of enzymes activities should be recognized as soon as possible, earlier than tissue changes and diabetic complications become irreversible.