Association of ACE2 and TMPRSS2 genes variants with disease severity and most important biomarkers in COVID-19 patients in Bosnia and Herzegovina.

AIM: To assess the association of single nucleotide polymorphisms (SNPs) in the ACE2 and TMPRSS2 genes with COVID-19 severity and key biomarkers. METHODS: The study involved 750 COVID-19 patients from Bosnia and Herzegovina, divided into three groups: mild, moderate, and severe cases. Genetic variations within the ACE2 (rs2285666) and TMPRSS2 (rs2070788) genes were examined with real-time polymerase chain reaction. Biochemical markers were determined with standard procedures. RESULTS: There was a significant difference in the rs2070788 genotype distribution between patients with mild and moderate symptoms, but not between other groups. For the rs2285666 polymorphism, no significant difference in genotype distribution was found. In patients with mild symptoms, carriers of the GG genotype of rs2070788 had significantly higher total bilirubin levels than carriers of the AA genotype. Similarly, carriers of the TT genotype of rs2285666 had significantly higher activated partial thromboplastin time and international normalized ratio, and lower lactate dehydrogenase levels compared with the CC genotype. Among patients with severe symptoms, carriers of the GG genotype showed significantly higher potassium levels than carriers of the AA genotype, while carriers of the TT genotype showed significantly higher erythrocyte count as well as hemoglobin and hematocrit levels compared with the CC genotype. CONCLUSION: This study highlights the role of genetic factors, particularly SNPs in the ACE2 and TMPRSS2 genes, in determining COVID-19 severity, aiding patient risk assessment and prognosis.

Principal component analysis of the oxidative stress, inflammation, and dyslipidemia influence in patients with different levels of glucoregulation.

Background: The aim of the study was to explore the mutual relationship between oxidative stress, inflammation and metabolic biomarkers in subjects with prediabetes (PRE), newly diagnosed type 2 diabetes patients (NT2D) and overt type 2 diabetes (T2D) using principal component analysis (PCA) as a thorough statistical approach. Methods: Glycated hemoglobin, lipid parameters, inflammation (IL-6, CRP and fibrinogen) and oxidative stress markers pro-oxidants (AOPP, PAB, TOS) and antioxidants (PON1, tSHG, TAS) were measured. PCA was applied to explore the factors that the most strongly influenced glucoregulation. Results: A total of 278 subjects were (i.e., 37 PRE, 42 NT2D and 99 T2D) were compared with 100 healthy subjects as a control group (CG). PCA emphasized 4 different factors explaining 49% of the variance of the tested parameters: oxidative stress-dyslipidemia related factor (with positive loading of TG and tSHG, and with negative loading of HDL-c and TAS), dyslipidaemia related factor (i.e., total cholesterol and LDL-c, both with positive loading), Anthropometric related factor (i.e., waist and hip circumference, both with positive loading) and oxidative stressInflammation related factor (i.e., PAB, fibrinogen, and CRP all with positive loading). Out of these 4 factors, only oxidative stress - dyslipidaemia related factor showed a significant predictive capability towards poor glucoregulation. An increase in this factor by one unit showed a 1.6 times higher probability for poor glucoregulation. Conclusions: Redox imbalance (determined with lower TAS and higher tSHG), in addition to higher TG and lower HDLc was associated with poor glucoregulation.

IDegLira Improves Metabolic Control in Patients with Type 2 Diabetes Previously Treated with Premix Insulin.

Background: IDegLira( fixed combination of GLP 1 receptor agonist and insulin) has been shown to be effective in improving the glucoregulation in patients previously treated with oral therapy as well as individual components, GLP-1 receptor agonist or basal insulin. Objective: The aim of this study is to examine the parameters of metabolic control in patients treated with IDegLira who were previously treated with premix insulin in several daily doses and to compare them with patients whose premix insulin dose was increased. Methods: The study included 100 patients who had been previously treated with two or three daily doses of premix insulin. Half of the patients were switched to IdegLira( group I), and half (group II) had their insulin dose increased according to the clinical assessment of the physician. Fasting glucose, 2h postprandial glucose, HbA1c, BMI and insulin dose were determined at baseline and at follow-up after 6 months. Results: Patients treated with IDegLira compared to patients whose insulin dose was increased achieved significantly lower fasting glucose (p <0.001), postprandial glucose (p <0.001), HbA1c (p <0.001), BMI (p <0.001) with a significantly lower insulin dose (p <0.001). Comparison of the same parameters within the groups of patients at the beginning and after 6 months showed that patients who were switched from insulin premix to IDegLira achieved significantly lower fasting blood glucose (p <0.001), postprandial glucose (p <0.001), HbA1c (p < 0.001), BMI (p <0.001) with significantly lower insulin dose within the fixed combination (p <0.001). Patients with gradually increased insulin dose achieved significant reduction in fasting glucose (p = 0.021) and postprandial glucose (p = 0.036),but with a significantly higher insulin dose (p = 0.005). There was also a slight increase in BMI that was not statistically significant (p = 0.267). Conclusion: The obtained data suggest that switching patients from a complex insulin regimen to a fixed combination of basal insulin and GLP 1 receptor agonist in comparison to increases in insulin dose results in a significant improvement in fasting glucose, postprandial glucose, HbA1c, and BMI. The results were achieved with a significantly lower daily insulin dose.

Chest x-ray resolution after SARS-CoV-2 infection.

Aim To analyse the resolution of chest X-ray findings in relation to laboratory parameters in patients infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a two- month followup. Analysis of chest X-ray findings in the first few months after the disease is the main goal of our work. Methods Out of the total of 343 patients chest X-ray findings were followed in 269 patients. Patients were divided into groups according to the severity of findings. D-dimer, inflammatory markers, blood cell count, neutrophil lymphocyte ratio (NLR) were analysed. Chest X-ray was analysed during the hospitalization on the day of admission, on the third, the seventh and the fourteenth day (scoring method was used). After discharge chest X-ray was performed in a two-week follow-up, then after one and two months, and after three months if necessary. Results Incomplete chest X-ray resolution was identified in 24 (39.34%) patients with severe, 27 (22.31 %) patients with moderate and in three (3.91%) patients with mild findings. Statistical significance was established in overall score by comparison between all groups (p<0.001), and in the moderate compared to the mild group (p=0.0051). The difference of NLR in the severe compared to the moderate group was observed (p=0.0021) and in the severe group compared to the mild group (p=0.00013). Conclusion Chest X-ray findings persisted mostly in the severe group followed by the moderate and mild ones. Long-term followup is necessary for the appropriate treatment and prevention of fibrosis, and reduction of symptoms.

Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype.

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.

Pharmacogenetics of new classes of antidiabetic drugs.

Type 2 diabetes (T2D) has a continuously rising prevalence worldwide. Pharmacogenetics has been recognized as a promising concept for pharmacological treatment of T2D, as antidiabetic drugs are not equally effective and safe for all patients, and the costs of diabetes treatment are increasing. The latest published guidelines on T2D treatment firmly endorse the use of newer antidiabetic drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-IVi), and glucagon-like peptide-1 receptor agonists (GLP-1RA), considering their satisfactory pharmacological effect and good safety profile. Furthermore, SGLT2i and GLP-1RA show protective effects in patients with established atherosclerotic cardiovascular disease and chronic kidney disease. However, there has been growing evidence that the effectiveness and safety of these drug classes could depend on genetic variability. Here, we summarized the results of the published studies on the pharmacogenetic biomarkers for the three drug classes. A number of genetic variations have been investigated so far. The explored candidate genes mostly encode drug targets, drug-metabolizing enzymes, and genes linked to T2D risk. Although many of the results are promising, it is still necessary to obtain more information from larger controlled studies to confirm their clinical significance. This approach may lead towards more personalized treatment for patients with T2D.

Assessment of hematologic indices and their correlation to hemoglobin A1c among Bosnian children with type 1 diabetes mellitus and their healthy peers.

BACKGROUND: Altered levels of many hematological parameters have been directly associated with diabetes in adults, while studies on children with type 1 diabetes mellitus are lacking. The aim of this study was to determine hematological indices in diabetic Bosnian children in comparison to healthy controls as well as to correlate their levels to blood glucose and hemoglobin A1c. METHODS: 100 healthy and 100 children with type 1 diabetes mellitus (age 1-18) were included in this study. Complete blood count, hemoglobin A1c, and glucose were tested. Results were analysed by IBM SPSS Statistics version 23. RESULTS: Significant differences (p<0.05) between healthy and diabetic children were found in relation to HbA1c, glucose, mean platelet volume, the number of white blood cells and erythrocytes, hematocrit, hemoglobin and MCH values. No gender differences or significant age differences were seen for hemoglobin, hematocrit, and MCV, while platelets, MPV, and MCH differed by age only in healthy children. When diabetic children were classified according to HbA1c levels, significant differences were seen for erythrocyte count and hematocrit value (p=0.013 and 0.019, respectively). The number of erythrocytes and white blood cells correlated significantly with HbA1c (p=0.037 and 0.027, respectively). CONCLUSIONS: Lower levels of erythrocytes, hematocrit, and hemoglobin in diabetic compared to healthy children indicate possible development of anemia, while higher MCV, MCH, and MPV values indicate an alteration in erythrocyte morphology. Hematological indices could be a useful inexpensive tool in the diagnosis and follow up of type 1 diabetes in children.

Effects of TCF7L2 rs7903146 variant on metformin response in patients with type 2 diabetes.

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, HbA1c, 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.

Association of FTO Gene Variant (rs8050136) with Type 2 Diabetes and Markers of Obesity, Glycaemic Control and Inflammation.

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 Tesanj 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 role of metabolic therapy with trimetazidine in effort tolerance in patients with ischemic heart disease.

Aim To investigate whether or not additional treatment of ischemic heart disease with trimetazidine could improve effort tolerance and overall quality of life of patients with ischemic heart disease. Methods The study included 200 patients with ischemic heart disease. The sample was divided into 2 randomly selected groups: experimental and control group. The diagnostic procedures included: trade-mill test according to Bruce protocol, heart ultrasound for assessment of ejection fraction, test for the assessment of quality of life and subjective problems (Short Form SF 36). Patients were tested for time of discharge from hospital, after 6 and 12 months, including re-evaluation of the overall condition of the previous period. Results Patients have been tested for the tolerance of effort with the measurement Metabolic Equivalent of TASK (METs), which is the equivalent of physical labor. Patients treated with trimetazidine since the time of hospital discharge achieved an average of 3.68, after 6 months 5.68, and after 12 months 7.79 METs. The control group achieved 3.68, 3.59 and 3.87 METs, respectively. Using Mann-Whitney test no difference at discharge time (p=0.880), but after six and twelve months there was some difference (p<0.001). Results of ejection fraction measured by echocardiography were similar. No difference between the two groups with regard to time of discharge (p=0.821, but p<0.001 after six and twelve months, respectively). Conclusion Patients treated with conventional therapy including trimetazidine have better tolerance to effort and better ejection fraction on heart ultrasound examination in comparison with those treated without trimetazidine, so trimetazidin improve the metabolic balance of heart muscle.

Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study.

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty-nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR, 2.81; 95% CI, 1.30-6.09; P = .009) and better response to SU treatment (ß, -0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

Importance of inflammatory markers and IL-6 for diagnosis and follow up of patients with type 2 diabetes mellitus.

Aim To analyse the long-term impact of altered metabolism on the level of mediators of inflammatory response in female patients with type 2 diabetes. Methods This study included 97 female patients with type 2 diabetes and 107 female, nondiabetic control subjects, who were recruited at the Clinical Centre University of Sarajevo and the General Hospital Tesanj. The effects of glycaemic control on markers of inflammatory response represented by C-reactive protein (CRP), fibrinogen, leukocytes, sedimentation rate, and cytokine IL-6 were tested. All subjects were free of evidence of infections, surgery, thyroid disease, polycystic ovarian syndrome, active liver and kidney damage. All biochemical analyses were performed according to standard International Federation of Clinical Chemistry (IFCC) protocols. Results A significant increase of fibrinogen (p<0.001), CRP (p=0.001), interleukin-6 (p=0.013), leukocytes (p<0.001) and sedimentation rate (p=0.008) in diabetic female population compared to control subjects was found. A significant correlation between CRP and haemoglobin A1c (p=0.035), interleukin-6 and glucose (p=0.032), IL-6 and body mass index (p=0.007) was found. Conclusion Our data suggest that inflammation plays an important role in the pathogenesis of diabetes in female diabetic population. A more detailed study on a far larger number of subjects is needed if they were to be used effectively as biomarkers in the primary prevention of type 2 diabetes in this population.

Effect of Cigarette Smoking on Haematological Parameters in Healthy Population.

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<0,001), hemoglobin (p=0,042), mean corpuscular volume (p=0,001) and mean corpuscular hemoglobin concentration (p<0,001). All other measured parameters did not differ significantly. Cigarette smoking caused a significant increase (p<0,001) in red blood cells, white blood cells (p=0,040), hemoglobin (p<0,001), hematocrit (p=0,047) and mean corpuscular hemoglobin (p<0,001) in males in comparison to female smokers. CONCLUSION: In conclusion, our study showed that continuous cigarette smoking has severe adverse effects on haematological parameters (e.g., hemoglobin, white blood cells count, mean corpuscular volume, mean corpuscular hemoglobin concentration, red blood cells count, hematocrit) and these alterations might be associated with a greater risk for developing atherosclerosis, polycythemia vera, chronic obstructive pulmonary disease and/or cardiovascular diseases.

Incidence of prediabetes and risk of developing cardiovascular disease in women with polycystic ovary syndrome.

Our aim was to determine the incidence of prediabetes and risk of developing cardiovascular disease (CVD) in women with polycystic ovary syndrome (PCOS). This prospective, observational study included 148 women with PCOS, without Type 2 diabetes mellitus (T2DM) and CVD present at baseline. In the fasting blood samples, we measured lipids, glucose, and insulin levels during oral glucose tolerance test, levels of C-reactive protein (CRP), steroids, 25-hydroxyvitamin D (25-OHD), prolactin, thyroid-stimulating hormone, and parathyroid hormone. The follow-up period was 3 years. At baseline, prevalent prediabetes was present in 18 (12%) of PCOS cases and it progressed to T2DM in 5 (3%) of the cases. Incident prediabetes during the follow-up was noted in 47 (32%) women or 4.7 per 1000 persons/year. Prediabetes was associated with elevated body mass index (BMI) (odds ratio [OR] = 1.089, confidence interval [CI]: 1.010; 1.174, p = 0.026), high baseline levels of CRP (OR = 3.286, CI: 1.299; 8.312, p = 0.012), homeostatic model assessment - insulin resistance (IR) (OR = 2.628, CI: 1.535; 4.498, p < 0.001), and high lipid accumulation product (LAP) (OR = 1.009, CI: 1.003; 1.016, p = 0.005). Furthermore, prediabetes was associated with low 25-OHD (OR = 0.795, CI: 0.724; 0.880, p ≤ 0.05). In addition, cardiovascular risk in PCOS women with prediabetes was high (hazard ratio = 1.092, CI: 1.036; 1.128, p < 0.001). We showed association of prediabetes with high BMI, IR, markers of inflammation, LAP, and low serum 25-OHD concentration. IR appears to be more relevant than the other predictors of prediabetes risk in this study. PCOS women are considered as a high-risk population for prediabetes.

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Effect of Serotonin Transporter 5-HTTLPR Polymorphism on Gastrointestinal Intolerance to Metformin: A GoDARTS Study.

OBJECTIVE: The mechanism causing gastrointestinal intolerance to metformin treatment is unknown. We have previously shown that reduced-function alleles of organic cation transporter 1 (OCT1) are associated with increased intolerance to metformin. Considering recent findings that serotonin reuptake transporter (SERT) might also be involved in metformin intestinal absorption, and the role of serotonin in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in the SERT gene and metformin gastrointestinal intolerance. RESEARCH DESIGN AND METHODS: We explored the effect of composite SERT 5-HTTLPR/rs25531 genotypes, L*L* (LALA), L*S* (LALG, LAS), and S*S* (SS, SLG, LGLG), in 1,356 fully tolerant and 164 extreme metformin-intolerant patients by using a logistic regression model, adjusted for age, sex, weight, OCT1 genotype, and concomitant use of medications known to inhibit OCT1 activity. RESULTS: The number of low-expressing SERT S* alleles increased the odds of metformin intolerance (odds ratio [OR] 1.31 [95% CI 1.02-1.67], P = 0.031). Moreover, a multiplicative interaction between the OCT1 and SERT genotypes was observed (P = 0.003). In the analyses stratified by SERT genotype, the presence of two deficient OCT1 alleles was associated with more than a ninefold higher odds of metformin intolerance in patients carrying the L*L* genotype (OR 9.25 [95% CI 3.18-27.0], P < 10-4); however, it showed a much smaller effect in L*S* carriers and no effect in S*S* carriers. CONCLUSIONS: Our results indicate that the interaction between OCT1 and SERT genes might play an important role in metformin intolerance. Further studies are needed to replicate these findings and to substantiate the hypothesis that metformin gastrointestinal side effects could be related to the reduced intestinal serotonin uptake.

Use of Databases for Early Recognition of Risk of Diabetic Complication by Analysis of Liver Enzymes in Type 2 Diabetes Mellitus.

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.

Association of LPIN1 gene variations with markers of metabolic syndrome in population from Bosnia and Herzegovina.

AIM: To investigate association of two LPIN1 gene variations with main traits of metabolic syndrome (MS) (waist circumference, body mass index, blood pressure, triglycerides, HDL-cholesterol and fasting glucose levels) in population from Bosnia and Herzegovina. METHODS: This study included 43 patients with metabolic syndrome and 43 healthy controls from General Hospital in Tesanj, Bosnia and Herzegovina. Subjects were genotyped for two LPIN1 gene variations (rs11693809: C>T and rs2716610: C>T) by real time PCR method. RESULTS: In control subjects LPIN1 polymorphism, rs2716610: C>T, was significantly associated with a lower body mass index (BMI) (p=0.008) and waist circumference (p=0.008). The second analyzed rs11693809: C>T polymorphism was associated with lower blood HbA1c levels (p=0.048) in a group of MS patients. CONCLUSION: Results of our study suggest that rs2716610: C>T polymorphism of LPIN1 gene could have a protective effect against development of metabolic syndrome, while rs11693809: C>T might affect a glucose control in patients with MS.

Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study.

Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.

Pharmacogenetics and personalized treatment of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic with considerable health and economic consequences. T2DM patients are often treated with more than one drug, including oral antidiabetic drugs (OAD) and drugs used to treat diabetic complications, such as dyslipidemia and hypertension. If genetic testing could be employed to predict treatment outcome, appropriate measures could be taken to treat T2DM more efficiently. Here we provide a review of pharmacogenetic studies focused on OAD and a role of common drug-metabolizing enzymes (DME) and drug-transporters (DT) variants in therapy outcomes. For example, genetic variations of several membrane transporters, including SLC2A1/2 and SLC47A1/2 genes, are implicated in the highly variable glycemic response to metformin, a first-line drug used to treat newly diagnosed T2DM. Furthermore, cytochrome P450 (CYP) enzymes are implicated in variation of sulphonylurea and meglitinide metabolism. Additional variants related to drug target and diabetes risk genes have been also linked to interindividual differences in the efficacy and toxicity of OAD. Thus, in addition to promoting safe and cost-effective individualized diabetes treatment, pharmacogenomics has a great potential to complement current efforts to optimize treatment of diabetes and lead towards its effective and personalized care.