AimsMetformin 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.MethodsThis 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.ResultsForty‐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).ConclusionsIn 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.

The aim of study was to evaluate endocrine changes in PCOS women during metformin treatment. One hundred women with PCOS, aged 20-40 years were included. A complete hormonal and metabolic pattern was recorded for each subject every 6 months. Metformin treatment after 6 and 12 months significantly reduced weight, BMI, waist circumference, insulin and HOMA-IR (p=0.000) with high differences of variances within repeated measurements. There was significant reduction of PRL, testosterone and estradiol (p=0.000) with small differences within repeated measurements. Metformin did not have effect on TSH. However, results showed important reduction of CRP, LH, LH/FSH, androstendione, DHEA-S and progesterone (p=0.000) with moderate differences within measures. Metformin restored menstrual cyclicity in most participants. At baseline in study group was 69% women with oligomenorrhoea, amenorrhoea or polymenorrhoea. After 12 months of treatment, only 20% PCOS women had irregular menstrual cycle (p=0.000). Hirsutism was also reduced. Intriguingly, during first 6 months of treatment in PCOS women 9 pregnancies occurred (p=0.000), while during last 6 months treatment were 2 pregnancies (p=0.317), in total 11(13%). Multiple regression model revealed that the presence of anovulation in PCOS women was strongly associated with BMI, waist, FSH and age. Insulin resistance was significantly predicted by BMI, cholesterol, progesterone and presence of hirsutism. The metformin therapy significantly improved insulin resistance, imbalance of endocrine hormones, hirsutism and menstrual cyclicity in women with PCOS. The most important predictors for duration of metformin treatment in PCOS women were testosterone, progesterone, FSH, CRP and presence of anovulation.

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.

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.