67 68 Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its 69 mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium 70 reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of 71 different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the 72 facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10) greater 73 metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the 74 top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in 75 regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% 76 (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the 77 effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of 78 metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. 79

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.

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.

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.

Summary Background: Peroxisome proliferator-activated receptor gamma (PPARg) is a key transcription factor in adipogene-sis, and also regulates a number of genes associated with lipid storage and insulin sensitivity. Single nucleotide polymorphisms (SNPs) in the PPARG gene have been associated with obesity and diabetes. In this study, we explored the relationship of three PPARG gene variants with the metabolic syndrome (MetS) and related traits in a population from Bosnia and Herzegovina. Methods: Anthropometric and biochemical parameters were measured in 43 patients with MetS and 43 healthy controls. Subjects were genotyped for Pro12Ala (rs1801282) and 1431C>T (rs3856806) SNPs by classic PCR–restriction fragment length polymorphism analysis, and for-681C>G (rs10865710) variant by real-time PCR. Results: The genotype distributions for the three polymorphisms were not significantly different between MetS patients and controls. The Pro12Ala and 1431C>T variants were associated with lower body mass index in the control subjects (p=0.012 and p=0.049, respectively). In this group, the carriers of Pro12Ala had also lower waist circumference compared to the wild-type homozygotes (p=0.045). Conclusions: Results of our preliminary study indicate a beneficial effect of a common Pro12Ala variant on the metabolic phenotype in healthy non-obese subjects.

Abstract Common variants in MTNR1B, encoding melatonin receptor 1B, have been recently associated with impaired glucose homeostasis and an increased risk for developing Type 2 diabetes (T2D). In this study we investigated the association of MTNR1B variant rs10830963 with T2D and related quantitative traits in a population from Bosnia and Herzegovina (BH). A total number of 268 subjects were recruited in the study (162 T2D patients and 106 nondiabetic controls). Subjects were genotyped for MTNR1B rs10830963 SNP by using hydrolysis probes. Our data showed that the prevalence of the MTNR1B rs10830963 risk G-allele in BH population was 26%. Furthermore, we demonstrated a significant association of MTNR1B rs10830963 variant with fasting plasma glucose (FPG) levels in nondiabetic subjects. Under the additive genetic model, each variant G-allele was associated with an increased FPG levels of 0.29 mmol/L (95% CI 0.12, 0.46, p=0.001). Strikingly, our results also showed a significant association of this MTNR1B polymorphism with increased glycated hemoglobin (HbA1c) levels in nondiabetic subjects (p=0.040, additive genetic model). An association of the MTNR1B variant rs10830963 with T2D risk was not detected in our cohort. In conclusion, here we have demonstrated the association between the common MTNR1B rs10830963 variation and fasting plasma glucose levels in BH population. Furthermore, the influence of this polymorphism on the HbA1c levels was also shown in this study, further strengthening its role in blood glucose control.

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 SLC22A1/2 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.