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This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A > G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A > C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T > A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan. Communicated by Ramaswamy H. Sarma.

Objectives: Type 2 diabetes is a complex genetic disorder, and a large number of genetic polymorphisms may be involved in its pathogenesis. Pharmacologically, type 2 diabetes can be treated with 9 different approved classes of drugs, but metformin is suggested as the first line of therapy, followed by sulfonylureas., Methods: This was a case-control study consisting of 300 metformin responders and 300 metformin nonresponders in patients with type 2 diabetes and 300 healthy Pakistani subjects. Genotyping of the SLC22A3 G>A polymorphism was performed by allele-specific polymerase chain reaction (PCR) for microRNA 147 expression; real-time polymerase chain reaction was used, and expressional analysis of SLC22A3 was done by semiquantitative polymerase chain reaction., Results: GA and AA genotypes were highly significantly associated with the drug treatments when compared with controls. A statistically significant difference was observed in the distribution of the SLC22A3 A allele between healthy subjects and patients with type 2 diabetes. When odds ratios were adjusted for glycated hemoglobin levels and postprandial and fasting blood glucose levels, our findings showed that the overexpression of allele A of the rs3088442 G>A variant may act as a protective allele and is associated with the clinical response to metformin. microRNA 147 expression was found to be increased in patients who were metformin responders compared with the nonresponder group and controls. mRNA expression of SLC22A3 was significantly reduced in patients taking metformin as compared to other groups., Conclusions: These results suggested that the SLC22A3 rs3088442 at position 2282 A allele may confer metformin clinical responses in patients with type 2 diabetes in the Pakistani population. Overexpression of microRNA 147 is associated with a downward expression of the SLC22A3 gene in patients who have type 2 diabetes., (Copyright © 2018 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the frequencies of single nucleotide polymorphisms rs201919874 and rs138244461 in genes SLC22A2 and SLC47A2 respectively in Pakistani diabetes patients in order to characterise the genetic variants and determine their association with the pharmacokinetics of metformin., Methods: The case-control study was conducted at the International Islamic University, Islamabad, Pakistan, from June 2016 to June 2017, and comprised genotypes of diabetic cases and matching controls which were determined following allele-specific polymerase chain reaction. Cases were further divided into Group A and Group B. The former consisted of diabetics who were on monotherapy of metformin, while the latter consisted of diabetics treated with a combination of metformin and sulfonylureas. In-silico analysis was performed to verify the effect of single nucleotide polymorphisms rs201919874 and rs138244461 on the structure of genes. Association was statistically determined using SPSS 18., Results: Of the 1200 subjects, 800(66.6%) were cases and 400(33.3%) were controls. Among the cases, 400(50%) each were in Group A and Group B. Significant difference was observed in the distribution of rs201919874 between Group A and controls (p<0.05) and between Group B and controls (p<0.05) for heterozygous genotypic frequency and for allelic frequency. Conversely, statistically significant difference was observed in rs138244461 (p<0.05) for all genotypic and allelic frequencies. Genotypes were significantly associated with glycated haemoglobin, random and fasting glucose levels in Group A compared to Group B (p<0.05). In-silico analysis showed that both single nucleotide polymorphisms were expected to create significantly damaging structural changes in domains and helix (p<0.05 each)., Conclusions: Both exonic single nucleotide polymorphisms were found to be associated with the pharmacokinetics of metformin.

Objective: To compare the effects of bedtime NPH Insulin vs Metformin combined with Glibenclamide in patients who are obese and had secondary failure to sulphonylurea treatment., Design and Methods: Prospective, randomized, comparative study of patients having type-II diabetes, without complications with associated obesity and secondary failure to sulphonylureas. Thirty-six obese patients who continued to have blood glucose values of fasting > 150 mg/dl and/or random > 220 mg/dl, after 8 weeks of intensive dietary and drug therapy., Interventions: For the 20 weeks of study, the patients were randomised in two equal groups, one receiving 20 to 40 units of NPH Insulin at bed time and the second group, Metformin upto a maximum dose of 3 grams, along with Sulphonylureas., Results: Both the groups showed, a significant reduction in the blood glucose values, with an average decrease of 50 mg/dl. The other monitored parameters, such as, serum cholesterol, triglycerides and blood pressure values, also demonstrated a similar downwards trend. However, the drop out rate was high in the Insulin treated group and the remainder group did show slight increase in weight and BMI, while the reverse, stood true, for the metformin group, with 100% compliance rate., Conclusion: Metformin, in obese, type II diabetics, with secondary failure to Sulphonylureas, is an effective, safe and well tolerated treatment, which not only improves the metabolic control but also favourably modifies other parameters such as weight, total cholesterol and triglyceride values.