A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.

Shape optimal design of the stem of a cemented hip prosthesis to minimize stress concentration in the cement layer.

An optimal shape of the metal stem of a cemented total hip prosthesis minimizing stress concentration in the cement layer was searched for. A gradient projection method of numerical optimization and a finite element method of stress analysis were employed. A two-dimensional model of the femoral part of a total hip prosthesis was derived equivalent to a simplified three-dimensional axisymmetric model. The result of the stress analysis of the two-dimensional model compared favorably with that of the three-dimensional axisymmetric model. Using this two-dimensional model, an optimal shape of the stem, minimizing stress concentration in the cement layer, was obtained by a gradient projection method and the shape was checked again by the three-dimensional finite element analysis. The resulting optimal shape of the stem profile was in good agreement with conventional ones, except in the proximal region where a significant amount of stress reduction in the cement layer was achieved by tapering the stem to the limit that the stem still could withstand the increased stem stress.