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.

Risk of progression of nephropathy in a population-based sample with type 2 diabetes.

AIMS: Progression through stages of nephropathy has not been well described in a large, well-characterized, population-based study. Our aims were to describe the progression of nephropathy and identify characteristics associated with progression in a U.S. population-based sample. METHODS: We identified 10,290 members of a managed care organization who had hypertension and type 2 diabetes, a urine albumin-to-creatinine ratio (UACR) measurement in 2001-2003, and at least 2 follow-up UACRs. Progression of nephropathy was defined as progression to a higher stage of nephropathy than was present at baseline. RESULTS: At baseline, 57% had normoalbuminuria, 31% had microalbuminuria, and 12% had macroalbuminuria. The incidence of nephropathy progression (per 1000 person-years) was 94.7, 35.1, and 6.5 for normo-, micro-, and macro-albuminuria, respectively. ACEi/ARB use ranged from 61-67%, except among patients with macroalbuminuria at follow-up. Age, diabetes duration, and A1C were significant predictors of progression. CONCLUSIONS: Our study, one of the first to examine the progression of nephropathy in a U.S. population-based sample, showed that among adults with diabetes and hypertension, the burden of nephropathy and its progression may be greater than previously reported. Further, the use of ACEi/ARBs was not optimal.

Initial experience with multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction.

The feasibility and safety of simultaneous multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction was analyzed in a retrospective, case-controlled study. Patients who underwent multivessel coronary intervention had a higher risk of adverse clinical outcomes through 6 months compared with matched controls in whom coronary intervention was limited to the infarct-related artery.

Incremental prognostic value of RNA ejection fraction measurements during pharmacologic stress testing: a comparison with clinical and perfusion variables.

UNLABELLED: This investigation examined the prognostic power of first-pass radionuclide angiocardiography (RNA) ejection fraction compared with clinical information and myocardial perfusion imaging in patients undergoing pharmacologic stress testing. The value of RNA and myocardial perfusion imaging in predicting death or nonfatal myocardial infarction (MI) is well established. However, limited information exists on the usefulness of combined myocardial perfusion imaging and RNA to predict prognosis, especially in patients undergoing pharmacologic stress testing. METHODS: We identified 240 patients who underwent pharmacologic stress testing with myocardial perfusion imaging and combined RNA. The patients were followed for a mean of 1.4 y. Cox proportional hazards models were used to assess the value in predicting death and MI. Multivariable models were generated to assess the independent incremental predictive value of clinical and nuclear imaging variables. Kaplan-Meier survival and event-free survival estimates were examined in patients with low (< or = 45%) versus high (>45%) ejection fractions. RESULTS: Clinical information, myocardial perfusion imaging, and RNA ejection fraction were significant predictors of the death/MI composite outcome (chi(2) = 7.4, 14.0, and 21.8, respectively). The addition of myocardial perfusion imaging to the clinical information provided incremental prognostic information (chi(2) = 15.2). The addition of RNA ejection fraction provided further predictive information (chi(2) = 22.5). However, when RNA ejection fraction was first added to the clinical information, myocardial perfusion imaging had no incremental prognostic value. CONCLUSION: For hard cardiac events, RNA ejection fraction provides prognostic information besides that provided by clinical and myocardial perfusion imaging. In patients who cannot exercise and are undergoing noninvasive evaluation with pharmacologic stress testing and myocardial perfusion imaging, ejection fraction should be measured simultaneously for risk assessment optimization.