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DeFronzo R.A.,University of Texas Health Science Center at San Antonio | Tripathy D.,University of Texas Health Science Center at San Antonio | Schwenke D.C.,Phoenix Veterans Affairs VA Health Care System | Schwenke D.C.,Arizona State University | And 14 more authors.
New England Journal of Medicine

BACKGROUND: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima-media thickening (31.5%, P = 0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P = 0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P = 0.007). CONCLUSIONS: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. Copyright © 2011 Massachusetts Medical Society. Source

Levinger L.,York College | Serjanov D.,York College | Serjanov D.,Health Science Center at Brooklyn
RNA Biology

Numerous mutations in the mitochondrial genome are associated with maternally transmitted diseases and syndromes that affect muscle and other high energy-demand tissues. The mitochondrial genome encodes 13 polypeptides, 2 rRNAs and 22 interspersed tRNAs via long bidirectional polycistronic primary transcripts, requiring precise excision of the tRNAs. Despite making up only ∼10% of the mitochondrial genome, tRNA genes harbor most of the pathogenesis-related mutations. tRNase Z endonucleolytically removes the pre-tRNA 3′ trailer. The flexible arm of tRNase Z recognizes and binds the elbow (including the T-loop) of pre-tRNA. Pathogenesis-related T-loop mutations in mitochondrial tRNAs could thus affect tRNA structure, reduce tRNase Z binding and 3′ processing, and consequently slow mitochondrial protein synthesis. Here we inspect the effects of pathogenesis-related mutations in the T-loops of mitochondrial tRNAs on pretRNA structure and tRNase Z processing. Increases in KM arising from 59A > G substitutions in mitochondrial tRNAGly and tRNAIle accompany changes in T-loop structure, suggesting impaired substrate binding to enzyme. © 2012 Landes Bioscience. Source

Biro D.,Health Science Center at Brooklyn
Culture, Medicine and Psychiatry

Medicine regards pain as a signal of physical injury to the body despite evidence contradicting the linkage and despite the exclusion of vast numbers of sufferers who experience psychological pain. By broadening our concept of pain and making it more inclusive, we would not only better accommodate the basic science of pain but also would recognize what is already appreciated by the layperson-that pain from diverse sources, physical and psychological, share an underlying felt structure. © 2010 The Author(s). Source

DeFronzo R.A.,The Texas Institute | DeFronzo R.A.,University of Texas Health Science Center at San Antonio | Tripathy D.,The Texas Institute | Tripathy D.,University of Texas Health Science Center at San Antonio | And 19 more authors.
Diabetes Care

OBJECTIVE-Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM).We examined which characteristics at baseline predicted the development of T2DMversus maintenance of IGT or conversion to normal glucose tolerance. RESEARCH DESIGN AND METHODS-We studied 228 subjects at high risk with IGT who received treatment with placebo in ACTNOWand who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years. RESULTS-In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ΔG0-120 during OGTT, HbA 1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ΔI0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [ΔI0-120/ ΔG0-120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [ΔI0-120/ΔG0-120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P<0.0001)was the variablemost closely associated with reduced risk of diabetes. CONCLUSIONS-In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001). © 2013 by the American Diabetes Association. Source

Preiss D.,University of Glasgow | Tikkanen M.J.,University of Helsinki | Welsh P.,University of Glasgow | Ford I.,University of Glasgow | And 14 more authors.
JAMA - Journal of the American Medical Association

Context: Statin therapy has been associated with pancreatitis in observational studies. Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, fibrates may lead to the development of gallstones, a risk factor for pancreatitis. Objective: To investigate associations between statin or fibrate therapy and incident pancreatitis in large randomized trials. Data Sources: Relevant trials were identified in literature searches of MEDLINE, EMBASE, and Web of Science (January 1, 1994, for statin trials and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data were tabulated where available (6 trials). Unpublished data were obtained from investigators (22 trials). Study Selection: We included randomized controlled cardiovascular end-point trials investigating effects of statin therapy or fibrate therapy. Studies with more than 1000 participants followed up for more than 1 year were included. Data Extraction: Trial-specific data described numbers of participants developing pancreatitis and change in triglyceride levels at 1 year. Trial-specific risk ratios (RRs) were calculated and combined using random-effects model meta-analysis. Betweenstudy heterogeneity was assessed using the I 2 statistic. Results: In 16 placebo- and standard care-controlled statin trials with 113 800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62-0.97; P=.03; I 2=0%]). In 5 dose-comparison statin trials with 39 614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59-1.12; P=.21; I 2=0%]). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65-0.95; P=.01; I 2=0%). In 7 fibrate trials with 40 162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P=.053; I 2=0%]). Conclusion: In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels. ©2012 American Medical Association. All rights reserved. Source

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