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Metabolic and cardiovascular effects of chronic mild hyperuricemia in rodents
  1. Sun K Park1,
  2. Tara R Rosenthal2,
  3. Jessica S Williams2,
  4. John M Shelton2,3,
  5. Masaya Takahashi4,5,
  6. Shanrong Zhang5,
  7. Ion Alexandru Bobulescu1,2
  1. 1The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas, USA
  2. 2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  3. 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  4. 4Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  5. 5The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  1. Correspondence to Dr Ion Alexandru Bobulescu, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; alexandru.bobulescu{at}utsouthwestern.edu

Abstract

Mildly elevated serum uric acid levels are common in people with metabolic syndrome and type 2 diabetes mellitus (T2DM), but whether elevated uric acid has a causal role in the pathogenesis of diabetes remains uncertain. We tested whether chronic mild hyperuricemia in rodents under controlled laboratory conditions can cause glucose intolerance in otherwise healthy animals, or whether it can worsen glucometabolic control in animals that are genetically predisposed to T2DM. We used an established model of experimental hyperuricemia in rodents with potassium oxonate dietary supplementation, which led to sustained, approximately two-fold elevation of uric acid compared with control animals. We also reversed the hyperuricemic effect of oxonate in some animals by treatment with a xanthine oxidase inhibitor. Manipulation of serum uric acid levels in Sprague-Dawley rats for up to 18 weeks did not affect fasting glucose and glucose tolerance. Blood pressure was also not affected by hyperuricemia in rats fed a Western-type diet. We next sought to determine whether uric acid may aggravate or accelerate the onset of glucometabolic abnormalities in rats already predisposed to T2DM. Chronic oxonate treatment in Zucker diabetic fatty (ZDF) and lean control rats for up to 6 weeks did not affect fasting glucose, insulin, and glucose tolerance in ZDF rats. Taken together, these findings indicate that elevated uric acid does not directly contribute to the pathogenesis of glucose intolerance and T2DM in rodents.

  • diabetes mellitus
  • rats
  • hypertension

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Footnotes

  • Contributors Conceived and designed experiments: IAB. Performed experiments: SKP, TRR, JSW, SZ and IAB. Analyzed the data: SKP, TRR, MT, SZ and IAB. Interpreted results, prepared figures and drafted manuscript: SKP and IAB. Edited and revised manuscript: SKP, JSW, JMS, MT and IAB. Approved the final version: SKP, TRR, JSW, JMS, SZ, MT and IAB.

  • Funding IAB was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant nos K01-DK090282 and R01-DK113377. The authors also acknowledge support from the research cores of the University of Texas Southwestern O’Brien Kidney Research Center (NIDDK grant P30-DK079328) and the Mineral Metabolism laboratories.

  • Competing interests This work was supported in part by an Investigator Initiated Sponsored Research (IISR) grant from Takeda Pharmaceuticals USA (Takeda) to IAB. This grant provided one study drug (Febuxostat) free of charge for animal experiments, as well as research costs that were paid directly to the University of Texas Southwestern Medical Center. Takeda did not provide honoraria, fees, travel costs, or any other form of payment to the study investigators and had no role (direct or indirect) in study design, data collection and analysis, preparation of the manuscript, or decision to publish. The authors have no other conflicts of interest to disclose.

  • Patient consent Not required.

  • Ethics approval Institutional Animal Care and Use Committee (IACUC) at University of Texas Southwestern Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data are available upon request.

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