Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats

Edgars Liepinsh, Reinis Vilskersts, Liga Zvejniece, Baiba Svalbe, Elina Skapare, Janis Kuka, Helena Cirule, Solveiga Grinberga, Ivars Kalvinsh, Maija Dambrova

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Background and purpose: Mildronate [3-(2,2,2-trimethylhydrazinium) propionate] is an anti-ischaemic drug whose mechanism of action is based on its inhibition of L-carnitine biosynthesis and uptake. As L-carnitine plays a pivotal role in the balanced metabolism of fatty acids and carbohydrates, this study was carried out to investigate whether long-term mildronate treatment could influence glucose levels and prevent diabetic complications in an experimental model of type 2 diabetes in Goto-Kakizaki (GK) rats. Experimental approach: GK rats were treated orally with mildronate at doses of 100 and 200 mg-kg-1 daily for 8 weeks. Plasma metabolites reflecting glucose and lipids, as well as fructosamine and b-hydroxybutyrate, were assessed. L-carnitine concentrations were measured by ultra performance liquid chromatography with tandem mass spectrometry. An isolated rat heart ischaemia-reperfusion model was used to investigate possible cardioprotective effects. Pain sensitivity was measured with a tail-flick latency test. Key results: Mildronate treatment significantly decreased L-carnitine concentrations in rat plasma and gradually decreased both the fed-and fasted-state blood glucose. Mildronate strongly inhibited fructosamine accumulation and loss of pain sensitivity and also ameliorated the enhanced contractile responsiveness of GK rat aortic rings to phenylephrine. In addition, in mildronate-treated hearts, the necrosis zone following coronary occlusion was significantly decreased by 30%. Conclusions and implications: These results demonstrate for the first time that in GK rats, an experimental model of type 2 diabetes, mildronate decreased L-carnitine contents and exhibited cardioprotective effects, decreased blood glucose concentrations and prevented the loss of pain sensitivity. These findings indicate that mildronate treatment could be beneficial in diabetes patients with cardiovascular problems.

Original languageEnglish
Pages (from-to)1549-1556
Number of pages8
JournalBritish Journal of Pharmacology
Volume157
Issue number8
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • Diabetes
  • Glucose
  • Goto-Kakizaki rat
  • L-carnitine
  • Mildronate
  • Myocardial infarction
  • Pain sensitivity

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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