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


METHODS
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 beta-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.


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
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.
Liepinsh
Edgars
E
Latvian Institute of Organic Synthesis, Riga, Latvia. ledgars@biomed.lu.lv
Vilskersts
Reinis
R
Zvejniece
Liga
L
Svalbe
Baiba
B
Skapare
Elina
E
Kuka
Janis
J
Cirule
Helena
H
Grinberga
Solveiga
S
Kalvinsh
Ivars
I
Dambrova
Maija
M
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002331:Carnitine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D019270:Fructosamine / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control; D017288:Pain Threshold; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D002317:Cardiovascular Agents; D007004:Hypoglycemic Agents; D008055:Lipids; D008763:Methylhydrazines; D019270:Fructosamine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002331:Carnitine; D020155:3-Hydroxybutyric Acid