Mildronate decreases carnitine availability and up-regulates glucose uptake and related gene expression in the mouse heart.
OBJECTIVE
l-carnitine has been shown to play a central role in both fat and carbohydrate metabolisms. This study investigated whether acute and long-term treatments with an l-carnitine biosynthesis inhibitor, mildronate (3-(2,2,2-trimethylhydrazinium) propionate), modulate glucose uptake.


METHODS
The effects of acute and long-term administration of mildronate at a dose of 200 mg/kg (i.p. daily for 20 days) were tested in mouse blood plasma and heart.


RESULTS
Acute administration of mildronate in vivo, or in vitro administration with perfusion buffer in isolated heart experiments, did not induce any effects on glucose blood concentration and uptake in the heart. Mildronate long-term treatment significantly decreased carnitine concentration in plasma and heart tissues, as well as increased the rate of insulin-stimulated glucose uptake by 35% and the expression of glucose transporter 4, hexokinase II, and insulin receptor proteins in mouse hearts. In addition, expression of both carnitine palmitoyltransferases IA and IB were significantly increased. Mildronate long-term treatment statistically significantly decreased fed state blood glucose from 6+/-0.2 to 5+/-0.1 mM, but did not affect plasma insulin and C-peptide levels.


CONCLUSIONS
Our experiments demonstrate for the first time that long-term mildronate treatment decreases carnitine content in the mouse heart and leads to increased glucose uptake and glucose metabolism-related gene expression.
Liepinsh
Edgars
E
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia. ledgars@biomed.lu.lv
Vilskersts
Reinis
R
Skapare
Elina
E
Svalbe
Baiba
B
Kuka
Janis
J
Cirule
Helena
H
Pugovics
Osvalds
O
Kalvinsh
Ivars
I
Dambrova
Maija
M
D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000032:analysis; D002096:C-Peptide / Q000032:analysis; D002331:Carnitine / Q000032:analysis / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006321:Heart / Q000187:drug effects; D006593:Hexokinase / Q000235:genetics; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation
D002096:C-Peptide; D051275:Glucose Transporter Type 4; D008763:Methylhydrazines; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D006593:Hexokinase; D005947:Glucose; D002331:Carnitine