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

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.

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

“…Наши результаты о влиянии милдроната на метаболизм глюкозы согласуются с данными литературы. Известно, например, что у интактных мышей и у крыс Гото-Кокизаки милдронат в дозе 200 мг/кг значительно снижал уровень глюкозы после трёхнедельного курса [11,12].…”

“…Схема на рисунке 3 поясняет этот механизм. Недавно показано, что милдронат стимулирует инсулин-зависимое потребление глюкозы в изолированных сердцах мыши и повышает экспрессию некоторых генов и ферментов, вовлечённых в метаболизм глюкозы [11], кроме того, препарат снижал уровень глюкозы у крыс Гото-Кокизаки [12], используемых в качестве модели инсулин-независимого диабета. Таким образом, милдронат потенцирует действие инсулина.…”

“…В клинике милдронат оказался эффективным для лечения некоторых осложнений инсулин-независимого сахарного диабета [6][7][8][9]. В экспериментальных исследованиях милдронат 490 * -адресат для переписки оказывал влияние на потребление глюкозы и метаболизм кетоновых тел, стимулировал инсулин-зависимое потребление глюкозы [10][11][12]. Показано также, что милдронат ускоряет окисление глюкозы в сердцах крыс при гипоксии [13].…”

Effects of Melatonin in Prevention of Neuropathy in STZ-Induced Diabetic Rats

“…For each animal rat, tail flick latency was measured for three times and the average was reported as tail flick latency. Between every test, rats were left free for half an hour (Liepinsh et al, 2009).…”

Processing Short Time Series with Data Mining Methods

“…In medicine this method can be used in cardiology to cure heart ischemia by analyzing changes in heartbeat when a specific period of time has passed after introducing a stimulating substance. Similar tasks are solved in pharmacology when analyzing laboratory examination data for a research; like data obtained in a model of isolated heart ischemia -reperfusion [16], [17] using Wistar rats that were fed the studied substances for a certain period of time. The aim of this research was to assess the efficiency of the studied substances in heart cell protection from ischemic -reperfusion damages by determining the size of the heart necrosis (necrotic tissue).…”