Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats

Liepinsh, Edgars; Skapare, Elina; Švalbe, Baiba; Makrecka, Marina; Cirule, Helena; Dambrova, Maija

doi:10.1016/j.ejphar.2011.02.019

Cited by 32 publications

(29 citation statements)

References 30 publications

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“…Furthermore, increased myocardial PPARα activity has been associated with improved adaptation to hyperglycemia and hyperlipidemia-induced metabolic disturbances [17]. In our experiment, increases in the expression of PPARα, γ, and δ in the AAR correlated with rising total cholesterol and LDL:HDL ratio.…”

Section: Discussionsupporting

confidence: 54%

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

et al. 2012

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Ossabaw miniswine have been naturally selected to efficiently store large amounts of lipids offering them a survival advantage. Our goal was to evaluate the myocardial response to chronic ischemia of the Ossabaw consuming a hypercaloric, high-fat/cholesterol diet with and without metformin supplementation. At 6 weeks of age animals were fed either a regular diet (OC, n = 9), a hypercaloric high-fat/cholesterol diet (OHC, n = 9), or a hypercaloric high-fat/cholesterol diet supplemented with metformin (OHCM, n = 8). At 9 weeks, all animals underwent ameroid constrictor placement to the left circumflex coronary artery to simulate chronic ischemia. Seven weeks after ameroid placement, all animals underwent hemodynamic and functional measurements followed by cardiac harvest. Both OHC and OHCM animals developed significantly greater weight gain, total cholesterol, and LDL:HDL ratio compared to OC controls. Metformin administration reversed diet-induced hypertension and glucose intolerance. There were no differences in global and regional contractility, myocardial perfusion, capillary and arteriolar density, or total protein oxidation between groups. Myocardial protein expression of VEGF, PPAR-α, γ, and δ was significantly increased in the OHC and OHCM groups. Microvessel reactivity was improved in the OHC and OHCM groups compared to controls, and correlated with increased p-eNOS expression. Overfed Ossabaw miniswine develop several components of metabolic syndrome. However, impairments of myocardial function, neovascularization and perfusion were not present, and microvessel reactivity was paradoxically improved in hypercholesterolemic animals. The observed cardioprotection despite metabolic derangements may be due to lipid-dependant upregulation of the PPAR pathway which is anti-inflammatory and governs myocardial fatty acid metabolism.

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Section: Discussionsupporting

confidence: 54%

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

et al. 2012

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“…At the same time, mildronate, which decreases the blood glucose concentration in mice and diabetic rats, usually does not affect plasma insulin and C-peptide levels (Liepinsh et al, 2008;Liepinsh et al, 2009b). In addition, in study in Zucker rats mildronate along with decrease in glucose concentration also decreased pathologically elevated insulin concentration in fed Zucker rats (Liepinsh et al, 2011b). Moreover, mildronate induces a statistically significant 35% increase in insulin-stimulated glucose uptake in isolated mouse hearts (Liepinsh et al, 2008).…”

Section: Effects On Insulin Signallingmentioning

confidence: 87%

“…In obese Zucker rats, mildronate induced a moderate increase in the FA and TG concentrations, and it significantly improved insulin sensitivity and reduced blood glucose and insulin concentrations (Fig. 5C) (Liepinsh et al, 2011b). Thus, mildronate treatment, by www.intechopen.com …”

Section: Metabolic Flexibility and Protection Against Lipid Overloadmentioning

confidence: 99%

“…A significant 2-fold increase in the expression of both PDC enzymes, E1/E2, in mildronate-treated mouse hearts compared with non-treated controls was observed. In addition, in several studies, a decrease in lactate concentration in ischemic hearts of mildronate-treated animals has been noted, which indicates that long-term mildronate treatment not only facilitates glucose uptake but also enhances the aerobic oxidation of glucose (Asaka et al, 1998;Hayashi et al, 2000b;Liepinsh et al, 2011b). Besides the direct effects of insulin on glucose homeostasis, stimulation of the insulin receptor leads to the activation of signalling pathways such as the phosphatidylinositol-3-kinase and the mitogen-activated protein kinase cascades, which are involved in cardioprotection from reperfusion injury (Jonassen et al, 2001;Youngren, 2007).…”

Section: Effects On Insulin Signallingmentioning

confidence: 99%

“…4). In a very recent study to elucidate the molecular mechanism of mildronate, PPAR-and PPAR-nuclear content and the expression of glucose and FA metabolism genes were determined in obese Zucker rats (Liepinsh et al, 2011b). The hearts of obese Zucker rats had a significant impairment in the PPAR-system, and the response to increased FA and triglyceride (TG) was disrupted.…”

Section: The Modulation Of Ppars and Fatty Acid Metabolism-related Gementioning

confidence: 99%

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The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

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Acute and long‐term administration of palmitoylcarnitine induces muscle‐specific insulin resistance in mice

et al. 2017

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Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of dietinduced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity.

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Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats

Cited by 32 publications

References 30 publications

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Acute and long‐term administration of palmitoylcarnitine induces muscle‐specific insulin resistance in mice

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