In vivo metabolic phenotyping of myocardial substrate metabolism in rodents: differential efficacy of metformin and rosiglitazone monotherapy.
In vivo metabolic phenotyping of myocardial substrate metabolism in rodents: differential efficacy of metformin and rosiglitazone monotherapy.
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DOI：
10.1161/circimaging.108.843227
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Welch MJ
中科院分区：
文献类型：
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作者：
Shoghi KI;Finck BN;Schechtman KB;Sharp T;Herrero P;Gropler RJ;Welch MJ
心血管疾病是糖尿病患者死亡的主要原因，心肌基质代谢的改变可能是原因之一。我们旨在无创性地评估二甲双胍和罗格列酮单独治疗在2型糖尿病动物模型中使心肌基质代谢正常化的效果。本研究选用18只雄性ZDF大鼠(FA/FA)，每组6只：未治疗组、二甲双胍组(16.6 mg/kg/d)和罗格列酮组(4 mg/kg)。每只大鼠在14周(基线)和19周时用小动物PET进行扫描，以评估心肌葡萄糖利用率(MGU)和心肌利用率(MFAU)、氧化(MFAO)和酯化(MFAE)。在基线成像后，治疗持续5周。在第19周，处死大鼠，提取心脏，用于编码过剩转运蛋白、脂肪酸运输和氧化基因的选择基因的表达分析。此外，在第13周和第18周进行超声心动图(ECHO)测量，以表征心功能。二甲双胍对MGU、MFAU和MFAO均无明显影响。相反，罗格列酮倾向于提高MGU，显著降低MFAU和MFAO。罗格列酮诱导的葡萄糖摄取增加与GLUT4表达增加显着相关，而MFAO降低与FATP-1和MCAD表达降低显着相关。最后，作为心功能测量指标的短轴缩短率的变化在整个研究过程中没有变化。罗格列酮治疗可提高葡萄糖利用率，减少MFAO，从而逆转糖尿病心脏的代谢表型。
Cardiovascular disease is the leading cause of death among diabetic patients with alterations in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of Metformin and Rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type-2 diabetes mellitus. The study utilized 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with Metformin (16.6mg/kg/day) and a group treated with Rosiglitazone (4mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small animal PET to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO) and esterification (MFAE). Treatment lasted for 5 weeks following baseline imaging. At week 19, rats were sacrificed and hearts extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography (ECHO) measurements were obtained at week 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, Rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4 while diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study. Treatment with Rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart.