Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Int J Mol Sci. 2022 Jan 26;23(3):1392. doi: 10.3390/ijms23031392.
Metabolic remodeling is at the heart of diabetic cardiomyopathy. High glycemic fluctuations increase metabolic stress in the type 1 diabetes mellitus (T1DM) heart. There is a lack of understanding on how metabolites and genes affect metabolic remodeling in the T1DM heart. We hypothesize that differential expression of metabolic genes and metabolites synergistically influence metabolic remodeling preceding T1DM cardiomyopathy. To test our hypothesis, we conducted high throughput analysis of hearts from adult male hyperglycemic (Akita) and littermate normoglycemic (WT) mice. The Akita mouse is a spontaneous, genetic model of T1DM that develops increased levels of consistent glycemic variability without the off-target cardiotoxic effects present in chemically- induced models of T1DM. After validating the presence of a T1DM phenotype, we conducted metabolomics via LC-MS analysis and genomics via next-generation sequencing in left ventricle tissue from the Akita heart. Ingenuity Pathway Analyses revealed that 108 and 30 metabolic pathways were disrupted within the metabolomics and genomics datasets, respectively. Notably, a comparison between the two analyses showed 15 commonly disrupted pathways, including ketogenesis, ketolysis, cholesterol biosynthesis, acetyl CoA hydrolysis, and fatty acid biosynthesis and beta-oxidation. These identified metabolic pathways predicted by the differential expression of metabolites and genes provide the foundation for understanding metabolic remodeling in the T1DM heart. By limited experiment, we revealed a predicted disruption in the metabolites and genes behind T1DM cardiac metabolic derangement. Future studies targeting these genes and metabolites will unravel novel therapies to prevent/improve metabolic remodeling in the T1DM heart.
代谢重构是糖尿病心肌病的核心。高血糖波动增加了 1 型糖尿病（T1DM）心脏的代谢应激。对于代谢物和基因如何影响 T1DM 心脏的代谢重构，人们的理解还很有限。我们假设代谢基因和代谢物的差异表达协同影响 T1DM 心肌病发生前的代谢重构。为了验证我们的假设，我们对成年雄性高血糖（Akita）和同窝正常血糖（WT）小鼠的心脏进行了高通量分析。Akita 小鼠是一种自发性、遗传性 T1DM 模型，其血糖水平持续升高，且血糖变异性增加，而不会出现化学诱导的 T1DM 模型中存在的非靶向性心脏毒性作用。在验证了 T1DM 表型的存在后，我们通过 LC-MS 分析进行了代谢组学分析，通过下一代测序进行了基因组学分析，分析对象为 Akita 心脏的左心室组织。Ingenuity 通路分析显示，代谢组学和基因组学数据集中分别有 108 个和 30 个代谢通路受到干扰。值得注意的是，这两项分析的比较显示，有 15 个共同受到干扰的通路，包括酮体生成、酮体分解、胆固醇生物合成、乙酰辅酶 A 水解以及脂肪酸生物合成和β氧化。这些代谢途径是由代谢物和基因的差异表达预测的，为理解 T1DM 心脏的代谢重构提供了基础。通过有限的实验，我们揭示了 T1DM 心脏代谢紊乱背后的代谢物和基因的预测性破坏。未来针对这些基因和代谢物的研究将为预防/改善 T1DM 心脏的代谢重构提供新的治疗方法。
