Abstract
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 Ins2+/− (Akita) and littermate normoglycemic Ins2+/+ (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.
Highlights
The limited impact of intensive glycemic control on reducing the risk of heart failure in diabetes mellitus (DM) patients, combined with the complex etiology, and rapidly increasing prevalence of DM make diabetic cardiomyopathy (DMCM) a significant clinical problem with dire consequences [1,2,3]
type 1 diabetes mellitus (T1DM).inTo the Akita regated Akita and WTOur mice based on the presence or absence of mutant
The severity of T1DM is relatively higher than type 2 diabetes mellitus (T2DM) due to increased fluctuations in blood glucose levels that lead to increased metabolic stress
Summary
The limited impact of intensive glycemic control on reducing the risk of heart failure in diabetes mellitus (DM) patients, combined with the complex etiology, and rapidly increasing prevalence of DM make diabetic cardiomyopathy (DMCM) a significant clinical problem with dire consequences [1,2,3]. Glycemic control further increases metabolic adaptive stress due to inconsistent fluctuations in glucose uptake, in the T1DM heart. Metabolic adaptations occur so cardiomyocytes can maintain a consistent turnover of ATP. These adaptations precede and increase the risk of cardiovascular events in T1DM patients [5]. Due to DMCM’s complex etiology, there is a lack of knowledge on how differentially expressed genes and metabolites can be used to understand the metabolic remodeling behind DMCM
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