Proteomics of the Rat Myocardium during Development of Type 2 Diabetes Mellitus Reveals Progressive Alterations in Major Metabolic Pathways

Congestive heart failure and poor clinical outcome after myocardial infarction are known complications in patients with type-2 diabetes mellitus (T2DM). Protein alterations may be involved in the mechanisms underlying these disarrays in the diabetic heart. Here we map proteins involved in intracellular metabolic pathways in the Zucker diabetic fatty rat heart as T2DM develops using MS based proteomics. The prediabetic state only induced minor pathway changes, whereas onset and late T2DM caused pronounced perturbations. Two actin-associated proteins, ARPC2 and TPM3, were up-regulated at the prediabetic state indicating increased actin dynamics. All differentially regulated proteins involved in fatty acid metabolism, both peroxisomal and mitochondrial, were up-regulated at late T2DM, whereas enzymes of branched chain amino acid degradation were all down-regulated. At both onset and late T2DM, two members of the serine protease inhibitor superfamily, SERPINA3K and SERPINA3L, were down-regulated. Furthermore, we found alterations in proteins involved in clearance of advanced glycation end-products and lipotoxicity, DCXR and CBR1, at both onset and late T2DM. These proteins deserve elucidation with regard to their role in T2DM pathogenesis and their respective role in the deterioration of the diabetic heart. Data are available via ProteomeXchange with identifiers PXD009538, PXD009554, and PXD009555