Type 1 and Type 2 Diabetes Exacerbate Myocardial Infarction-Induced Cardiac Inflammation and Metabolic Dysfunction

Diabetes mellitus (DM), which is characterized by glucose intolerance and impaired insulin signaling, is an ever growing worldwide epidemic. While type 1 DM (T1DM) is typically due to genetic or viral factors, type 2 DM (T2DM) appears to be linked to obesity. DM highly increases the risk of myocardial infarction (MI), and impairs post-MI recovery, increasing the risk of heart failure and mortality. However, the mechanisms by which DM exacerbates cardiac injury after MI remain unclear. In this study, we induced T1DM in adult C57BL/6J male mice using streptozotocin (STZ, single high dose of 125mg/kg), and T2DM by feeding mice a high fat/fructose diet for 6 weeks, then injecting a low dose of STZ (40mg/kg) over 3 consecutive days. Control mice were fed a standard chow diet. T1DM was confirmed by fasting hyperglycemia (509±26mg/dL vs 134±12mg/dL control) and fasting hypoinsulinemia. T2DM was characterized by milder fasting hyperglycemia (287±23mg/dL), fasting hyperinsulinemia, hyperlipidemia, and increased body weight/fat mass (EchoMRI). Two weeks after STZ administration, MI was induced by permanent ligation of the left coronary artery. Mice were euthanized 1 or 4 weeks (WK1 or WK4) later. No differences in mortality or infarct sizes occurred among groups. T1DM and T2DM mice had exacerbated thinning of the infarcted wall at WK1 and WK4 after MI as assessed by echocardiography. T1DM mice displayed increased posterior wall thinning at WK4, while T2DM had decreased stroke volume and ejection fraction at WK4. T1DM mice displayed pulmonary congestion, (increased wet/dry lung mass ratio). To elucidate the molecular mechanisms underlying these adverse outcomes, we performed RNA-sequencing on the infarct area at WK1. There were 636 differentially expressed (DE) in T1DM (vs controls; ≥ 2-fold change), and 198 DE genes in T2DM. Pathway analysis revealed activation of classical monocyte/neutrophil genes in T1DM, and activation of T lymphocyte genes in T2DM. Both T1DM and T2DM displayed downregulation of genes associated with extracellular matrix remodeling. T1DM mice had lower collagen density in the infarct region (picrosirius red), indicating impairment in scar tissue formation. In the remote area, T1DM mice had higher levels of Anp, Bnp, Il6, and Ccl2 relative to controls, indicating more injury and inflammation. T1DM mice displayed increased Pdk1 expression, inhibitory phosphorylation of pyruvate dehydrogenase-E1 alpha, decreased Akt phosphorylation, and increased Pfkfb3 expression in the remote area, indicating impairment in cardiomyocyte glucose oxidation and a glycolytic shift. Our results indicate that T1DM and T2DM mice are more prone to MI-induced cardiac injury and dysfunction, which is linked to distinct inflammatory pathways and metabolic dysfunction. T32HL105324 and NHLBI R01 HL166737) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.