Fig. 2
From: Metabolic rewiring and inter-organ crosstalk in diabetic HFpEF
Perturbations in cardiac substrate metabolism in diabetic HFpEF. Diabetic HFpEF exhibits impaired cardiac substrate metabolism, marked by reduced metabolic flexibility. Despite systemic insulin resistance, myocardial fatty acid oxidation decreases, contrasting with diabetes-related lipid overload, while glucose utilization is suppressed via GLUT4 downregulation and pyruvate dehydrogenase inhibition. Mitochondrial dysfunction and oxidative stress coexist with disrupted tricarboxylic acid cycle intermediates. Accumulated metabolites (e.g., acetyl-CoA, ceramides) drive lipotoxicity and epigenetic dysregulation. Concurrently, amino acid and ketone metabolism alterations exacerbate energetic inefficiency. AcAc, acetoacetate; ACAT, acetoacetyl CoA thiolase; ATP, adenosine triphosphate; BCAA, branched-chain amino acids; BCATm, mitochondrial BCAA amimotransferase; BCKA, branched-chain keto acids; BCKDH, branched-chain α-ketoacid dehydrogenase; BDH1, b-hydroxybutyrate dehydrogenase 1; CD36, the cluster of differentiation 36; CPT, carnitine palmitoyltransferase; Cyt C, cytochrome C; ETC, electron transport chain; FACS, fatty acid CoA synthetase; LAT, L-type amino acid transporters; LCAD, long-chain acyl-CoA dehydrogenase; LDH, lactate dehydrogenas; MCT1, monocarboxylate transporter 1; GLUT1/4, glucose transporter 1/4; MPC, mitochondrial pyruvate carrier; NAD, nicotinamide adenine dinucleotide; SCOT, succinyl-CoA:3-ketoacid CoA transferase; TCA, tricarboxylic acid; βHAD, 3-OH-acyl-CoA dehydrogenase; βOHB, b-hydroxybutyrate