Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodeling

To identify the nature of myocardial alterations associated with diabetes, cardiac function, structural remodeling, and gene expression in hearts of type 2 diabetic db/db mice were studied. Db/db mice showed typical characteristics of type 2 diabetes and preserved cardiac function up to 18 wks of age under non‐challenging conditions. However, β‐adrenergic stimulation with dobutamine revealed impaired contractile and relaxation reserve capacity. Tissue analyses showed no signs of structural remodeling. Neither β1‐adrenoceptor (β1AR) expression nor phosphorylation state of contractile protein targets of β1AR – protein kinase A (PKA) signaling were altered. In contrast, the substantially increased expression of uncoupling protein‐3 (UCP3) and angiopoietin‐like‐4 (Angptl4), along with decreased phosphorylation of AMP‐activated protein‐kinase (AMPK) in the heart of diabetic animals, are indicative of altered mitochondrial efficiency, decline in plasma triacylglycerol consumption and changes in intermediary substrate metabolism, respectively, which together may compromise ATP synthesis, required for maintenance of cardiac function at increased work load. We conclude that impaired cardiac functional reserve capacity during maximal β‐adrenergic stimulation, is an early sign of cardiac dysfunction in db/db mice which is primarily associated with unfavorable changes in cardiac metabolism.