Abnormal in vivo myocardial energy substrate uptake in diet-induced type 2 diabetic cardiomyopathy in rats

<jats:p>The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET (μPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [<jats:sup>18</jats:sup>F]fluorodeoxyglucose ([<jats:sup>18</jats:sup>F]FDG) was reduced by ∼81% ( P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [<jats:sup>18</jats:sup>F]fluorothia-6-heptadecanoic acid ([<jats:sup>18</jats:sup>F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [<jats:sup>11</jats:sup>C]acetate and myocardial perfusion index as assessed by [<jats:sup>13</jats:sup>N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by μPET was reduced by 26% in HFHFS rats ( P < 0.05). Without glucose clamp, NEFA uptake was ∼40% lower in HFHFS rats ( P < 0.05). However, myocardial uptake of [<jats:sup>18</jats:sup>F]FTHA administered by gastric gavage was significantly higher in HFHFS rats ( P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity ( P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA.</jats:p>