Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From db/db Mice

Abstract

Glucose and palmitate metabolism and contractile function were measured with ex vivo perfused working hearts from control (db/؉) and diabetic (db/db) female mice at 6, 10 -12, and 16 -18 weeks of age. Palmitate oxidation was increased by 2.2-fold in 6-week-old db/db hearts and remained elevated in 10-to 12-and 16-to 18-week-old hearts. Carbohydrate oxidation was normal at 6 weeks but was reduced to 27 and 23% of control at 10 -12 and 16 -18 weeks, respectively. At 6 weeks, db/db hearts exhibited a slight reduction in mechanical function, whereas marked signs of dysfunction were evident at 10 -12 and 16 -18 weeks. Mechanical function after ischemia-reperfusion was examined in hearts from male mice; at 6 weeks, db/db hearts showed normal recovery, whereas at 12 weeks it was markedly reduced. Fatty acid oxidation was the predominant substrate used after reperfusion. Thus, diabetic db/db hearts exhibit signs of a progressive cardiomyopathy; increased fatty acid oxidation preceded reductions in carbohydrate oxidation. Postischemic recovery of function was reduced in db/db hearts, in parallel with age-dependent changes in normoxic contractile performance. Finally, peroxisome proliferator-activated receptor-␣ treatment (3 weeks) did not affect sensitivity to ischemiareperfusion, even though carbohydrate oxidation was increased and palmitate oxidation was decreased. Diabetes 52:434 -441, 2003 N on-insulin-dependent (type 2) diabetes is a prevalent disease that results in a marked increase in cardiovascular complications (1) that are in part due to a specific cardiomyopathy, characterized by ventricular dysfunction in the absence of atherosclerotic coronary heart disease or hypertension (2,3).Diabetic db/db mice provide an animal model of type 2 diabetes, with obesity and insulin resistance (4,5). Recently, we have reported that isolated perfused hearts from db/db mice at 10 -14 weeks of age exhibited characteristics of a diabetic cardiomyopathy, with decreased contractile performance and altered cardiac metabolism (6,7).The natural history of db/db mice follows a distinct pattern (8,9). Initially, peripheral insulin resistance is overcome by increased insulin secretion, so hyperinsulinemia produces normoglycemia. Hyperglycemia develops when enhanced insulin secretion can no longer compensate for insulin resistance. The maximal extent of hyperinsulinemia occurs at 2-3 months of age. Subsequently, insulin levels fall rapidly as ␤-cells exhibit a severe secretory defect, resulting in a progressive increase in hyperglycemia. Thus, the metabolic features of db/db mice are similar to the pathogenesis of type 2 diabetes in humans (10).The first objective of this investigation was to study age-dependent changes of cardiac function and metabolism in db/db mice assessed with ex vivo perfused hearts (7,11,12). Of particular interest was to establish whether the onset of metabolic alterations coincided with contractile dysfunction. Previously, evidence for contractile dysfunction in perfused db/db hearts has been obtained from norm...

Cardiovascular consequences of obesity and targets for treatment

“…In a study of young women with uncomplicated obesity, our group found that myocardial FA upake, utilization, and oxidation all were increased as BMI and whole body insulin resistance increased, paralleling what was found in animal models of obesity [56,58]. It appears that this increased FA oxidation capacity in humans may also be overwhelmed, as it can be in animal models because autopsy and magnetic resonance spectroscopy studies both demonstrate that in subjects with diabetes there is an increase in intramyocellular triglyceride compared with normal controls [59].…”

“…In response to an increase in FA delivery, the myocardium typically increases betaoxidation of FAs (Figure 2). This increase in beta-oxidation of FAs occurs in animal models of obesity, even before the onset of diabetes [56]. However, it appears that if excessive FA delivery to the myocardium persists, even the myocardium's great capacity for FA oxidation may be overwhelmed leading to increased FA storage (Figure 2).…”

Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury

“…The heart tissues from type 2 diabetic db/db mice and their control db/ϩ mice were kindly provided by Dr. Paul Epstein, University of Louisville. The db/db mice are a well characterized insulin-resistant diabetic model with early onset cardiomyopathy (35). All protocols involving animal use were reviewed and approved by the Internal Animal Care and Use Committee at the University of South Dakota.…”

Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women

“…[2][3][4] In addition, data from studies conducted in animal models suggest that obesity and insulin resistance cause alterations in myocardial fatty acid metabolism and efficiency (cardiac work/myocardial oxygen consumption) that occur early in the cascade of events that lead to impaired LV contractility. 5,6 In animal models, obesity and insulin resistance increase plasma fatty acid availability and myocardial fatty acid uptake (MFAUp), which causes a shift in substrate metabolism toward a preference for fatty acid utilization (MFAU). 5,6 In these models, there is an initial increase in myocardial fatty acid oxidation (MFAO) and myocardial oxygen consumption (MV O 2 ), which can decrease cardiac efficiency.…”

“…5,6 In animal models, obesity and insulin resistance increase plasma fatty acid availability and myocardial fatty acid uptake (MFAUp), which causes a shift in substrate metabolism toward a preference for fatty acid utilization (MFAU). 5,6 In these models, there is an initial increase in myocardial fatty acid oxidation (MFAO) and myocardial oxygen consumption (MV O 2 ), which can decrease cardiac efficiency. 6 -9 Over time, a mismatch between MFAUp and MFAO develops and leads to an accumulation of fatty acid intermediates and increased ceramide production, which cause cardiomyocyte apoptosis and impairment of cardiac function.…”