Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function

Abstract

Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high-fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/dt and stroke work) and diastolic (-dP/dt and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 ± 0.3 versus 4.6 ± 0.7, 4.3 ± 0.4, and 4.2 ± 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3β protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF.

Fig. 1.

Hemodynamic measurements from cardiac catheterization. Animals were divided into the following groups: sham operated with a normal chow (NC) diet (sham + NC group), sham operated with a high-saturated fat diet (sham + SAT group), heart failure (HF) with a normal chow diet (HF + NC group), and HF with a high-saturated fat diet (HF + SAT group). A: peak left ventricular (LV) +dP/dt. B: stroke work. C: peak LV −dP/dt. D: time constant of relaxation (τ). *P < 0.05 vs. the dietary control group; †P < 0.05 vs. the surgical control group.

Fig. 2.

Glucose clearance and insulin sensitivity as assessed by glucose tolerance tests (GTTs). A: blood glucose concentrations over time after a glucose bolus at time 0. B: areas under the curve (AUCs) taken from the glucose clearance time course. C: peak insulin, taken at the 30-min time point of the GTT. D: homeostasis model assessment of insulin resistance (HOMA-IR) scores, calculated from fasting glucose and fasting insulin levels during the GTT. #P < 0.05 vs. the sham + NC group.

Fig. 3.

Cardiac glucose uptake measurements during PET imaging. A: time course of specific uptake values (SUVs) under basal (fasting) conditions. B: basal SUVs at 90 min. C: time course of SUVs under insulin + glucose stimulation in the same animals as in A and B. D: insulin + glucose-stimulated SUVs at 90 min.

Fig. 4.

Representative reconstructed images of cardiac PET imaging from sham + NC (A), sham + SAT (B), HF + NC (C), and HF + SAT (D) animals under insulin + glucose-stimulated conditions. Notice the lack of enhancement over the area of the LV scar in HF + NC and HF + SAT animals.

Fig. 5.

Insulin sensitivity measurements calculated from PET experiments. A: ratio of 90-min insulin-stimulated SUV divided by 90-min basal SUV. B: glucose metabolic rate ratio calculated from blood glucose concentrations and kinetic constants as described in materials and methods. *P < 0.05 vs. the dietary control group; †P < 0.05 vs. the surgical control group.

Fig. 6.

Protein expression analysis of Akt and glycogen synthase kinase (GSK)-3β. A: representative samples from each treatment group (sham + NC, sham + SAT, HF + NC, and HF + SAT) run under both basal (fasting) and insulin-stimulated conditions. The images shown are examples but were not used for quantitation (see materials and methods). Phosphorylated (p)GSK-3β was detectable in fasted samples, although at much lower levels than insulin-stimulated samples, so exposure was optimized to show insulin-stimulated pGSK-3β. Phosphorylated protein, total protein levels, and heat shock complement (HSC)70 (used as a loading control) are shown. B: basal (fasting) protein levels were analyzed for pAkt/total Akt, total Akt/HSC70, pGSK-3β/total GSK-3β, and total GSK-3β/HSC70. Averages were calculated from 21–26 total samples run on 3 distinct gels. C: insulin-stimulated protein levels were analyzed for pAkt/total Akt, total Akt/HSC70, pGSK-3β/total GSK-3β, and total GSK-3β/HSC70. Averages were calculated from 21–26 total samples run on 3 distinct gels and measured from the same membranes used for quantitation in B. *P < 0.05 vs. the dietary control group; †P < 0.05 vs. the surgical control group.