Cardiomyocyte Dysfunction in Sucrose-Fed Rats Is Associated With Insulin Resistance

Abstract

Diabetes is associated with impaired cardiac dysfunction in both humans and animals. Specific phenotypic changes—prolonged action potentials, slowed cytosolic Ca2+ clearing, and slowed relaxation—that contribute to this whole heart dysfunction occur in isolated ventricular myocytes. The present study was designed to determine whether cardiomyocyte abnormalities occur early in the development of type 2 diabetes (in this case, insulin resistance) and whether an insulin-sensitizing drug (metformin) is cardioprotective. In the study, high-sucrose feeding was used to induce whole-body insulin resistance. Wistar rats were maintained for 7–10 weeks on a starch (ST) diet, sucrose (SU) diet, or diet supplemented with metformin (SU + MET). Whole-body insulin resistance was measured in SU and SU + MET rats by performing euglycemic-hyperinsulinemic clamps. Mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection, and [Ca2+]i transients were evaluated with Fura-2 AM. Untreated SU rats were insulin-resistant (glucose infusion rate [GIR] = 14.5 ± 1.1 mg · kg−1 · min−1); metformin treatment in SU + MET rats prevented this metabolic abnormality (GIR = 20.0 ± 2.2 mg · kg−1 · min−1). Indexes of myocyte shortening and relengthening were significantly longer in SU rats (area under the relaxation phase [AR/peak] = 103 ± 3 msec) when compared to ST and SU + MET rats (AR/peak = 73 ± 2 and 80 ± 1 msec, respectively). The rate of intracellular Ca2+ decay and the integral of the Ca2+ transient through the entire contractile cycle were significantly longer in myocytes from SU than from ST rats (Ca2+ signal normalized to peak amplitude = 152 ± 8 vs. 135 ± 5 msec, respectively). Collectively, our data showed the presence of cardiomyocyte abnormalities in an insulin-resistant stage that precedes frank type 2 diabetes. Furthermore, metformin prevented the development of sucrose-induced insulin resistance and the consequent cardiomyocyte dysfunction.