Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance

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 [A_R/peak] = 103 ± 3 msec) when compared to ST and SU + MET rats (A_R/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.