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.
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