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.
Footnotes
-
Address correspondence and reprint requests to Amy J. Davidoff, PhD, University of New England, 11 Hills Beach Rd., Biddeford, ME 04005. E-mail: adavidoff{at}mailbox.une.edu.
Received for publication 24 August 2000 and accepted in revised form 23 January 2001.
AC, area under the contractile phase; AR, area under the relaxation phase; AreaCa2+, Ca2+ signal normalized to peak amplitude; 2-DG, 2-deoxy-d-[1-14C]glucose; GIR, glucose infusion rate; KHBB, Krebs-Henseleit bicarbonate buffer; PS, peak fractional shortening; PT, peak twitch amplitude; ST, high-starch; SU, high-sucrose; SU + MET, SU diet supplemented with metformin; TPT, time to peak twitch amplitude; TR, time of relengthening from peak twitch amplitude.
