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 [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.
Dutta
K
K
College of Osteopathic Medicine, University of New England, Biddeford, Maine 04005, USA.
Podolin
D A
DA
Davidson
M B
MB
Davidoff
A J
AJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D004040:Dietary Carbohydrates; D019422:Dietary Sucrose / Q000494:pharmacology*; D005215:Fasting; D005456:Fluorescent Dyes; D016257:Fura-2 / Q000031:analogs & derivatives; D015309:Glucose Clamp Technique; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006352:Heart Ventricles; D006946:Hyperinsulinism / Q000097:blood / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D018715:Microscopy, Video; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D013213:Starch / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D019422:Dietary Sucrose; D005456:Fluorescent Dyes; D007328:Insulin; C049925:fura-2-am; D013213:Starch; D002118:Calcium; D016257:Fura-2