Faculty Bibliography

In order to determine whether diabetic cardiomyopathy in rats is associated with altered contractile proteins, male and female rats were made diabetic with intravenous streptozotocin (STZ). Calcium ATPase activity of cardiac actomyosin was significantly decreased after 1 week of diabetes and was depressed by 60% by 2 weeks. Rats pretreated with 3-O-methyl glucose to prevent the hyperglycemia caused by STZ had normal Ca2+-actomyosin ATPase activities, and non-diabetic rats whose food was restricted to keep their body and heart weights similar to those found in diabetic animals had only a slight fall in actomyosin ATPase activity. Ca2+-ATPase and actin-activated ATPase activities of pure myosin were similarly depressed in preparations from hearts of diabetic animals. Sodium dodecylsulfate gel electrophoresis and isoelectric focusing failed to reveal differences in the patterns of contractile proteins or light subunits between diabetics and controls, but pyrophosphate gels showed a shift in the myosin pattern. Because of depressed circulating thyroid hormone levels in diabetic animals, cardiac contractile proteins were also studied in preparations from thyroidectomized rats. Calcium activities of actomyosin and myosin ATPase were lower than values found in hearts of diabetic rats. When diabetic animals were kept euthyroid with thyroid replacement, actomyosin ATPase activity was still depressed. Thus STZ diabetes causes a significant decrease in cardiac contractile protein ATPase activity. This may be related to altered proportions of myosin isoenzymes.

Diabetes appears to cause a cardiomyopathy independent of atherosclerotic coronary artery disease and hypertension. Left ventricular papillary muscle function studies in rats made severely diabetic with streptozotocin have shown a slowing of relaxation and a depression of shortening velocity. However, the effects of insulin therapy on the myocardial mechanics of diabetic rats have not been studied. Therefore, rats diabetic for 6-10 weeks were treated with PZI insulin for 2, 6, 10, or 28 days and the mechanical performance of their left ventricular papillary muscles was compared to that of untreated diabetics and age-matched controls; cardiac contractile protein enzymatic activity was also measured. Neither 2 nor 6 days of therapy had any effects on the depressed cardiac muscle performance of diabetic animals, although plasma glucose concentration was restored to normal. By 10 days of therapy, recovery of mechanical performance was nearly complete, and by 28 days of therapy, complete reversal of the altered myocardial mechanics was observed. Crystalline insulin added to the bath (9 mU/ml) had no effect on myocardial mechanics in either diabetics or controls. A gradual recovery of actomyosin and myosin ATPase activity in the hearts of insulin-treated diabetic animals was also found, complementing the mechanical studies. In addition to demonstrating a gradual but complete reversibility of the abnormalities in papillary muscle function in diabetic rats (although control of hyperglycemia was less than ideal), this study confirms that this model of a cardiomyopathy is not a result of streptozotocin-induced cardiac toxicity. Additional data are provided indicating that depressed thyroid hormone levels in diabetic rats are not responsible for the mechanical changes observed.

Diabetes mellitus is associated frequently with congestive heart failure in humans, even in the absence of associated coronary disease or hypertension. Nevertheless, the effects of the diabetic state on myocardial mechanics have not been studied. Accordingly, diabetes was induced in female Wistar rats by injection of streptozotocin (60 mg/kg). Left ventricular papillary muscles were studied 5, 10, and 30 weeks later and compared with controls. Relaxation was delayed significantly and velocity of shortening was depressed at all loads. However, the passive and active force-length curves, as well as the series elastic properties, were not altered. The changes in cardiac performance were found over a range of muscle lengths, stimulus frequencies, and bath concentrations of calcium, glucose, and norepinephrine. The duration of diabetes had no major effect on the mechanical changes observed. The possible influences of drug-induced cardiac toxicity, malnutrition, and altered thyroid hormone levels have been considered; the latter two factors could not be excluded completely from having some influence on the mechanical properties of diabetic cardiac muscle. Evidence is cited showing abnormalities in calcium uptake by sarcoplasmic reticulum and depressed actomyosin ATPase activity. Thus a cardiomyopathic state has been produced in the rat consequent to the induction of experimental diabetes mellitus. Various mechanisms for this entity have been suggested.