Diabetic hearts exhibit decreased responsiveness to stimulation by ␤-adrenoreceptor (␤-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of ␤-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to ␤ 1 -AR agonist stimulation, but not to ␤ 2 -AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that ␤ 1 -AR mRNA and protein levels decreased by 34.9 ± 5.8 and 44.4 ± 5.8%, respectively, in 14 week-STZtreated diabetic rat hearts when compared with agematched controls. On the other hand, mRNA levels encoding ␤ 2 -and ␤ 3 -ARs increased by 72.5 ± 16.6 and 97.3 ± 26.1%, respectively. Although the latter translated into a proportional increase in ␤ 3 -AR protein levels (100.0 ± 17.0%), ␤ 2 -AR protein levels decreased to 82.6 ± 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored ␤ 1 -AR mRNA and protein levels to 60.1 ± 8.4 and 83.2 ± 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding ␤ 2 -and ␤ 3 -ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of ␤-AR agonists may be due to a decrease in ␤ 1 -AR and an increase ␤ 3 -AR expression. Diabetes 50: [455][456][457][458][459][460][461] 2001

Selenium is a trace element that exerts certain insulin-like actions in vitro. In this study, we evaluated its in vivo effects on the glucose homeostasis of rats made diabetic and insulin-deficient by streptozotocin. Na2SeO4 was administered ad libitum in drinking water and/or food for 10 weeks. The elevated plasma glucose levels (approximately 25 mmol/l) and glucosuria (approximately 85 mmol/day) of untreated rats were decreased by 50 and 80%, respectively, by selenate treatment. The beneficial effect of selenate was also evident during oral and intravenous glucose tolerance tests: the integrated glucose responses were decreased by 40-50% as compared to those in untreated rats. These effects were not due to an increase in plasma insulin levels. Compared to non-diabetic rats, pancreatic insulin reserves were reduced by more than 90% in treated and untreated diabetic rats. The hepatic activities and mRNA levels of two key glycolytic enzymes, glucokinase and L-type pyruvate kinase were blunted in diabetic rats. They increased approximately two- to threefold after selenate treatment, to reach 40-75% of the values in non-diabetic rats. In contrast, elevated activity and mRNA levels of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, were reduced by 40-65% after selenate administration. Since selenate induced a moderate decrease in body weight due to an anorexigenic effect, we checked that there was no improvement of glucose homeostasis or hepatic glucose metabolism in an additional group of calorie-restricted diabetic rats, which was weight-matched with the selenate group. In addition, no obvious toxic side-effects on the kidney or liver were observed in the rats receiving selenate. In conclusion, selenate induces a sustained improvement of glucose homeostasis in streptozotocin-diabetic rats by an insulin-like action, which involves partial correction of altered pretranslational regulatory mechanisms in liver metabolism.

Despite the significant developments in the treatment of diabetes mellitus, diabetic patients still continue to suffer from cardiac complications. The increase of cardiac adrenergic drive may ultimately contribute to the development and progression of diabetic cardiomyopathy. beta-Adrenoceptors play an important role in the regulation of heart function. However, responsiveness of diabetic heart to beta-adrenoceptor agonist stimulation is diminished. The chronotropic responses mediated by beta(1)-subtype, which is mainly responsible for cardiac effects of catecholamines are decreased in the atria of diabetic rats. The expression of cardiac beta(1)-subtype is significantly decreased in diabetic rats as well. beta(2)-Adrenoceptors also increase cardiac function. Although the expression of this subtype is slightly decreased in diabetic rat hearts, beta(2)-mediated chronotropic responses are preserved. On the other hand, functional beta(3)-adrenoceptor subtype was characterized in human heart. Interestingly, stimulation of cardiac beta(3)-adrenoceptors, on the contrary of beta(1)- and beta(2)-subtypes, mediates negative inotropic effect in human ventricular muscle. Cardiac beta(3)-adrenoceptors are upregulated in experimental diabetes as well as in human heart failure. These findings suggest that each beta-adrenoceptor subtype may play an important role in the pathophysiology of diabetes-induced heart disease. However, it is still not known whether the changes in the expression and/or responsiveness of beta-adrenoceptors are adaptive or maladaptive. Therefore, this review outlines the potential roles of these receptor subtypes in cardiac pathologies of diabetes.

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