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
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.
There have been several attempts published in the literature related with orally effective insulin formulations, which are increasing in popularity. Some of the results indicate that it is possible to reduce blood glucose level by orally administered liposomal insulin formulations, but there is general need to understand the mechanism and effective components of the liposome formulations. In our study, liposomal insulin formulations were prepared using insulin (Humulin R) or protamine- containing insulin (Humulin N) with cholesterol, dipalmitoyl phosphatidylcholine (egg) (DPPC)-cholesterol mixture, and mucoadhesive agent (methyl cellulose, MC)-added DPPC-cholesterol mixture. A tablet formulation of insulin was also prepared. Formulations of liposomal insulin were introduced to mice and rats orally and reduced blood glucose levels were observed. The composition of phospholipid (DPPC, cholesterol and MC mixture) was found to be quite effective in reducing blood glucose levels. The pH of the solution and the presence of the protamine sulfate were found to be important. The application site was also found to be important because liposomal insulin formulations administered through the mouth or esophagus resulted in reduced blood glucose levels. Reduced blood glucose levels were also observed when tablet formulations of insulin were administered to rats orally.
Patients with chronic diabetes mellitus usually develop reductions in rate and force of cardiac contractions. Since calcium-release channels (ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP(3)Rs)) play integral roles in effecting these processes, we rationalize that alterations in their expression may underlie these defects. To test this hypothesis, right atrial appendages were obtained from diabetic (65.0 +/- 4.5 years) and nondiabetic (56.2 +/- 2.6 years) patients undergoing coronary arterial by-pass grafting and reverse transcription-polymerase chain reactions were used to compare steady state levels of mRNA encoding the three major isoforms of RyRs and IP(3)Rs. In this study we did not detect either RyR1 or RyR3 in human atrial appendage. When compared with nondiabetic patients, mRNA encoding RyR2 from diabetic patients decreased by 74.2 +/- 6.2% (p< 0.01). Diabetes also significantly decreased steady-state levels of mRNA encoding the IP(3)Rs in human atrial appendage. IP(3)R1 decreased by 24.2 +/- 4.6%, IP(3)R2 decreased by 63.0 +/- 4.6% and IP(3)R3 decreased by 55.5 +/- 6.5%. Since a reduction in steady-state mRNA is usually indicative of a decrease in protein levels, these data suggest that the decrease in chronotropy and inotropy seen in chronic diabetic patients may be due in part to a decrease in expression of calcium-release channels.
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