Adenine Nucleotide Metabolism in Hearts of Diabetic Rats: Comparison to Diaphragm, Liver, and Kidney

Abstract

High-performance liquid chromatography analysis of acid-extracted tissues revealed decreases of high-energy nucleotides and increases in low-energy nucleotides and metabolites in heart, diaphragm, and liver but not in kidneys of diabetic rats. In comparison with nondiabetic rats, the total adenine nucleotide content of diabetic rat heart and diaphragm but not liver decreased, indicating an increase in catabolism of AMP. Maximal initial rates of the AMP catabolic enzymes 5′-nucleotidase, adenosine deaminase, and AMP deaminase were elevated in the hearts of BB/Wistar and streptozocin-induced diabetic rats. Nucleotide salvage enzymes adenylosuccinate synthetase and adenylosuccinate lyase were elevated above normal in the diabetic heart, whereas hypoxanthine-guanine phosphoribosyl transferase was not altered. Cytosolic-to-mitochondrial ratios from maximal initial rates after correction for mitochondrial breakage were increased above controls in diabetic hearts for nucleoside diphosphokinase and aspartate aminotransferase. Nucleotide levels, degradation rates, and substrate compartmentation between cytosol and mitochondria are discussed in relation to concurrent diabetes.

Regulation of muscle creatine kinase by phosphorylation in normal and diabetic hearts

“…If the 5-AMP levels were to increase in diabetic hearts, PKC-mediated phosphorylation of M-CK would then decrease, and the resulting increase in the reverse CK reaction would increase the conversion of phosphocreatine to maintain ATP levels. This mechanism remains to be further investigated as, to our knowledge, there is no information available about the effect of prolonged STZ-induced diabetes on 5-AMP levels in the heart, although an ATP to 5-AMP ratio of 4.5 was reported in hearts from BBWistar diabetic rats [31]. Elevation of 5-AMP levels in the heart causes activation of AMPK, which was demonstrated to phosphorylate M-CK in vitro and in a muscle cell line, resulting in inhibition of the reverse CK reaction and reduced ATP formation [6].…”

“…This was presumably measured in the reverse direction (phosphocreatine to ATP), although the assay methods for CK activity were not specifically stated [26,28,29]. The velocity of the reverse CK reaction measured by 31 P-NMR was also found to be reduced by about 30 % in intact hearts in two of the studies [28,29]. The reasons for the inconsistent findings among different groups are not entirely clear.…”

Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism

“…Earlier reports showed the inhibitory effect of MPA on GSIS and guanine nucleotide levels, but did not fully recognize the impact of MPA on the adenine branch of nucleotide metabolism, and did not identify S-AMP as a regulated metabolite (Li et al, 2000). Another report describes altered adenine nucleotide metabolism in the diabetic heart in the BB/Wistar and streptozotocin diabetes rat models, with increases in the AMP catabolic enzymes 5′-nucleotidase, adenosine deaminase, and AMP deaminase, and apparent compensatory induction of the nucleotide cycle enzymes ADSS and ADSL (Jenkins et al, 1988), but islet studies were not reported. More recently, a study of the thiazolidinedione (TZD)/PPARγ activators rosiglitazone and pioglitazone in normal rats revealed increases in cardiac IMP and AMP levels in response to drug treatment, accompanied by transcriptional upregulation of G6PDH, the PRPP synthesizing enzyme Prps1, and ADSS (Liu et al, 2013), but again, S-AMP was not measured and islet studies were not performed.…”

Excessive glucocorticoid exposure during late intrauterine development modulates the expression of cardiac uncoupling proteins in adult hypertensive male offspring

“…Changes in cardiac UCP mRNA expression might be predicted to have an impact on cardiac growth and development as a result of altered energy efficiency. Indeed, ATP deficiency [15] and impaired function of the diabetic rat heart [1,17,22,28,29] might be caused by proton leakage following upregulation of UCP-3 expression by fatty acids. It is also possible that cardiac UCP-2 and UCP-3 expression may be selectively regulated.…”