Effects of diabetes on cardiac glycogen metabolism in rats

Nakao, Masahide; Sakamoto, Nobuo

doi:10.1007/bf01744738

Cited by 13 publications

(8 citation statements)

References 22 publications

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“…1). In the diabetic heart, glucose usage has been shown to shift away from glycolysis and toward an increased flux through the pentose phosphate pathway (1,8,70,84,105,118). In agreement with those reports, we observed that 13 days of elevated glucose presentation resulted in a significant increase in cardiomyocyte glucose-6-phosphate dehydrogenase (G6PdH) activity ( Fig.…”

Section: Resultssupporting

confidence: 91%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. Am J Physiol Heart Circ Physiol 304: H903-H915, 2013. First published February 1, 2013 doi:10.1152/ajpheart.00567.2012.-Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic GotoKakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H 2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetesinduced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium. diabetic cardiomyopathy; type 2 diabetes; mitochondrial DNA damage; mitochondrial dysfunction CARDIOVASCULAR DISEASE is responsible for a higher incidence of mortality in diabetics than the general population. Diabetic cardiomyopathy (DCM) is characterized by the development of a myopathy that manifests initially as diastolic dysfunction, but evolves into increased cavitary dilation and mural thinning, which is reflective of decompensated eccentric hypertrophy. DCM is considered to be independent of atherosclerosis or hypertension but is exacerbated by either (94). Mitochondrial dysfunction has long been known to have a significant role in the development and complications of DCM (32,46,66,82,92). Mitochondrial dysfunction is also associated with other pathologies including cancer, skeletal muscle disorders, and neurodegenerative diseases such as Wolfram syndrome or Leber's hereditary optic neuropathy (LHON) (18,36,54,104).Separate from inborn errors, mitochondrial DNA (mtDNA) mutations are thought to accumul...

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Section: Resultssupporting

confidence: 91%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…As glycogen accumulation is a reported characteristic of the diabetic myocardium (11,14,19), we sought to identify evidence of glycophagy activity in left ventricular homogenate tissue from streptozotocin (STZ) -induced diabetic rats. STBD1 expression and GABARAPL1 expression were observed to be higher in diabetic rat hearts (ϳ60 and ϳ 20% increased, respectively, as depicted; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DISTURBED SYSTEMIC GLYCEMIC and insulinemic status elicits cardiomyocyte metabolic stress and altered glucose handling. In diabetes, myocardial glycogen accumulation is evident in humans and in a range of experimental models (8,11,14,19). Cardiac glycogen excess has been linked to hypertrophy, arrhythmias, and contractile dysfunction (3).…”

mentioning

confidence: 99%

Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose

Mellor

Varma

Stapleton

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Disturbed systemic glycemic and insulinemic status elicits cardiomyocyte metabolic stress and altered glucose handling. In diabetes, pathological myocardial glycogen accumulation occurs. Recently, evidence of a specific myocardial autophagic degradation pathway for glycogen ("glycophagy") has been reported, differentiated from the more well-characterized protein "macrophagy" pathway. The goal of this study was to identify potential mechanisms involved in cardiac glycogen accumulation, glycophagy, and macrophagy regulation using cultured neonatal rat ventricular myocytes (NRVMs). In NRVMs, insulin-induced Akt phosphorylation was evident with 5 mM-glucose conditions (∼2.3-fold increased). Under high-glucose (30 mM) conditions, insulin-augmented phosphorylation was not observed. Accumulation of glycogen was observed in response to insulin only in high-glucose conditions (∼2-fold increase). Increased expression of the glycophagy marker starch-binding domain-containing protein-1 (STBD1, 25% increase) was observed under high-glucose and insulin conditions. Expression levels of the macrophagy markers p62 and light chain protein 3BII:I were not increased by insulin at either glucose level. Preliminary results from hearts of streptozotocin-treated diabetic rats are supportive of the findings obtained in NRVMs, suggesting diabetes induced elevated expression of STBD1 and of an additional glycophagy marker GABA(A) receptor-associated protein-like 1. Confocal microscopy demonstrated that light chain protein 3B and STBD1 immunomarkers were not colocalized in NRVMs. These findings provide the first evidence that cardiomyocyte glycophagy induction occurs under the influence of insulin and is responsive to extracellular high glucose. This study suggests that the regulation of glycogen content and glycophagy induction in the cardiomyocyte may be linked, and it is speculated that glycogen pathology in diabetic cardiomyopathy has glycophagic involvement.

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“…Insulin also plays an important role in the regulation of glycogen synthesis and protein metabolism. Interestingly, differences in the regulation of these pathways have been reported between the heart and skeletal muscles 27,32,33 . For example, diabetes augments glycogen levels in the heart, but not in skeletal muscles 32,34,35 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, differences in the regulation of these pathways have been reported between the heart and skeletal muscles 27,32,33 . For example, diabetes augments glycogen levels in the heart, but not in skeletal muscles 32,34,35 . Thus, differences in the levels of insulin‐signalling intermediates may contribute to the tissue‐specific regulation of these pathways by diabetes.…”

Section: Discussionmentioning

confidence: 99%

Tissue‐ and Fibre‐specific Modifications of Insulin‐signalling Molecules in Cardiac and Skeletal Muscle of Diabetic Rats

Ekladous

Mehdi

Costa

et al. 2008

Clin Exp Pharma Physio

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1. Levels of insulin-signalling molecules are altered in streptozotocin (STZ)-induced diabetes, a model of Type 1 diabetes. However, the tissue-specific regulation of these changes and the effect of insulin supplementation on signalling molecule protein levels have not been well characterized. 2. In the present study, we evaluated the level of proximal insulin-signalling intermediates in the heart and in red and white gastrocnemius muscles of 2 week diabetic rats and diabetic rats supplemented with insulin. 3. Diabetes augmented levels of the insulin receptor and the p85 regulatory subunit of phosphatidylinositol 3-kinase in the red gastrocnemius, but not in the white gastrocnemius or the heart. Furthermore, diabetes reduced insulin receptor substrate-1 levels in both the red and white gastrocnemius, but not in the heart. Examination of the levels and basal activities of distal insulin-signalling intermediates (protein kinase B (PKB)/Akt, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (MAPK)) also failed to reveal a specific pattern in these changes. Thus, diabetes reduced basal ERK1/2 and PKB/Akt phosphorylation in the heart and white gastrocnemius, respectively, whereas it augmented basal p38 MAPK activity in the red gastrocnemius. Insulin supplementation normalized the levels and activities of some but not all proteins. 4. In conclusion, the results of the present study demonstrate that adaptation to STZ-induced diabetes varies among skeletal muscle fibre types and the heart, emphasizing the complex tissue-specific responses to diabetes.

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Effects of diabetes on cardiac glycogen metabolism in rats

Cited by 13 publications

References 22 publications

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose

Tissue‐ and Fibre‐specific Modifications of Insulin‐signalling Molecules in Cardiac and Skeletal Muscle of Diabetic Rats

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