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Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts
- Source :
- Diabetes
- Publication Year :
- 2017
- Publisher :
- American Diabetes Association, 2017.
-
Abstract
- Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy (DCM), but the mechanism remains largely unclear. We found that diabetic hearts exhibited decreased phosphorylation of total Akt and isoform Akt2 but not Akt1 in wild-type (WT) male FVB mice, which was accompanied by attenuation of Akt downstream glucose metabolic signal. All of these signal changes were not observed in metallothionein cardiac-specific transgenic (MT-TG) hearts. Furthermore, insulin-induced glucose metabolic signals were attenuated only in WT diabetic hearts. In addition, diabetic hearts exhibited increased Akt-negative regulator tribbles pseudokinase 3 (TRB3) expression only in WT mice, suggesting that MT may preserve Akt2 function via inhibiting TRB3. Moreover, MT prevented tert-butyl hydroperoxide (tBHP)–reduced insulin-stimulated Akt2 phosphorylation in MT-TG cardiomyocytes, which was abolished by specific silencing of Akt2. Specific silencing of TRB3 blocked tBHP inhibition of insulin-stimulated Akt2 phosphorylation in WT cardiomyocytes, whereas overexpression of TRB3 in MT-TG cardiomyocytes and hearts abolished MT preservation of insulin-stimulated Akt2 signals and MT prevention of DCM. Most importantly, supplementation of Zn to induce MT preserved cardiac Akt2 signals and prevented DCM. These results suggest that diabetes-inhibited cardiac Akt2 function via TRB3 upregulation leads to aberrant cardiac glucose metabolism. MT preservation of cardiac Akt2 function by inhibition of TRB3 prevents DCM.
- Subjects :
- 0301 basic medicine
Cardiac function curve
Lipopolysaccharides
Male
medicine.medical_specialty
Complications
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
AKT1
Cell Cycle Proteins
Mice, Transgenic
Biology
03 medical and health sciences
Mice
Downregulation and upregulation
Internal medicine
Diabetic cardiomyopathy
Internal Medicine
medicine
Myocyte
Animals
Hypoglycemic Agents
Insulin
Myocytes, Cardiac
Phosphorylation
Protein kinase B
Cells, Cultured
Errata
Myocardium
Heart
medicine.disease
Oxidants
Mice, Mutant Strains
Oxidative Stress
030104 developmental biology
Endocrinology
Diabetes Mellitus, Type 1
Organ Specificity
embryonic structures
Metallothionein
RNA Interference
Insulin Resistance
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- Language :
- English
- ISSN :
- 1939327X and 00121797
- Volume :
- 67
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....5b120032dd45cbe4d0b6b0d83b4167cd