Cardiac PI3K-Akt Impairs Insulin-Stimulated Glucose Uptake Independent of mTORC1 and GLUT4 Translocation

Abstract

Impaired insulin-mediated glucose uptake characterizes cardiac muscle in humans and animals with insulin resistance and diabetes, despite preserved or enhanced phosphatidylinositol 3-kinase (PI3K) and the serine-threonine kinase, Akt-signaling, via mechanisms that are incompletely understood. One potential mechanism is PI3K- and Akt-mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin-mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation. To gain mechanistic insights by which constitutive activation of PI3K or Akt may desensitize insulin-mediated glucose uptake in cardiomyocytes, we examined mice with cardiomyocyte-restricted, constitutive or inducible overexpression of a constitutively activated PI3K or a myristoylated Akt1 (myrAkt1) transgene that also expressed a myc-epitope-tagged glucose transporter type 4 protein (GLUT4). Although short-term activation of PI3K and myrAkt1 increased mTOR and S6 signaling, there was no impairment in insulin-mediated activation of IRS1/2. However, insulin-mediated glucose uptake was reduced by 50-80%. Although longer-term activation of Akt reduced IRS2 protein content via an mTORC1-mediated mechanism, treatment of transgenic mice with rapamycin failed to restore insulin-mediated glucose uptake, despite restoring IRS2. Transgenic activation of Akt and insulin-stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin-stimulated wild-type controls. Despite preserved GLUT4 translocation, glucose uptake was not elevated by the presence of constitutive activation of PI3K and Akt. Hexokinase II activity was preserved in myrAkt1 hearts. Thus, constitutive activation of PI3K and Akt in cardiomyocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.

Integrative Proteomics and Targeted Transcriptomics Analyses in Cardiac Endothelial Cells Unravel Mechanisms of Long-Term Radiation-Induced Vascular Dysfunction

“…77 The mechanisms of endothelial dysfunction and insulin pathway impairment share many similar features. It has been shown that PI3K-Akt-NO pathway is involved in the glucose uptake and translocation of Glut4 to cell surface in different cell types including cardiomyocytes 78 and adipocytes. 79 Interestingly, it has been reported that administration of chemoradiation for head and neck carcinoma alters glucose metabolism during and after treatment.…”

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

“…In fact, decreased insulin-stimulated GLUT4 translocation, glucose uptake and utilization precede significant alterations in signaling molecules such as IRS, Akt and Akt substrate 160 (AS160) [48, 49]. Moreover, we recently reported that persistent PI3K signaling could impair cardiomyocyte glucose uptake despite normal GLUT4 translocation [50]. Future studies will investigate the molecular links between insulin-stimulated GLUT4 translocation, oxidative stress, and mitochondrial function in the heart.…”

Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α

“…Gas chromatography-mass spectrometry (GC-MS) was used to measure glucose, glucose-6-phosphate, and other metabolic intermediates in snap-frozen heart tissue using previously described protocols at the University of Utah Metabolomics Core (36).…”