Effects of chronic Akt activation on glucose uptake in the heart

Abstract

Acute activation of the serine-threonine kinase Akt is cardioprotective and increases glucose uptake, at least in part, through enhanced expression of GLUT4 on the sarcolemma. The effects of chronic Akt activation on glucose uptake in the heart remain unclear. To address this issue, we examined the effects of chronic Akt activation on glucose uptake, glycogen storage, and relevant glucose transporters in the hearts of transgenic mice. We found that chronic cardiac activation of Akt led to a substantial increase in the rate of basal glucose uptake (P < 0.05) but blunted the response to insulin (1.9 vs. 18.1-fold increase compared with baseline) using NMR in ex vivo perfused heart. Basal glucose uptake was also increased in Akt transgenic mice in vivo (P < 0.005). These changes were associated with an increase on glycogen deposition, examined with histochemical staining, biochemical (>6-fold, P < 0.001) and in vivo radioactive (5-fold, P < 0.01) assays. Studies in chimeric hearts of female X-linked transgenic Akt mice suggested that increased glycogen deposition occurred as a cell autonomous effect of transgene expression. Interestingly, although sarcolemmal GLUT1 was not significantly altered, chronic Akt activation actually decreased plasma membrane GLUT4. Moreover, intracellular pools of GLUT1 were modestly reduced, whereas intracellular GLUT4 was substantially reduced. It seems likely that neither GLUT1 nor GLUT4 explains the increase in basal glucose uptake but that these reductions contribute to the loss of insulin responsiveness that we observed. These data demonstrate that chronic Akt activation increases basal glucose uptake and glycogen deposition while inhibiting the response to insulin.

FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases

“…Chronic activation of Akt in heart in vivo results in impaired insulin responsiveness (54), a finding consistent with our results. That said, FoxO may also affect steps in the insulin signaling cascade that are Akt-independent, such as Ca 2ϩ /calmodulindependent protein kinase kinases (CaMKKs) and AMPK (7,55).…”

Akt1 in Endothelial Cell and Angiogenesis

“…As an example, whereas short-term Akt activation in the heart resulted in increased angiogenesis, chronic activation led to decreased angiogenesis and increased fibrosis. 19,21,54 A similar phenomenon was observed in Akt1 knockout mice: Short-term Akt1 deficiency affected the activation of eNOS in response to growth factors, 5,20 whereas the long-term repression of Akt1-mediated signaling influenced the expression of extracellular matrix proteins in skin and blood vessels. 5 These effects can be explained by the change in repertoire of downstream signaling molecules, leading to prevalence of pro-or anti-angiogenic signaling events (Fig.…”

Uremic Cardiomyopathy and Insulin Resistance

“…121 The net effect of acute Akt2 stimulation is increased glucose and decreased fatty acid oxidation, a beneficial effect during hypoxic conditions; however, once again, the consequences of acute and chronic Akt activation differ, with chronic stimulation increasing basal but significantly blunting insulin-stimulated glucose uptake as a result of decreased GLUT4 expression in insulin-sensitive intracellular vesicles, 122 a picture similar to that seen in hypertrophy with uremia. Reduced myocardial insulin sensitivity could lead to a decreased ability to increase ATP generation in times of need or alter substrate use to match supply, leaving it susceptible to energy depletion.…”