Inhibition by insulin in the heart

Read Also

The energy necessary to maintain the myocardial contraction/relaxation cycle is derived from the mitochondrial oxidation of carbohydrates and long chain fatty acids. Under physiological conditions, fatty acid oxidation provides 60-70% of the heart energy requirements (Bertrand et al., 2008). This substrate preference can be attributed to inhibition of glucose uptake and catabolism via the Randle cycle (Randle et al., 1963). Following myocardial infarction, fatty acid oxidation accounts for almost all the heart ATP production (Neely and Morgan, 1974; Opie, 1975). This over-reliance on fatty acid oxidation is detrimental to functional reperfusion recovery of ischemic hearts (Lopaschuk et al., 1990; Lopaschuk et al., 1993). Under such conditions, the beneficial effects of insulin are important for maintaining proper cardiac function. Insulin can increase glucose use by the heart both by activating key steps of glycolysis, namely the recruitment of GLUT-4 to the plasma membrane and the activation of 6-phosphofructo-2-kinase (Bertrand et al., 2008; Rider and Hue, 1984; Russell et al., 1999) and by decreasing the extracellular fatty acid concentration. Also, insulin can directly alter fatty acid oxidation in the normoxic heart. The mechanism behind this involves inactivation of AMPK (Gamble and Lopaschuk, 1997; Kudo et al., 1995) which contributes to accelerated fatty acid oxidation via direct phosphorylation and inactivation of ACC (Carling et al., 1989; Hardie, 1992) resulting in decreased  malonyl-CoA, a potent inhibitor of fatty acid transport into the mitochondrial matrix (McGarry et al., 1989). Witters and Kemp have previously observed this inhibitory effect of insulin on AMPK activity in hepatoma cells (Witters and Kemp, 1992).

As insulin is a very potent PKB/Akt activator in the heart (Lefebvre et al., 1996), Kovacic and coworkers investigated if increased PKB/Akt activity could lead to inactivation of AMPK. They demonstrated that hearts from transgenic mice expressing constitutively active PKB/Akt show a dramatic reduction in AMPK phosphorylation, when compared to control hearts that do not express the transgene, indicating that insulin-induced down-regulation of AMPK is mediated by Akt-dependent pathways (Kovacic et al., 2003). PKB/Akt and AMPK have been shown to be inversely correlated in other occurrences too. For example, ischemia in heart causes activation of AMPK and inhibits insulin signaling (Beauloye et al., 2001a), whereas  priming of the hearts by insulin pre-treatment in the aerobic period blunts the AMPK response to a subsequent period of ischemia (Beauloye et al., 2001b; Bertrand et al., 2006). The molecular mechanism of the effect of insulin on AMPK signaling pathways has been elucidated as direct phosphorylation of AMPK by PKB/Akt on Ser 485/491 (Horman et al., 2006). This phosphorylation can prevent subsequent activation of AMPK at Th172 by LKB1. It is possible, as suggested by Zou and coworkers, that phosphorylation at Ser 485/491 hinders the physical association of AMPK with LKB1 (Zou et al., 2004). Although insulin inhibits AMPK under ischemia the glycolysis should remain elevated because both insulin and ischemia stimulate glycolysis by activating the same key steps. Physiological relevance of this inhibition in ischemic hearts could also modulate other targets of AMPK, as yet unknown. The ability of PKB/Akt to negatively regulate AMPK activity becomes especially relevant in the physiology of myocardial ischemia-reperfusion. It is possible that PKB/Akt regulates fatty acid oxidation rates secondarily to inhibition of AMPK activity. In addition, PKB/Akt is supposed to be protective by promoting the post-ischemic synthesis of contractile proteins and by inhibiting myocyte apoptosis (Fujio et al., 2000; Miao et al., 2000 ; Ruan et al., 2009), two processes conversely regulated by AMPK (Horman et al., 2003; Meisse et al., 2002). However, the role of PKB/Akt remains controversial and remains to be further investigated, as others argue against the beneficial effects of PKB/Akt negatively regulating AMPK (Nagoshi et al., 2005). Although the metabolic effects of AMPK and PKB/Akt have been largely studied, the ability of PKB/Akt to inhibit AMPK has implications beyond cardiac metabolism. Insulin and IGF-1 have been shown to induce protein synthesis and cardiac hypertrophy via PKB/Akt activation (Proud and Denton, 1997). AMPK antagonizes the stimulating effect of insulin by inhibiting the TSC2/mTOR/p70S6K (Inoki et al., 2003) and eEF2 pathway (Horman et al., 2002). It is therefore possible that the reduction of AMPK activity may be a contributing factor to PKB/Akt-induced cardiac hypertrophy. Studies are ongoing to investigate this relationship.