Inhibition by high glucose concentration

Read Also

AMPK can be negatively regulated by chronic exposure to high glucose. Acute hyperglycemia reduces AMPK activation in muscle, liver (Kraegen et al., 2006) and kidney (Lee et al., 2007b). Decreased AMPK activity observed after glucose infusion does not depend on changes in plasma insulin and FFA levels, as alterations in AMPK activity are also observed following incubation with high glucose concentrations in isolated muscles (Itani et al., 2003) as well as in cultured HepG2 hepatocytes (Zang et al., 2004), human umbilical vein endothelial cells (Ido et al., 2002), b-cells (da Silva Xavier et al., 2003; Gleason et al., 2007; Salt et al., 1998b) and islets (Leclerc et al., 2004). Upon elevation of glucose concentration over the physiological range, AMPK activity is rapidly down-regulated, concomitant with decrease of phosphorylation at Thr172. According to the classic view, glucose-dependent regulation of AMPK activity and phosphorylation is presumably induced by the activation of ATP synthesis and consequent changes in AMP/ATP ratio (da Silva Xavier et al., 2000; da Silva Xavier et al., 2003; Salt et al., 1998b). However, no change in creatine phosphate or adenine nucleotides was reported in muscle incubated with a high concentration of glucose (Itani et al., 2003), indicating that novel regulation mechanisms of AMPK may be operative in response to glucose oversupply. Under circumstances, where no significant change in high-energy phosphate molecules was observed, diminished AMPK activity and phosphorylation were attributed to alterations in phosphorylation and inhibition of AMPK by Akt (Hahn-Windgassen et al., 2005; Lee et al., 2007b), action of specific phosphatases on phosphorylated AMPK (Ravnskjaer et al., 2006), changes in redox state (Rafaeloff-Phail et al., 2004), modification in intracellular free Ca²⁺ concentration (Leclerc and Rutter, 2004) and alterations in glycogen content (Jorgensen et al., 2004). Regulation of AMPK by glucose might be important to limit glucose uptake into tissues and to protect cells against the adverse effects of sustained hyperglycemia, such as oxidative stress.

Recent work in animal models demonstrated that glucose and fasting/refeeding change AMPK activity in several hypothalamic nuclei (Kim et al., 2004b; Minokoshi et al., 2004). These studies described reduced AMPK activity and phosphorylation state in the basomedial hypothalamus in response to intracerebroventricular (icv) injection of glucose and showed reciprocal effects of AMPK activation or inhibition on feeding behaviour (Kim et al., 2004b; Minokoshi et al., 2004). Hypothalamic neurons appear to mediate the effects of glucose via changes in AMPK activity (Mountjoy et al., 2007). It was established that AMPK responds to changes in blood glucose and functions in transmitting the malonyl-CoA signal (Wolfgang et al., 2007). AMPK activation allows the dephoshorylation/activation of acetyl-CoA carboxylase (ACC) which increases the level of hypothalamic malonyl-CoA resulting in food intake suppression and increased energy expenditure. Interestingly, AMPK has been shown to play an important role in the glucose-sensing mechanism used by the ventromedial hypothalamus, a key brain region involved in the detection of hypoglycemia (Fan et al., 2009). These findings indicate that minute changes in neuron glucose concentration modulate AMP/ATP ratio which can be sensed by AMPK signaling pathway in discrete hypothalamic regions to generate hunger or satiety signals (see below).