http://biomed.gerontologyjournals.org/cgi/content/full/60/11/1378#GRNA-60-10-21-B20
http://www.youtube.com/watch?v=RQG5XLi0feg
http://www.youtube.com/watch?v=fkthr6OCbT0
In view of the role of SIRT1 and autophagy in the control of glucose and amino acid homeostasis, respectively, in fasting conditions, and in view of the role of autophagy and FOXO-dependent ubiquitin ligases in the turnover of damaged mitochondria and contractile proteins, respectively (see above), it is reasonable to assume that a well balanced downregulation of the insulin receptor signaling cascade may also be required to maintain the integrity of postmitotic tissues in humans. However, in view of the positive role of insulin in metabolic regulation and the negative consequences of insulin receptor dysfunction (see, e.g., 43,44), it is reasonable to assume that the persistent impairment of insulin receptor function by genetic or other means may not be the method of choice for humans and may not even be the optimal method for life extension in worms, flies, and mice.
As the response to insulin is needed to ensure glucose clearance and to stimulate protein synthesis after food intake, insulin receptor signaling must be sufficiently strong in the postprandial (fed) state. In healthy human persons, downregulation of insulin receptor signaling is therefore only found in the postabsorptive (fasted) state (reviewed in 20), implying that optimal induction of SIRT1 activity, autophagy, and FOXO1 and FOXO3 transcription factor activity is largely restricted to this state. This conclusion is in agreement with the putative role of these activities in the maintenance of glucose and amino acid homeostasis during the fasted state as mentioned above. Any attempt to further downregulate insulin receptor signaling in humans must be restricted to the fasted state, i.e., it must involve the basal insulin receptor activity. A series of recent reports have shown that the insulin-independent basal activity of the insulin receptor is weak (but clearly detectable) and subject to regulation by the redox status. [...] Work from several laboratories has shown that autophosphorylation of the insulin receptor is facilitated by hydrogen peroxide and enhanced by procedures that decrease intracellular levels of glutathione (55–60). (attivazione della insulin signaling in assenza dell'ormone per il solo effetto dei ROS o in alternativa per deplezione di glutatione) Prolonged exposure to hydrogen peroxide, however, strongly inhibits insulin action (61–65), suggesting that insulin signaling is enhanced only by moderate oxidative conditions (tipico fenomeno ormetico ) but inhibited by excessive exposure to hydrogen peroxide. In diabetes, hyperglycemia leads to glucose oxidation and oxidative degradation of glycated proteins, which result in the production of reactive oxygen species (ROS) (reviewed in 66). As hyperglycemia was found to be ameliorated in diabetic patients by certain antioxidants, such as -lipoic acid and NAC (66,67), it has been suggested that oxidative inhibition of insulin signaling accounts at least in part for the decrease in insulin responsiveness seen in this clinical condition. These findings do not preclude, however, that administration of antioxidants to nondiabetic persons decreases insulin reactivity due to the enhancing effect of moderate oxidative conditions on insulin receptor activity.[...]
As downregulation of insulin receptor signaling in humans must be restricted to the fasted state (altrimenti potrebbe verificarsi un aumento anomalo di glucosio ematico), and the insulin-independent basal insulin receptor tyrosine kinase activity is increased under (moderately) oxidative conditions, the following section deals with clinical trials on the effect of cysteine supplementation on functional parameters relevant to aging.[...] NAC, either with or without creatine, has been shown to modulate both basal and postprandrial insulin responsiveness (48).[...] The available evidence suggests that a well balanced increase in the dietary cysteine supply may allow us to decrease basal insulin receptor signaling without compromising postprandial glucose clearance to an unacceptable extent.
Beré tè in fasted state potrebbe non essere una opzione per via che è gluconeogenico, e insulin mimic. pareri?
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