LOLOLOLOLOLOLOLOLOLOL
Here we go for another controversial thread.
High levels of insulin are related to so many pathologies, I really don't get why people want to use it.
Especially when taking the combination of a simple carb and protein and/or isolated amino acids post workout will spike your insulin.
High levels or insulin are related to cognitive decline and Altzheimers disease (AD)
I suppose it isn't a big deal if you loose your mind when you get older, cause really, if you are a dribbling old geezer you probably wouldn't realise you have lost the plot.
Here is a link related to elevated insulin and AD.
Type 2 Diabetes
and an abstract
Insulin Resistance Alzheimer's Disease: Pathophysiology and Treatment
ABSTRACT
Insulin and insulin resistance likely play a significant role in the pathophysiology and cognitive decline associated with Alzheimer's disease (AD).
Insulin, insulin receptors, and insulin-sensitive glucose transporters are selectively localized the brain, including medial temporal areas that support memory.
Raising brain insulin levels can facilitate memory and increase cerebrospinal fluid levels of β-amyloid (Aβ) and inflammatory markers. Insulin's effects on cognition may reflect normal regulation of glucose metabolism, long-term potentiation, and neurotransmitter levels.
Consequently, insulin abnormalities may disrupt normal memory functioning and promote pathophysiological processes observed in patients with neurodegenerative disorders.
Conversely, restoring normal insulin activity may exert a beneficial effect on pathophysiological processes. For example, peroxisome proliferator-activated receptor (PPAR)-gamma agonists (insulin sensitizing agents used to treat type 2 diabetes mellitus) modulate neuronal cell survival, inflammatory responses, mitochondrial functioning, and possibly Aβ processing and deposition.
One PPAR-gamma agonist, rosiglitazone, facilitates memory and modulates plasma Aβ levels in patients with AD. Likewise, a healthy diet and regular exercise may improve insulin sensitivity and decrease the risk for both AD. Furthermore, intranasal insulin administration rapidly delivers insulin to the brain without altering plasma insulin or glucose levels.
Studies to date suggest that this procedure can facilitate memory and modulate plasma Aβ levels in memory-impaired adults. Interestingly, the adverse effects of insulin abnormalities and the beneficial effects of improving insulin sensitivity may differ by apolipoprotein E (APOE) genotype, an established risk factor for AD.
Patients who do carry lower doses of the APOE e4 allele have an enhanced risk for insulin abnormalities and are also more responsive to the memory enhancing effects of both rosiglitazone and intranasal insulin administration, relative to other patients. Therefore, future therapeutic trials should consider the moderating effects of APOE genotype.
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Role of insulin in cognitive defects
The activation of insulin signalling pathways has been shown to be important for many aspects of neuronal function.
Studies in rats have shown that disruption of the insulin receptor (INSR) gene leads to progressive cognitive impairment, while human studies have demonstrated that older diabetic patients perform poorly compared to controls on a variety of cognitive function tests (reviewed by Stewart and Liolitsa, 1999 Correspondingly, insulin improves cognition not only in normal healthy individuals, but in patients with mild AD (reviewed by Watson and Craft 2004 Induced hyperglycaemia results in an increased plasma level of insulin and enhanced cognitive performance in these patients, and these improvements were dependent on insulin (reviewed by Watson and Craft 2004 Nonetheless, these effects were not observed in patients with severe AD, but this may be due to the effects of chronic hyperglycaemia and hyperinsulinaemia in later disease stages (reviewed by Watson and Craft 2004
In addition to these functional observations, post-mortem evidence corroborates this alteration in insulin signalling. Not only are there increased insulin receptors in AD brains indicating a possible upregulation in response to insulin resistance, but there is a decrease in the levels of tyrosine phosphorylation, suggesting a failure in signal transduction processes (Frolich et al 1998). This indicates that insulin may mediate its observed effect on cognition via signal transduction pathways. However, signal transduction is not the sole means by which insulin can influence cognition. Several key neurotransmitters in the brain are directly dependent on exogenous glucose for their synthesis, for example glutamate and acetylcholine (reviewed by Messier 2004).
Both of these neurotransmitters have important functions in learning and memory, and it is widely recognised that there is a loss of cholinergic neurons in the brains of AD patients. Nonetheless, since the majority of glucose uptake in the brain is insulin-independent it is perhaps more likely that the effects on cognition induced by insulin are due to enhanced insulin signalling.
The signal transduction cascades activated by insulin are not solely involved in mediating glucose metabolism and cognition. Insulin is involved in many diverse signalling pathways (reviewed by Taha and Klip, 1999 Gasparini et al 2002 Craft and Watson, 2004 Hoyer 2004 and recent evidence has shown that insulin signalling can be linked to the processing of both APP and tau.
Insulin signalling affects APP processing and Tau phosphorylation
Insulin signalling is activated by the binding of insulin to the insulin receptor (INSR), which is a receptor tyrosine kinase. The INSR is a tetramer, with two extracellular α-subunits and two cytoplasmic β-subunits. Insulin binds to the α-subunits of the INSR and this activates autophosphorylation on tyrosine residues, leading to downstream signalling events mediated by Ser/Thr phosphorylation. The PI3-K, MAPK and atypical PKC signalling cascades are activated by insulin, while the PI3-K and atypical PKC pathways can also be activated by proteins from the insulin receptor substrate family (IRS). Following phosphorylation these proteins recruit PI3-K and activate it, leading to the subsequent activation of PKB/Akt and PKC. The MAPK pathway is activated by the recruitment of SHC to the INSR, followed by GRB2 then SOS. SOS catalyses the nucleotide exchange of Ras-GDP to Ras-GTP, which activates Raf and leads to MEK activation. The MAPK pathway is not very sensitive to insulin and so the main responses to this hormone are via PI3K pathways (reviewed by Taha and Klip, 1999 Additionally, the MAPK and PI3K pathways have been shown to interact at the level of Ras-GTP.
In addition to its effects on cognition, numerous reports implicate impaired insulin signalling in the development of AD pathologies. The transgenic mouse Tg2576 is an ideal animal model for understanding the pathogenesis of amyloid plaques in AD. These mice over express the Swe-APP mutation and have increased Aβ levels, although they do not develop Aβ plaques until 12 months of age and there is no development of NFTs or neuronal loss (Hsiao et al 1996 However, the lack of fully-fledged AD pathology in these mice may be due to the increased expression of the insulin-like growth factor (IGF2), which activates Akt/PKB and leads to both the deactivation of pro-apoptotic proteins and the activation of neuroprotective ones (Stein and Johnson 2002
Given that obesity is a risk factor for T2D and that there is a potential association between T2D and dementia, recent studies have examined the effect that diet has on Tg2576 mice. A high fat diet not only led to insulin resistance and attenuated brain insulin signalling, but an increase in brain Aβ burden and increased activation of both GSK3α and GSK3β, which correlated with increased -secretase activity (Ho et al 2004 Furthermore, reduced insulin signalling led to the reduced expression and activity of IDE suggesting that not only is Aβ generation increased, but that degradation is inhibited (Ho et al 2004 A further study by this same group examined the opposing effects of feeding Tg2576 mice a calorie restricted (CR) diet (Wang et al 2005 A CR diet prevented the generation of Aβ and increased the levels of the -secretase ADAM10, leading to increased levels of the neuroprotective APP fragment sAPP (Wang et al 2005 Increased sAPPα has also been observed following activation of the PI3K pathway by insulin (Solano et al 2000 and the activation of another α-secretase, ADAM17, is known to be stimulated by conventional PKC signalling (Gillespie et al 1992
These results indicate that a CR diet may stimulate insulin signalling and promote non-amyloidogenic APP processing and the production of neuroprotective sAPPα, whereas a high fat diet is associated with insulin resistance and amyloidogenic APP processing. This effect of diet on APP processing is not entirely surprising given that proteolysis is affected by membrane lipid content (Vetrivel et al 2005 Furthermore, amyloidogenic processing occurs primarily in the late secretory pathway, and insulin has been shown to influence location of APP through regulation of intracellular trafficking.
Treatment of neuronal cells with insulin increases the extracellular concentration of Aβ and decreases the intracellular level of Aβ, and this is caused by the increased the trafficking of APP/Aβ to the plasma membrane in a process dependent on MAPK (Gasparini et al 2001 Impaired insulin signalling may influence trafficking by altering oxidative cellular metabolism, leading to disturbed pH balances in the ER and GA, and altered APP trafficking (reviewed by Hoyer 2002 Hoyer 2004 Deficient APP transport would increase the amount of protein in contact with γ-secretase activity in the trans-Golgi network and lead to an increase in intracellular levels of Aβ. Hence, the beneficial effect of insulin on cognition supports the recent addition to the [amyloid cascade hypothesis] that intracellular amyloid is the Aβ species responsible for cognitive decline in AD.
Further support for the pathogenicity of intracellular Aβ comes from learning and memory studies carried out using Tg2576 mice The cognitive defects in these mice were due to small Aβ assemblies and not insoluble amyloid plaques (Westerman et al 2002 Furthermore, although some of these mice had a high plaque load they were cognitively normal (Westerman et al 2002 Interestingly, the observed memory loss in Tg2576 mice was reversible following treatment with Aβ antibodies, indicating the pathological features of these mice represent early stages of AD where memory loss may not be permanent (Kotilinek et al 2002
Impaired insulin signalling has also been implicated in the generation of phosphorylation of tau protein.
Insulin signalling regulates GSK3 phosphorylation and mice that are knocked out for insulin receptor substrate-2 (IRS2) show insulin resistance and have increased levels of phosphorylated tau in the hippocampus (Schubert et al 2003 Neuron-specific INSR KO mice also display neuronal insulin resistance and increased tau phosphorylation, although no abnormalities in spatial learning and memory were reported (Schubert et al 2004 This increase in tau phosphorylation was due to decreased activation of the PI3K pathway and the failure of Akt/PKB to inhibit GSK3β (Schubert et al 2003 ;Schubert et al 2004 Regulation of GSK3β is precise and insulin signalling can also activate GSK3β, via tyrosine phosphorylation by Fyn tyrosine kinase (Lesort et al 1999 In addition, GSK3α is required for the maximal processing of APP to produce Aβ peptides (Phiel et al 2003
Overall, the available data indicates that insulin signalling can affect both AD pathologies. Furthermore, the development of tangles can be linked through insulin signalling to altered APP processing with the observation that Aβ peptides can activate GSK3β in cell culture models (reviewed by Kaytor and Orr 2002 Both insulin and Aβ contain consensus sequences for binding to the INSR, and they are direct competitors of each other (Xie et al 2002 Aβ activates GSK3β by downregulating insulin signalling (Xie et al 2002 and increased levels of extracellular A can therefore explain the hyperinsulinaemia and insulin resistance observed in AD patients. Furthermore, this finding explains why Tg2756 mice are insulin resistant (Pedersen and Flynn 2004
This shared consensus sequence also mediates the binding of Aβ and insulin to the [insulin degrading enzyme]. IDE is a thiol metalloendopeptidase that not only degrades insulin, but extracellular Aβ (Qiu et al 1998 Furthermore, IDE knock out mice have a > 50% decrease in both Aβ and insulin degradation, leading to accumulation of endogenous Aβ, hyperinsulinaemia and glucose intolerance, indicating that IDE regulates degradation in vivo (Farris et al 2003 Hence, IDE is an excellent candidate gene for late-onset AD (LOAD) and indeed, recent studies have shown that polymorphisms in IDE may be associated with LOAD. However, this association may be dependent on APOE genotype, and this observation may help to explain the APOE allele specific effects reported in many studies.
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