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Table 2 Water, proteins or fats affect PI3K/Akt and/or GSK3 activities

From: Chronic over-nutrition and dysregulation of GSK3 in diseases

Nutrient Model system Observed effects Ref. (model)
 Hypo-osmotic stress Human embryonic kidney cells, mouse osteoblast, human thyroid cancer cells, HRPE, human monocytes and human neuroblastoma. Hypo-osmotic pressure induces calcium influx that mediates PI3K and p53 activation, resulting in cell apoptosis, which involves high GSK3 activity due to overstimulation. [5, 15, 4648]
 Hyper-osmotic stress Monkey kidney cells, HeLa cells, human or mouse melanoma cells, HRPE, human monocytes. Despite inducing the p21-activated serine-threonine kinase, requiring PI3K activation, within 30-min, hyper-osmotic stress suppresses melanin production that also requires PI3K activation, for days of the treatment, suggesting overstimulation of the PI3K/Akt pathway. [5, 4952]
 Non-denatured protein Male SD rats, human embryonic kidney cells. Branched-chain amino acids in cow milk are highly insulinotropic and a potent activator of PI3K/Akt. [53, 54]
 Denatured proteins Rat muscle cells. Increase PI3K. [55]
 Excess protein Adult women, rats with intestinal ischemia-reperfusion injury, T2D mice. Raise calcium excretion; protein-generated sulfates activate PI3K/Akt via their receptors. [56, 58, 59]
 Glucose Humans with diabetes, rat extensor digitorum longus muscle, mouse cardiac fibroblasts. Cause insulin response; insulin resistance and stage 2 of the kinase insensitivity (Table 1); modulate PI3K/Akt/GSK3 activities; add inflammation and apoptosis. [6163]
 Fructose SD rats with diabetes, mouse hepatocytes. Increase NF-κB activity which associates with GSK3 activity. [96, 97]
 D-galactose Mice, human neuroblastoma cells. Activate caspase-3, which associates with GSK3/p53 binding. [15, 98]
 Polysaccharides Rats with diabetes, cancer patients, C57BL/6 mice [68, 99], human hepatocellular carcinoma, human melanoma cells, human osteosarcoma, human gastric carcinoma cells, Balb/c mice, T2D rats, human hepatocellular carcinoma cells,a KKAy mice. Modulate PI3K/Akt and/or GSK3 activities. [68, 99107]
 Intracellular lipid Human embryonic kidney cells, human monocytes, mouse embryonic fibroblasts. Modulate GSK3/PLIN2 association, GSK3 activity, expression of GSK3 substrates and cell growth/survival, and increase pYGSK3 levels (long-term). [6]
 Extracellular lipid including palmitic acid Human hepatocellular carcinoma cells, normal men. Generate insulin resistance and stage 3 of the kinase insensitivity (Table 1) and decrease insulin-induced PI3K activity. [67, 68]
 Sterol including androgen Human prostate cancer epithelial cells. Increase Akt activity. [69]
 Monoacylglycerol Mouse neural crest cells. Activate PI3K. [70]
 Diacylglycerol and medium-chain triacyglycerol Human breast cancer cells, human brain glioblastoma cells, human alveolar basal epithelial cells, livers of malnourished Wistar rats. Activate Akt. [71, 72]
 High-fat diet C57BL16 mice, Tg2576 mice, diabetes- and obesity-prone C57BL/6 J mice, C57BL/6J mice. Induce insulin insensitivity which can be improved by overexpression of PLIN2, increase glucose intolerance and insulin resistance, and decrease PI3K/Akt activities and raise GSK3 activity, stage 3 of the kinase sensitivity (Table 1), whereas glucose metabolism can be ameliorated if GSK3 activity is inhibited. [33, 43, 73, 74]
 High lipid levels Mouse myoblast cells. Overexpression of PLIN2 betters insulin sensitivity reduced by fatty acids. [33]
  1. aKKAy mice: The KK-Ay mouse is a T2D model that exhibits marked obesity, glucose intolerance, severe insulin resistance, dyslipidemia, and hypertension