Table 2.
Water, proteins or fats affect PI3K/Akt and/or GSK3 activities
| Nutrient | Model system | Observed effects | Ref. (model) |
|---|---|---|---|
| Water | |||
| 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, 46–48] |
| 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, 49–52] |
| Proteins | |||
| 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] |
| Carbohydrates | |||
| 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. | [61–63] |
| 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, 99–107] |
| Fats | |||
| 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] |
aKKAy mice: The KK-Ay mouse is a T2D model that exhibits marked obesity, glucose intolerance, severe insulin resistance, dyslipidemia, and hypertension