The PI3K/AKT pathway in obesity and type 2 diabetes

“AKT-mediated mTORC1 activation regulates a number of downstream effectors proteins through phosphorylation, including the well-characterized effectors p70 ribosomal S6 protein kinase-1 (S6K1) and eukaryotic translation initiation factor-4E (eIF4E)binding protein-1 (4E-BP1), to increase protein synthesis [43, 44].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“AKT regulates two processes by glycolysis Glucose 6-phosphate and glycogen synthase kinase 3 (GSK3) to produce cellular energy via glycolysis and promotes glycogen production by inhibiting [30].”

“In obese subjects, excess levels of circulating FFAs, which are caused by a blunted response of adipose tissues, impairs the function of β cells [150].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“Similar phosphorylation events are observed at corresponding residues in AKT2 (T309 and S474) and AKT3 (T305 and S472) [22].”

“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“Chronic metabolic inflammation and endoplasmic reticulum (ER) stress also impair hepatic insulin-AKT signalling and subsequently causes insulin resistance [106, 107].”

“The prevalence of obesity has grown at an alarming rate although specific public health policies and treatment efforts have been developed to resist the obesity epidemic [1], potentially leading to increased numbers of patients affected by complications of obesity, such as the most devastating type 2 diabetes mellitus…”

“Thus the dysregulation of PI3K/AKT signalling pathway is considered to be one of the mechanisms underlying the pathogenesis of type-2 diabetes mellitus [6].”

“This is explained by the recently discovered fact that adipose tissues are neither inert nor restricted to serving as an energy storage organ but instead are a major endocrine organ and play a substantial role in the etiology of T2DM and insulin resistance (IR) [7].”

“Under physiological conditions, insulin-induced activation of PI3K/Akt maintains metabolic homeostasis; however, chronic energy excess and elevated free fatty acid levels disrupt this pathway, leading to insulin resistance and promoting obesity and type 2 diabetes (14,15).”

“PI3K/Akt/mTOR сприяє реалізації основних метаболічних ефектів інсуліну, а саме: стимулює синтез білка, глікогену, ліпідів, пригнічує глюконеогенез і ліполіз [68, 69].”

“Proinflammatory markers like NFKB1 and TNFα, characteristic of the insulin resistance were present in the cluster along with lipid regulatory and obesity-linked PPARα and PPARγ [2628] The other critical markers were insulin signalling molecules like AKT1 and PI3K, demonstrating that these core pathways involved in dia…”

“However, excess energy, as in obesity, can impair the signaling of this pathway, causing insulin resistance (61).”