Fig. 3

A sketch of pathogenesis of T2D. Briefly, Under the stimulation of SFAs, hypoxia in adipocytes due to enhanced SFAs metabolism, and the release of inflammatory factors from macrophage infiltration cause chronic inflammation in adipose tissues, leading to adipocyte IR and increased lipolysis. NEFAs and glycerol from lipolysis causes increased lipid synthesis, gluconeogenesis, and ectopic fat deposition in the liver, which affects IRS-1/PI3K/Akt2 phosphorylation on the one hand, and increases hepatic release of glucose on the other. At the same time, ectopic fat deposition also occurs in the muscle and leads to elevated circulating VLDL, further exacerbating lipid metabolism disorders and IR in the liver. Persistent hyperglycemia and excess fatty acids in the circulation due to overnutrition and IR further damage β-cell function and mass by some shared pathways, involving inflammation, ERS, and oxidative stress. IR insulin resistance, SFAs saturated fatty acid, NEFAs non-esterified fatty acids, TNF-α tumor necrosis factor α, IL-1β interleukin-1β, JNK c-Jun N-terminal kinase, FASN fatty acid synthase, DAG diacylglycerol, FA-CoA Fatty acyl-coenzyme A, ANT-2 adenine nucleotide translocase 2, HIF-1α hypoxia-inducible factor 1 alpha, NLRP3 NOD-like receptor family pyrin domain-containing 3, GABA γ-aminobutyric acid, PP2A protein phosphatase 2A, PKC protein kinase C, AMPK adenosine 5’-monophosphate-activated protein kinase, VLDL very-low-density lipoprotein, ROS reactive oxygen species, NF-κB nuclear factor-kappa B, Cxcl8a neutrophil chemokine (C-X-C motif) ligand 8a, ERS endoplasmic reticulum stress, CHOP C/EBP homologous protein, PDX1 pancreatic and duodenal homeobox factor-1, MAFA MAF bZIP transcription factor A