Fig. 2

Distinct pathogenic pathways for non-obese T2D and obese T2D. For non-obese T2D, the interaction between environmental factors and genes on the MAP4K4 gene may enhance methylation of the MAP4K4 promoter, resulting in MAP4K4 downregulation. MAP4K4 downregulation in T cells subsequently results in overproduction of the proinflammatory cytokines IL-6 and IL-17, leading to insulin resistance of the insulin-targeted cells. In obese T2D, high-fat diet is a cause of obesity and visceral fat accumulation, resulting in overproduction of the proinflammatory cytokine IFN-γ from T cells [36, 37], the IgG autoantibodies from B cells [38], and the proinflammatory cytokines TNF-α, IL-1β, IL-6 from macrophages [46]. Besides macrophages, IL-6 is also produced from adipocytes, hepatocytes, muscle cells, and B cells of high-fat-diet fed mice [47]. High-fat-diet-induced B cells recruit macrophages into insulin-targeted tissues and activate T cells for IFN-γ production [38]. TNF-α and IFN-γ cause insulin resistance [46]. In both non-obese T2D and obese T2D, insulin resistance further induces hepatic and cardiac steatosis