FIGURE 2.

UPR^mt and coordinated UPR^ER increase insulin sensitivity, inhibit beta cell death and benefit T2D. Firstly, hyperglycemia induces UPR^mt and UPR^ER. As the downstream of PERK, ATF4, CHOP and ATF5 will inhibit beta cell death; thus, they have beneficial effects on T2D management. Secondly, SIRT1, SIRT3 and SIRT5 activate UPR^mt, which improves insulin sensitivity. In addition, the increased expression of mitochondrial chaperone proteins and proteases, such as HSP60, HSP70, HSP72, LONP1, CLPP, and OMA1, may reduce insulin resistance. Moreover, by inhibiting PGC-1a, LONP1 suppresses hepatic gluconeogenesis, thereby ameliorating hepatic insulin resistance.