Fig. 3

The cGAS–STING pathway is linked to diabetes through Akt. A Insulin-mediated activation of Akt is essential for glucose handling and metabolism. Insulin activates PI3K/Akt. Akt is activated and phosphorylates many of its substrates, which regulate glycogen synthesis, gluconeogenesis, and glucose uptake. Akt can regulate cellular uptake of glucose by stimulating GLUT4 from cytoplasm to cell membrane. mTOR is a serine/threonine kinase that responds to a variety of environmental stimuli, including nutrient, oxygen, and energy levels, and forms two functionally distinct complexes, mTORC1 and mTORC2. mTORC1 can act as a nutrient/energy/redox sensor, controlling protein synthesis and growth factors. Prolonged activation of mTOR1 by glucose/fatty acids can further promote cellular damage, thereby exacerbating diabetes-associated cell and tissue damage while mTORC2 may also activate Akt function. B The link between the cGAS–STING pathway and Akt was shown earlier in rheumatoid arthritis, where Akt expression was significantly decreased when cGAS expression was suppressed [149]. However, in virus infection conditions, the relationship between the cGAS–STING pathway and Akt exhibits differently. Akt activation reported in the earlier experiments inhibited the cGAS–STING pathway [41], but in later experiments, activated Akt positively regulated the cGAS–STING-mediated antiviral action [150, 151]. Reportedly TBK1 is able to inhibit mTORC1 activity in mice [153]. Given that the role of mTORC1 can be regulated by Akt and TBK1 (a downstream link of the cGAS–STING pathway), mTORC1 may be a key link connecting the cGAS–STING pathway to Akt. Limited information indicates that in HFD-treated Akt2-AMPKα2 double-knockout mouse hearts, Akt2-AMPKα2 double-knockout activated the cGAS–STING pathway, as the first evidence for the link between Akt and cGAS–STING pathway in metabolic disease. To date, there remains no study on whether knockdown of Akt alone activated the cGAS–STING pathway. Therefore, whether the cGAS–STING pathway functions in the pathogenesis of diabetes, whether the cGAS–STING pathway plays a role in the pathogenesis of diabetes, and what function does Akt play in these diseases all need to be further investigated. AMPK AMP-activated protein kinase, Akt protein kinase B PKB, Akt2 Akt serine/threonine kinase 2, GLUT4 glucose transporter type 4, mTORC1 mammalian target of rapamycin complex 1, mTORC2 mammalian target of rapamycin complex 2, PI3K phosphatidylinositol 3 kinase. The solid lines and dash lines indicate direct and indirect action, respectively