Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

Table 2 Mechanistic and physiologic effects of cyclic guanosine monophosphate-adenosine monophosphate synthase inhibitors associated with diabetes and its complications

Inhibitor	Mechanism	Physiologic effects
Compound 18	Small molecule inhibitors break the molecular structure of cGAS by binding to hydrogen bonds[91]	Compound 18 improves glucose tolerance in high fat diet mice[94]
RU.521, RU.356, RU332	Competes with ATP and GTP for enzyme binding sites by virtue of its own structural advantages[95]	RU521 attenuates cGAS-STING-mediated cardiac dysfunction in BRG1 knockout diabetic cardiac mice[96]
PF-06928215	Competes with cGMP for the cGAS binding site[97]	PF-06928215 attenuates cGAS-STING-mediated cardiac dysfunction in double knockout of Akt2 and AMPK mice[98]
HCQ	Prevents cGAS from binding to DNA by occupying the DNA binding site[97]	Improvement of inflammation by decreasing IFN-β release from Th1 cells
Aspirin	Aspirin acetylates cGAS to block cGAS-STING signaling. Aspirin’s metabolite salicylate may affect NF-κB nuclear translocation[89]	No relevant evidence. Aspirin is only a theoretical cGAS inhibitor because it is easily hydrolyzed in the body
Suramin	Similar to nucleic acid structure, competes for DNA and cGAS binding sites[99]	Suramin blocks dsDNA binding to cGAS and limit AIM2 inflammatory vesicle formation[100]

cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: Stimulator of interferon gene; ATP: Adenosine triphosphate; GTP: Guanosine triphosphate; cGMP: Cyclic guanosine monophosphate; NF-κB: Nuclear factor-κB; Akt: Activated protein kinase B; AMPK: Adenosine monophosphate-activated protein kinase; IFN: Interferon; Th1: T helper type 1; dsDNA: Double-stranded DNA; AIM2: Absent in melanoma 2.