Table 2.

The level changes of main molecules related to AKT pathway in DR and their therapeutic mediation.

Molecule name	Expression level	Patient/Animal models	Cells in retina	Purpose of regulation	Molecules used for regulation	References
AKT	Downregulated in the early stage of DR	Patient, rats, mouse, monkeys, cows, cells in vitro	Retinal neurons, RGCs, RPCs, RCVECs, RPECs	To increase its expression level or activate it	Insulin [39]; IGF-1 [40]	[8–10]
	Upregulated in PDR	Patient, rats, mouse	RCVECs, RPECs	To decrease its expression level or inhibit it	LY294002 [36]; wortmannin [37]; GDC-0941 [38]	[13–16]
Insulin	Downregulated	Patient	Retinal neurons, RPCs, RCVECs	To increase its expression level or activate it	/	[48]
IRS	Downregulated	Rats, mouse	RCVECs, RPECs	To increase its expression level or activate it	miR-126 [51]; miR-7a [52]	[49]
IGF-1	Downregulated	Patient, rats, mouse	Retinal neurons, RGCs, RPCs, RCVECs, RPECs	To increase its expression level or activate it	IGF-1 [59, 60], protein tyrosine phosphatase 1B [61]; quinic acid derivative KZ-41 [62]; anti-rat integrin-associated protein antibody [63]; miR-142-5p [64]; miR-18b [65]	[56]
IGFBP-3	Downregulated	Patient, mouse	RCVECs	To increase its expression level or activate it	miR-15b, miR-16 [67, 68]	[63]
VEGF	Upregulated	Patient, rats, mouse	RCVECs, RPECs	To decrease its expression level or inhibit it	IGF-1 and dopamine [58]; traditional VEGF inhibitors [72–75]; new small molecules or biological factors [76, 77, 88–100]; herbal or biological extracts [78–84]; quercetin [85–87]; miR-21 [104]; miR-19a [105]; miR-183 [106]; miRNA-20b-5p [107]; miR-199a-3p [108]; miR-7 [109]; miR-20b [110]; miR-126 [111, 112]; lncRNA HEIH, miR-939 [113]	[71]
	Excessive inhibition in medical procedures	Patient	Retinal neurons, RGCs	To reduce negative effects of anti-VEGF therapy	/	[118, 120, 121]
mTOR	Downregulated in the early stage of DR	Patient, rats, cells in vitro	Retinal neurons, RPCs, RPECs	To increase its expression level or activate it	Leukocyte cell-derived chemotaxin 2 [133]; curcumin [134]; mangiferin [135]; adiponectin [136]	[130, 131]
	Upregulated in PDR	Patient, pig, mouse	RCVECs, RPECs	To decrease its expression level or inhibit it	Conventional mTOR inhibitors, such as rapamycin [137]; INK128 [138]; REDD1 [139]; trimetazidine [140]; lncRNA MEG3 [141]; miR-7 [142]	[14]
FOXO	Upregulated	Patient	RPCs, RCVECs, RPECs	To decrease its expression level or inhibit it	/	[143–145]
	Activation in medical procedures to suppresses angiogenesis	Cells in vitro	RCVECs	To increase its expression level or activate it	Epigallocatechin-3 gallate [148, 150]	[147]
GSK-3	Upregulated	Patient, cells in vitro	Retinal neurons, RGCs, RPCs, RCVECs, RPECs	To decrease its expression level or inhibit it	Lithium chloride [155, 156]; pterostilbene [160]; ginsenoside Rg1 [161]; sauchinone [162]	[154]
Nrf2	Downregulated	Patient, cells in vitro	Retinal neurons, RGCs, RPCs, RCVECs, RPECs	To increase its expression or activate it	Lutein [163]; astaxanthin [164]; tetrahedral frame nucleic acids [165]	[153]
NF-κB	Upregulated	Patient, rats, cells in vitro	Retinal neurons, RGCs, RPCs, RCVECs, RPECs	To decrease its expression level or inhibit it	Melatonin [171–173]; anti-CD146 [174]; crocin [175, 176]; lncRNA SNHG16 [177]	[168, 170] (205)