Animal Models of Diabetic Retinopathy: Summary and Comparison

Table 2

Comparison of the morphological and functional lesions in mouse models of DR.

Animal model	Type of diabetes	Onset of hyperglycemia	Temporal morphological lesions in retina upon development of hyperglycemia		Temporal functional lesions in retina upon; development of hyperglycemia (ERG, SLO, fMRI)
			Cellular	Vascular
STZ injection	Type 1	Within 1 wk of injection	4 wk: astrocyte activation [32]; 5 wk: (i) Increased astrocyte number [33]; (ii) Reactive gliosis [33]; 6 wk: apoptosis of RGCs [35]; 6–14 wk: reduced RGCs [34, 35]*; 10 wk: reduced thickness of INL and ONL [35]; 6–9 mth: pericytes loss [32, 37]	8 days: upregulation of vascular permeability [41]; 4 wk: (i) Decreased retinal arteriolar and venular RBC velocity [45, 46]; (ii) Decreased retinal arteriolar and venular blood flow rate [45, 46]; (iii) Decreased arterial velocity [47]; (iv) Decreased arteriolar and venular diameters [48]; 8 wk: (i) Vessel leakage [42]; (ii) Increased leukocyte number [40]; (iii) Leukostasis [38]; 17 wk: (i) Capillary basal laminar thickening [43]; (ii) Neovascularization [44]; 6 mth: apoptosis of vascular cells [32]; 6–9 mth: acellular capillaries [32, 37]	4 wk: (i) Decreased OP3 and ΣOPs in ERG [49, 50]; (ii) Prolonged implicit time of; OP2-3 in ERG [50]; 7 wk: decreased pattern of ERG amplitude [51]; 6 mth: decreased a-wave and b-wave amplitudes [37]
Alloxan injection	Type 1	Within 4 days of injection	3 mth: shortening of dendrites of microglial cells [128]		3 wk: decreased b-wave in ERG [129, 130]; 3 mth: (i) Decreased b/a wave amplitude ratio in ERG [128]; (ii) Delayed OPs in ERG [128]
Galactose-fed	—	—	16–22 mth: decreased endothelial cell [132, 133]; 20–26 mth: pericyte loss [131, 133]	15–21 mth: acellular capillaries [131–133]; 21 mth: saccular microaneurysms [131]; 21-22 mth: capillary basal laminar thickening [131, 132]
Ins2^Akita	Type 1	4 wk of age	8 wk: reactivated microglia [134]; 12 wk: (i) Increased apoptosis [136]; (ii) Reduced RGCs in the peripheral retina [135]; (iii) Changes in dendrite of ON-type RGCs [135]; (iv) Abnormal swelling on somas, axons, and dendrites in RGCs [135]; 22 wk: (i) Change in astrocyte morphology and less contact with the vessels [134]; (ii) Reduced thickness of IPL and INL [134]; (iii) Reduced RGCs [134]*; 6 mth: decreased cholinergic and dopaminergic amacrine cells [136]	8 wk: increased leukocyte number [134]; 12 wk: increased retinal vascular permeability [134]; 26 wk: decreased arteriolar and venular RBC velocity, shear rate, and flow rate [138]; 31–36 wk: increased acellular capillaries [134]; 8 mth: (i) Retinal neovascularization [137]; (ii) Formation of new capillary beds [137]; (iii) Formation of new blood vessels in OPL [137]	8 mth: decreased a-wave and b-wave amplitudes in ERG [137]
NOD	Type 1	12–30 wk of age	4 wk: apoptosis of pericytes, endothelial cells, and RGCs [140]	4 wk: (i) Capillary basement membrane thickening [140]; (ii) Perivascular edema [140]; 4 mth: (i) Vasoconstriction or degeneration in some of the major vessels [141]; (ii) Poorly defined microvessels [141]; (iii) Disordered focal proliferation of new vessels [141]
db/db	Type 2	8 wks of age	6 wk: (i) Reduced RGC number [144]; (ii) Reduced thickness of the central total retina, INL, and photoreceptor layers [144]; 18 wk: pericyte loss [145]; 13 mth: glial reactivation [146]	14 wk: basement membrane thickening [147]; 26 wk: acellular capillaries [145]; 13 mth: (i) Vessel leakage [146]; (ii) Increased vessel density in the INL [146]
KKA^y	Type 2	6–8 wk of age	4 wk: increased neuroretinal apoptotic cells in RGC layer [149]; 3 mth: increased neuroretinal apoptotic cells in the INL [149]	3 mth: basement membrane thickening [149]
OIR	—	—	P18: (i) Reduced thickness of total retinal [153]; (ii) Reduced thickness of IPL [153]; (iii) Absence of the deep plexus [153]; (iv) Reduced outer segment length [153]; (v) Microglial reactivation [153]; (vi) Increased gliotic Müller cells and microglia [153]	P18: (i) Aberrant intravitreal neovascularization across all eccentricities [153]; (ii) Reduced vessels in the deep plexus [153]; (iii) Reduced vessels in the inner retinal plexus [153]	P18: (i) Reduced a-wave and b-wave amplitudes in ERG [153]; (ii) Delayed b-wave implicit time in ERG [153]; (iii) Reduced OP3 and OP4 in ERG [153]
Kimba	—	—	9 wk of age: pericyte loss [158]	P28 of age: (i) Microaneurysms [157]; (ii) Vascular leakage [157], but stops at 9 wk of age [158]; (iii) Capillary blockage, dropout, and hemorrhage [157]; 6 wk of age: (i) Leukostasis in veins and capillaries [158]; (ii) Acellular capillaries [158]; 9 wk of age: (i) Reduced vessel covered area [158]; (ii) Reduced vessel length [158]; (iii) Reduced crossing points [158]; (iv) Vessel tortuosity [158]
Akimba	Type 1	4 wk of age	8 wk of age: (i) Uneven thickness in the retina in OCT [159]; (ii) Reduced photoreceptor layer thickness [159]; (iii) Retinal edema [159]; (iv) Retinal detachment [159]; 24 wk of age: reduced RGCs number and neural; retinal thickness [159]	8 wk of age: (i) Capillary dropout [159]; (ii) Microaneurysm [159]; (iii) Hemorrhage [159]; (iv) Vascular leakage, stops by 20 wk of age [159]; (v) Vascular dilatation [159]; (vi) Venous loops [159]; (vii) Vessel tortuosity [159]; (viii) Vessel beading [159]; (ix) Neovascularization [159]

∗Some studies reported absence of reduction of RGCs [36–39].
The observations reported at a particular time point, which was chosen by the authors, may not totally reflect the sequential processes.