Animal Models of Diabetic Retinopathy: Summary and Comparison

Abstract

Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening.

Animal Models of Diabetic Retinopathy

“…Induced models have been created through five methods: surgical removal of the pancreas, administration of the drug alloxan, administration of the drug streptozotocin (STZ), highgalactose diets, and laser or chemical damage to the eye [27,[35][36][37][38][39][40][41][42][43][44][45][46]. While all methods of induction are still studied today, the most common is STZ administration, as it results in the fastest rate of disease development [41].…”

“…Pancreatectomy was observed as early as 1922 to increase blood sugar levels in dogs [35], and by 1968-1971, a technique of complete pancreatectomy in adult dogs had been developed to induce diabetes [36,37]. This technically difficult method is usually applied to large animals such as cats and monkeys [27]. In adult cats, hyperglycemia develops within 3 weeks postsurgery; this time can be reduced to within 1 week by combining pancreatectomy with administration of alloxan [47] (described in the "Alloxan" section).…”

“…STZ is now generally preferred over alloxan, as it is more effective in recapitulating the diabetic disease state, though both drugs are still commonly used [41]. Several protocols for STZ induction of diabetes in mice have been developed, ranging from 1 to 5 doses delivering a total of 150 to 400 mg/kg of STZ [27]. Hyperglycemia onset typically occurs within 2 weeks, regardless of dosage [27] and can be maintained for up to 22 months [71].…”

“…Rodents have also been the focus of most genetic studies, with the discovery of inherited hyperglycemia or obesity particular to certain strains [21, 22, 23•, 24-26]. DR phenotypes in dog models, however, appear to be most similar to human DR [27][28][29][30]. Surprisingly, nonhuman primates have proven relatively resistant to induced DR [31].…”

“…Cats generally do not develop cataracts [32]. Pigs and zebrafish, in contrast, are preferred for the similarity of their eye structure to humans, easily visualized vascular structures, short life spans, and large breeding sizes (zebrafish) [27,33,34]. Though no single animal model to date represents the complete range of vascular and neural complications of human DR in both early and late stages, the models described in this review have been instrumental in determining the mechanisms behind DR in the hopes of developing novel therapies.…”