Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy

Abstract

Unhealthy dietary habits are major modifiable risk factors for the development of type 2 diabetes mellitus, a metabolic disease with increasing prevalence and serious consequences. Microvascular complications of diabetes, namely diabetic peripheral neuropathy (DPN), retinopathy (DR), and nephropathy (DN), are associated with high morbidity rates and a heavy social and economic burden. Currently, available therapeutic options to counter the evolution of diabetic microvascular complications are clearly insufficient, which strongly recommends further research. Animal models are essential tools to dissect the molecular mechanisms underlying disease progression, to unravel new therapeutic targets, as well as to evaluate the efficacy of new drugs and/or novel therapeutic approaches. However, choosing the best animal model is challenging due to the large number of factors that need to be considered. This is particularly relevant for models induced by dietary modifications, which vary markedly in terms of macronutrient composition. In this article, we revisit the rodent models of diet-induced DPN, DR, and DN, critically comparing the main features of these microvascular complications in humans and the criteria for their diagnosis with the parameters that have been used in preclinical research using rodent models, considering the possible need for factors which can accelerate or aggravate these conditions.

Crescent-Like Lesions as an Early Signature of Nephropathy in a Rat Model of Prediabetes Induced by a Hypercaloric Diet

“…Additionally, the animals showed hypertriglyceridemia and increased serum oxidative stress, without changes in hs-CRP. This profile is in line with other studies performed in rats under HFD [22,39].…”

“…Regarding the histomorphological characterization, no significant tubulointerstitial lesions were observed, despite the presence of focal inflammatory infiltrate in 2 out of 8 of the HsuHF-fed animals, located in the tubular interstitial compartment of renal medulla, without signs of IFTA. However, we found the existence of several glomerular lesions, including mesangial expansion and thickening of the GBM, without atrophy or glomerulosclerosis (except in one animal), which collectively is in agreement with other models in initial stages of nephropathy [22]. Remarkably, we found an atypical pattern of extracapillary hyperplasia of glomerular capsule parietal layer surrounding and compressing Bowman's space in about 20% of the glomeruli of all prediabetic animals.…”

Diet‐induced rodent models of obesity‐related metabolic disorders—A guide to a translational perspective

“…and associated metabolic disorders. [10][11][12][13][14] However, unlike human diseases, the diagnostic criteria have not been clearly established for animal models of human diseases, and the research community is aware of their considerable drawbacks and limited predictability. 15 The absence of rigorous, standardized and clinically relevant criteria continues to hamper the translation of preclinical metabolic research findings into drug discovery programs regarding obesity and related metabolic disturbances and preclude biological understanding of the disease.…”

“…Various animal models, mostly involving rodents, have been used for several decades as fundamental tools for studying obesity, T2DM and associated metabolic disorders 10–14 . However, unlike human diseases, the diagnostic criteria have not been clearly established for animal models of human diseases, and the research community is aware of their considerable drawbacks and limited predictability 15 .…”

“…Although the majority of genetic or diet-induced models of metabolic diseases are obese, the presence or absence of obesity depends on the study purpose. Furthermore, some diet-induced models of obesity and related disorders evolve with other conditions, including dyslipidaemia and vascular complications,12 which may be essential for the study, or confounders, depending on the study objectives.The duration of the protocol is a strong determinant of the metabolic outcome, as mentioned throughout this article. In general, considering the above noted variations between different species and strains, obesity and MetS in rodents can be achieved by submitting the animals to few (up to 10) weeks of HFD, although the percentage of BW increase and the changes in fat composition and distribution may vary substantially between studies, as described above.…”