3.3.2. Models of diabetic neuropathy
Although animal models have been an invaluable tool in understanding the pathophysiology of diabetic vascular complications, the onset and progress of diabetic neuropathy in commonly used rodent models is not completely understood. Recent advances in animal models to study diabetic neuropathy have concentrated on models of Type2 diabetes. These advances have been made possible by creating models that are based on guidelines established by the Neurodiab Study Group of the European Association for the Study of Diabetes (NSGEASD) that determined that assessments of behaviour, motor and sensory nerve conduction velocity (NCVs), and nerve structure are essential requirements for a murine model of diabetic neuropathy[133].
Gregorio et al have characterized the onset and progression of Type2 diabetic neuropathy in the diabetic db/db mouse on a C57BLKS/J background. These mice show hyperphagia[134] as well as other signs of diabetic neuropathy including progressive sensory loss, electrophysiological impairments, decreases in intraepidermal nerve fibre density, Schwann cells apoptosis and infiltration of T lymphocyte[135]. Other studies investigating neuropathy have been performed in ob/ob  leptin-based mouse models of type 2 diabetes[136].
A growing number of animal studies in recent years have demonstrated that low dose STZ combined with a high-fat diet can recapitulate certain features of Type2 diabetes as seen in humans. In addition, fructose is now recognised as a major contributor to the T2D epidemic. Barrière et al have developed a high fat/high fructose (HF/HF)-STZ model of Type2 diabetes in the rat as useful model to study the long-term complications of Type 2 diabetes, including diabetic neuropathy, nephropathy and retinopathy[137]. Monitored over a period of 56 weeks, the HF/HF-STZ rats exhibited an early prediabetic phase of hyperinsulinemia with moderate dysglycaemia, developing into late stage hyperglycaemia, normalisation of insulinemia, marked dyslipidaemia, hepatic fibrosis and ultimately pancreatic β-cell failure. With respect to neuropathy, the HF/HF-STZ rats developed a gradual increase in mechanical hyperalgesia (an intense response to pain indicative of nerve damage) as measured by decreased mechanical nociceptive thresholds and displayed profound tactile allodynia, where HF/HF-STZ rats experience increased pain to relatively minor stimuli compared with controls. These phenotypic changes were accompanied by significant increases in impaired myelinated fibres of the sciatic nerves, increases in mitochondrial vulnerability and functional reorganization within the spinal dorsal horn circuitry[137].
In order to develop a more robust model of early onset neuropathy, O’Brien et al have characterised the development of neuropathy over time in a diet-induced obesity (DIO)-STZ mouse model of adult-onset Type2 diabetes and compared this with a model of DIO alone, the latter indicative of adolescent pre-diabetes. This has enabled a detailed analysis of neurogenic changes that align with the natural progression from obesity and impaired glucose tolerance to overt type 2 diabetes in adolescent and adult mice respectively[138]. To establish this model, one cohort was fed a high-fat diet starting at 5 weeks of age, whilst a second cohort additionally received low dose STZ at 12 weeks of age (75mg/kg body weight for the first injection and 50mg/kg body weight for the second injection, 72 hours later) to cause mild impairment of insulin secretion and mild hyperglycaemia. Comparisons between the 2 cohorts at 16, 24 and 36 weeks displayed similar levels of decreased motor and sensory NCVs as early as 16 weeks followed by hypoalgesia and cutaneous nerve fibre loss at the later timepoints, despite the two groups having vastly different metabolic profiles[138]. Hence, this dual animal model approach may be more useful in understanding neurological pathophysiology of the young, enabling the development of novel therapies to target early neurological changes that are much needed with the growing prevalence of obesity and neurological changes of adolescent and young adults.
A less well-known, albeit invasive approach to develop diabetic neuropathy can be achieved by sciatic nerve transection. Focusing on the changes occurring in sensory nerve fibres with initial degeneration and regeneration processes resulting in pain, Pham et al developed a Type2 diabetic mouse model using sciatic nerve transection to study pathogenesis and treatment of early diabetic neuropathy[139]. Type2 diabetes was induced by injection of STZ and nicotinamide (NA) which was used to partially protect pancreatic β cells from the toxic effects of STZ. This allowed the diabetic status to be more stable over a longer period of time, ensuring a high survival rate of the animals[140]. Sciatic nerve transection involves exposing the right sciatic nerve and inserting a silicone tube into the proximal and distal stumps leaving a gap between them. This model enables the evaluation of nerve regeneration in the same animal over several months. Of particular importance, these animals display mechanical hyperalgesia and a decrease in the number of intra-epidermal nerve fibres[140]. Since an effective treatment for diabetic neuropathy involves the prevention of progressive nerve degeneration whilst simultaneously promoting nerve regeneration, using the nerve transection-regeneration model enables the study of effective treatments for pre-diabetic and early stage diabetic neuropathy.
Conclusions and Perspectives
Animal models of diabetic complications have been developed over a number of years to best replicate the changes observed in humans. The need to more closely recapitulate critical aspects of the disease led to the establishment of the Animal Models of Diabetic Complications Consortium (AMDCC) in 2001 by the National Institutes of Health, with a guidelines paper published in 2007[141] specifically focused on the evaluation of cardiovascular complications. The goals of the AMDCC were to best characterize and validate various animal models of diabetic cardiovascular disease for basic, developmental, or translational research including outlining testing, prevention, early detection, therapy, and diagnostic imaging strategies. Since then, other consortia (e.g. NSGEASD: neuropathy; NIDDK Diab Complications Consortium (DiaComp): nephropathy, uropathy, retinopathy, wound healing, gastro-intestinal and liver disease, cardiovascular disease) have made available useful resources to standardise experimental protocols (https://www.diacomp.org). In this review, we have focussed on more recent advances as well as modifications to older methods that are allowing more nuanced analyses of diabetic micro and macrovascular complications. Careful choice of rodent model, as well as the mode of diabetes induction, duration of disease and window of study, whether that be younger (pre-diabetic models) or older more established T2D diabetic models, are all critical considerations that may impact the outcomes of a study. For example, this review has emphasized the appropriateness of using STZ in the induction of T1D with caveats around dose, gender, off-target toxicity and alterations in gut microbiota. In addition, this review has highlighted relevant murine models for both micro- and macrovascular complications and the need for the inclusion of both male and female models. Additionally, where appropriate, limitations of the models have been noted. These considerations will assist in effective study design to maximise results for the evaluation of novel therapies to limit these debilitating complications.
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