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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