Diabetes Metab J.  2022 Mar;46(2):198-221. 10.4093/dmj.2021.0347.

Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions

• Hossain MJ
• Kendig MD
• Letton ME
• Morris MJ
• Arnold R

• KMID: 2527715
• DOI: http://doi.org/10.4093/dmj.2021.0347

Abstract

Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the ‘Neurodiab’ criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

Keyword

Diabetes mellitus, type 2; Diabetic neuropathies; Diet, high-fat; Models, animal; Models, genetic; Peripheral nerves; Rats; Streptozotocin

Figure

• 

  Fig. 1. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram showing search results and study selection. T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; DPN, diabetic peripheral neuropathy.

• 

  Fig. 2. Graphical representation of publications examining diabetic peripheral neuropathy (DPN) endpoints in diet+chemically induced (blue) or transgenic (orange) rat models of type 2 diabetes mellitus before (pre) and after (post) the publication of the Neurodiab guidelines for phenotyping DPN in 2014. Dark shading and percentage values indicate the number of studies that assessed 3 DPN endpoints as recommended.

• 

  Fig. 3. Schematic representation comparing evidence for significant changes in key diabetic peripheral neuropathy (DPN) endpoints between diabetes models across disease duration. Arrows indicate the direction of significant change, while dots represent no change. Each data point represents the findings of papers that reported the timepoint at which the assessments were collected using the recommended DPN measures (behaviour assessed by Hargreaves paw withdrawal latency, electrophysiology assessed by motor and sensory nerve conduction velocity and peripheral nerve structure assessed by intraepidermal nerve fibre density). The darkness of the bar indicates the strength of evidence for impairment in the measure vs. control. High-fat high-fructose/streptozotocin (STZ), STZ/nicotinamide, Zucker diabetic Sprague-Dawley, and Nile grass rat were not included as they had ≤1 data point for each of the requisite DPN measures (Tables 2 and 3). Diabetes duration for Zucker diabetic fatty (ZDF) models was calculated as age minus 6 weeks. HFD, high-fat diet; HFHS, high-fat high-sugar.

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