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

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.

SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy

“…In our study, combined HFD and low‐dose STZ rat models were chosen since it is analogous to the development of human T2DM, 42 and it is the most frequently used in the studies of PDN. 43 Our study unveiled that mitophagy was inhibited in medium–small‐sized DRG neurons, as evidenced by TEM revealing a decrease in mitophagosome formation and the analysis of altered autophagy biomarkers in extracted mitochondrial protein. The increase of mitophagy in T1DM mice in a previous study may reflect an adaptive response to eliminate defective mitochondria at a single time point; however, it is likely that mitophagy would eventually decrease.…”

“…Defective mitophagy was found in DRG neurons in db/db mice, 39 but activated mitophagy in spinal cords 40 and DRG 41 was reported in the T1DM mice model. In our study, combined HFD and low‐dose STZ rat models were chosen since it is analogous to the development of human T2DM, 42 and it is the most frequently used in the studies of PDN 43 . Our study unveiled that mitophagy was inhibited in medium–small‐sized DRG neurons, as evidenced by TEM revealing a decrease in mitophagosome formation and the analysis of altered autophagy biomarkers in extracted mitochondrial protein.…”

HCV affects KATP channels through GnT-IVa-mediated N-glycosylation of GLUT2 on the surface of pancreatic β-cells leading to impaired insulin secretion

“…The rats showed hyperglycemia and insulin resistance or deficiency, consistent with the characteristics of T2DM. Most current studies simulate T2DM in rats induced by diet and STZ [ 22 ], and low-dose STZ(35 mg/kg) injection has been shown to have metabolic syndrome replication and a relatively stable rise in blood glucose concentration after T2DM [ 23 ]. It has been proposed that HCV is directly involved in islet beta cell dysfunction, and insulin resistance has been observed in HCV-positive patients [ 24 ].…”

Compound Qiying Granules Alleviates Diabetic Peripheral Neuropathy by Inhibiting Endoplasmic Reticulum Stress and Apoptosis

“…DPN may progress to physical injury with high morbidity and mortality (6). Despite the signi cant impact of DPN on quality of life and health care costs, there is no effective treatment for DPN other than strict glucose control (7).…”