1Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
2Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
3Department of Exercise and Rehabilitation, School of Medical, Indigenous and Health Science, University of Wollongong, Wollongong, Australia
Copyright © 2022 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
This work was supported by funding to Margaret J Morris (NHMRC, Australia, Grant 1126929). Ria Arnold was supported by a NHRMC Fellowship (NHMRC, Australia, Grant 1091006). Md Jakir Hossain was supported by a Scientia PhD scholarship from UNSW Sydney.
Model type | No. of articles included |
Proportion of articles assessing three DPN endpoints |
Articles observing significant change in ≥2 DPN endpoints |
|||
---|---|---|---|---|---|---|
Pre-Neurodiab | Post-Neurodiab | Pre-Neurodiab | Post-Neurodiab | |||
Diet and chemically induced models | ||||||
SD rat (HFD+low dose STZ) | 51 | 7/18 | 12/33 | 10/18 | 13/33 | |
Wistar rat (HFD+low dose STZ) | 9 | - | 0/9 | - | 6/9 | |
Wistar rat (STZ-NA model) | 3 | 0/1 | 0/2 | 1/1 | 2/2 | |
Total | 63 | 7/19 | 12/44 | 11/19 | 21/44 | |
Transgenic/spontaneous models | ||||||
ZDF rat | 36 | 4/20 | 1/16 | 8/20 | 4/16 | |
BBZDR/Wor rat | 3 | 1/3 | - | 2/3 | - | |
GK rat | 10 | 0/8 | 1/ 2 | 2/8 | 1/2 | |
SDT fatty rat | 5 | 0/3 | 0/2 | 2/3 | 0/2 | |
OLETF rat | 6 | 0/5 | 1/1 | 2/5 | 1/1 | |
ZDSD-Pco | 1 | 1/1 | - | 1/1 | - | |
NGR | 1 | - | 1/1 | - | 1/1 | |
WDF | 1 | 0/1 | - | 0/1 | - | |
Total | 63-1a | 6/41-1a | 4/22 | 17/41-1a | 7/22 | |
Grand total | 125 | 13/59 | 16/66 | 28/59 | 28/66 |
The Neurodiab guidelines were published on the 17th of June, 2014. A 12-month window was included, and thus ‘pre-Neurodiab’ refers to articles published on or before 16th June 2015, and ‘post-Neurodiab’ refers to articles published from 17th June, 2015, to 3rd November 2020.
DPN, diabetic peripheral neuropathy; SD, Sprague-Dawley; HFD, high-fat diet; STZ, streptozotocin; NA, nicotinamide; ZDF, Zucker diabetic fatty; BBZDR, Bio-Breeding Zucker diabetic rat; GK, Goto-Kakizaki; SDT, spontaneously diabetic Torii; OLETF, Otsuka Long-Evans Tokushima Fatty; ZDSD, Zucker diabetic Sprague-Dawley; NGR, Nile grass rat; WDF, Wistar diabetic fatty.
a One study was counted as both ZDF and WDF model and then subtracted from the total numbers. A dash (-) indicates no studies available. Note that in most cases, more studies reported neuropathy (at least 2 endpoints significantly different) than number of studies testing all 3 endpoints.
Rat strain/sex |
Diabetes induction paradigm |
Neuropathy phenotype (wk post-STZ) |
|||||
---|---|---|---|---|---|---|---|
Diet description | STZ Injection No. & dose, mg/kg | Diabetes duration, wk | Pain related behaviours | Nerve conduction | Peripheral nerve structure | ||
HFD | |||||||
SD/male & female [60] | HFD (58% fat) | 1×35 | 2 | m-von Frey (↔0.5, 1, 2) | |||
Needle-prick (↓0.5, 1, 2) | |||||||
PWL (radiant heat) (↔0.5, 1, 2) | |||||||
Cold latency (acetone test) (↔0.5, 1, 2) | |||||||
Wistar/male [48] | HFD (lard 310 g/kg) | 1×35 | 3 | e-von Frey (↓0, 1, 2, 3) | MNCV (↓3) | ||
PWL (Hargreaves) (↓0, 1, 2, 3) | |||||||
Cold water latency (↓0, 1, 2, 3) | |||||||
SD/male [62] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓3, 4) | |||
PWL (radiant heat) (↓3, 4) | |||||||
SD/male [63] | HFD (22% g fat) | 1×30 | 5 | m-von Frey (↓3–5) | |||
PWL (radiant heat) (↓3–5) | |||||||
SD/male [30] | HFD (24% g fat) | 4×30 (wkly 5–8 wk) | 4 | R/S (↓4) | |||
PWL (hot plate) (↑4) | |||||||
SD/male [64] | HFD (24% g fat, lard) | 1×30 | 4 | PWL (Hargreaves) (↑4) | MNCV (↓4) | IENFD (↓4) | |
SNCV (↓4) | CNFL (↓4) | ||||||
SD/male [65] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓1, 2, 3) | |||
PWL (radiant heat) (↓1, 2, 3) | |||||||
SD/male [66] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓2, 3) | |||
PWL (radiant heat) (↓2, 3) | |||||||
SD/male [50] | HFD (45% kcal fat) | 1×30 | 4 | PWL (Hargreaves) (↑4) | MNCV (↓4) | IENFD (↓4) | |
SNCV (↓4) | CNFL (↓4) | ||||||
SD/male [67] | HFD (22% g fat) | 1×30 | 5 | R/S (↓1, 2, 3, 4, 5) | |||
PWL (radiant heat) (↓1, 2, 3, 4, 5) | |||||||
SD/male [68] | HFD (60% kcal fat) | 1×45 | 5 | m-von Frey (↓2, 3, 4, 5) | |||
Wistar/male [69] | HFD (58% fat) | 1×35 | 6 | TFL (radiant heat) (↓6) | |||
Wistar/male [70] | HFD (30% fat) | 1×30 | 7 | m-von Frey (↓5, 7) | Sciatic-axonal, myelin and Schwann cell injury (7) | ||
PWL (hot plate) (↓1, 5, 7) | |||||||
SD/male [49] | HFD (60% kcal fat) | 1×35 | 8 | PWL (hot plate) (↓5, 6, 7, 8) | |||
Cold water latency (tail-flick) (↓5, 6, 7, 8) | |||||||
Walking function test performance (↓8) | |||||||
SD/NR [27] | HFD (lard 310 g/kg) | 2×25 (1 wk apart) | 9 | R/S (↓5, ↑9) | MNCV (↓6) | Sciatic-axonal injury and increased Schwann cells (9) | |
TFL (hot water immersion) (↓5, ↑9) | |||||||
SD/male [71] | HFD (58% fat) | 1×35 | 9 | ↓ IENFD (8.5) | |||
SD/male [72] | HFD (58% fat) | 1×35 | 9 | m-von Frey (↔2, 4, 6.5, 8.5) | ↓ IENFD (8.5) | ||
Needle-prick (↔2, 4, 6.5, 8.5) | |||||||
PWL (radiant heat) (↔2, 4, 6.5, 8.5) | |||||||
Cold latency (acetone test) (↔2, 4, 6.5, 8.5) | |||||||
SD/female [40] | HFD (60% kcal fat) | 1×30 | 12 | m-von Frey (↓12) | MNCV (↓12) | IENFD (↓12) | |
PWL (Hargreaves) (↑12) | SNCV (↓12) | CNFL (↓12) | |||||
SD/male [61] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↓15) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | CNFL (↓16) | ||||||
SD/male [52] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [42] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [43] | HFD (24% g fat, soybean oil and lard) | 1×30 | 16 | ↑ PWL (Hargreaves) (16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [41] | HFD (58% kcal fat) | 1×35 | 17 | m-von Frey and R/S (↓17) | ↓ MNCV (17) | Sciatic-axonal injury, lymphocyte infiltration (17) | |
PWL (hot plate) (↓17) | |||||||
TFL (hot water immersion) (↓17) | |||||||
SD/male [56] | HFD (45% kcal fat) | 1×30 | 18 | m-von Frey (↓18) | MNCV (↓18) | IENFD (↓18) | |
PWL (Hargreaves) (↑18) | SNCV (↓18) | CNFL (↓18) | |||||
SD/male [57] | HFD (45% kcal fat) | 1×30 | 20 | PWL (Hargreaves) (↑8) | MNCV (↓8) | IENFD (↓20) | |
SNCV (↓8) | CNFL (↓20) | ||||||
SD/male [59] | HFD (45% kcal fat) | 1×30 | 20 | PWL (Hargreaves) (↑20) | MNCV (↓20) | IENFD (↓20) | |
SNCV (↓20) | |||||||
SD/male [55] | HFD (45% kcal fat) | 1×30 | 28 | PWL (Hargreaves) (↑16, 28) | MNCV (↓16, 28) | IENFD (↓16, 28) | |
SNCV (↓16, 28) | CNFL (↓16, 28) | ||||||
HFD measured at multiple time points, in different cohorts | |||||||
SD/male [51] | HFD (45% kcal fat) | 1×30 | 2-8-16 | PWL (Hargreaves) (↑8, 16) | MNCV (↓2, 8, 16) | IENFD (↓2, 8, 16) | |
SNCV (↓2, 8, 16) | CNFL (↓2, 8, 16) | ||||||
SD/male [73] | HFD (45% kcal fat) | 1×30 | 4/16 | PWL (Hargreaves) (↑4, 16) | MNCV (↓4, 16) | IENFD (↓4, 16) | |
SNCV (↓4, 16) | CNFL (↓4, 16) | ||||||
SD/male [74] | HFD (45% kcal fat) | 1×30 | 4/16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [58] | HFD (45% kcal fat) | 1×30 | 8-18-32 | PWL (Hargreaves) (↑18, 32) | MNCV (↓8, 18, 32) | IENFD (↓8, 18, 32) | |
SNCV (↓8, 18, 32) | CNFL (↓8, 18, 32) | ||||||
SD/male [54] | HFD (45% kcal fat) | 1×30 | 24/36 | PWL (Hargreaves) (↑8, 24, 36) | MNCV (↓8, 24, 36) | IENFD (↓8, 24, 36) | |
SNCV (↓8, 24, 36) | CNFL (↓8, 24, 36) | ||||||
SD/male [75] | HFD (58% fat) | 1×35 | 2 wk/2 mo | m-von Frey (↔2, 4, 6.5, 8.5) | |||
Needle-prick (↔2, 4, 6.5, 8.5) | |||||||
PWL (radiant heat) (↔2, 4, 6.5, 8.5) | |||||||
Cold latency (acetone test) (↔2, 4, 6.5, 8.5) | |||||||
Wistar/male [76] | HFD | 1×40 | NR | MNCV (↓NR) | |||
HFHS | |||||||
SD/male [77] | HFHS (10% oil, 7% sugar) | 1×30 | 3 | m-von Frey (↓3) | |||
PWL (Hargreaves) (↓3) | |||||||
SD/male [45] | HFHS (10% lard, 10% sucrose) | 1×35 | 3 | e-von Frey (↓2) | Sciatic-axonal and myelin injury (3) | ||
SD/male [47] | HFHS (10% lard, 10% sucrose) | 1×35 | 3 | PWL (Hargreaves) (↓2, 3) | |||
SD/male [44] | HFHS (10% lard, 20% sucrose) | 1×35 | 4 | e-von Frey (↓2, 2.5, 3, 4) | |||
PWL (radiant heat) (↓2, 2.5, 3, 4) | |||||||
SD/male [31] | HFHS (10% lard, 20% sucrose) | 1× (30, 35, 40) | 4 | e-von Frey (↓2, 4) | |||
PWL (radiant heat) (↓2, 4) (only in 35 mg/kg group) | |||||||
SD/male [46] | HFHS (10% oil, 7% sugar) | 1×30 | 4 | m-von Frey (↓2, 3) | |||
PWL (Hargreaves) (↓1, 2, 3, 4) | |||||||
SD/male [78] | HFHS (20% sucrose) | 1×25 | 5 | m-von Frey (↓1, 2, 3, 4, 5) | |||
Albino/male [79] | HFHS (10% lard, 20% sucrose) | 1×30 | 5 | TFL (radiant heat) (↓5) | Sciatic-myelin injury, increased macrophage and mast cells (5) | ||
SD/male [37] | HFHS (10% lard, 20% sucrose) | 1×35 | 6 | MNCV (↓6) | |||
SNCV (↓6) | |||||||
Wistar/male [38] | HFHS (10% lard, 20% sucrose) | 1×30 | 6 | MNCV (↓6) | Sciatic-axonal and myelin injury (6) | ||
SNCV (↓6) | |||||||
SD/male [80] | HFHS (15% lard, 25% sucrose) | 1×25 | 8 | Sciatic-myelin injury (8) | |||
SD/male [81] | HFHS (10% fat, 70% carb) | 1×40 | 8 | ||||
SD/male [35] | HFHS (10% lard, 10% sucrose) | 1×30 | 11 | PWL (radiant heat) (↑8) | MNCV (↓11) | ||
SD/male [36] | HFHS (10% lard, 20% sucrose) | 1×35 | 12 | MNCV (↓12) | |||
SNCV (↓12) | |||||||
Wistar/female [82] | HFHS (10% lard, 20% sucrose) | 1×30 | 12 | m-von Frey (↓6) | |||
SD/male [28] | HFHS (15% lard, 10% white sugar) | 2×25 (1 wk apart) | 16 | MNCV (↓16) | Sciatic-myelinated fiber abnormality (16) | ||
SD/male [29] | HFHS (15% lard, 10% white sugar) | 2×25 (1 wk apart) | 16 | m-von Frey (↓16) | MNCV (↓16) | Sciatic-myelinated fiber abnormality (16) | |
PWL (hot plate) (↔16) | |||||||
SD/male [39] | HFHS (45% kcal as fat) | 1×35 | 2.5 | PWL (hot plate) (↓2.5) | NCV (↔2.5) | ||
HFHFr | |||||||
SD/male [83] | HFHFr (660 g fructose; 80 g fat/kg) | 1×35 | 8 | PWL (hot plate) (↓1–8) | Sciatic-axonal injury, reduced Schwann cells (8) | ||
TFL (hot water immersion) (↓1–8) | |||||||
SD/male [84] | HFHFr | 1×35 | 4 | e-von Frey (↓2, 3, 4) | |||
PWL (radiant heat) (↓2, 3, 4) | |||||||
SD/male [85] | HFHFr (660 g fruc- tose; 80 g fat/kg) | 1×35 | 8 | TFL (hot water immersion) (↓1–8) | Sciatic-axonal injury, reduced Schwann cells (8) | ||
Formalin-evoked hyperalgesia (tail-flinch) (↑8) | |||||||
Wistar/male & female [86] | HFHFr (10% fructose solution) | 1×35 | 12 | PWL (hot plate) (↓12) | Sciatic- (12) | ||
TFL (hot water immersion) (↓12) | |||||||
Cold water latency (↓12) | |||||||
Walking function test performance (↓12) | |||||||
Wistar/male [53] | HFHFr (25.7% g lard, 46.5% g fructose) | 4×25 (2, 8, 14, 20 wk diet) | 36 | m-von Frey (↓–2 to 36) | Sciatic- loss of small and large myelinated fibers (36) | ||
R/S (↓10–34) | |||||||
PWL (Hargreaves) (↔0–36) | |||||||
High caloric diet | |||||||
SD/male [87] | High-caloric (NR) | 1×30 | 2 | R/S (↓1) | |||
PWL (radiant heat) (↓1) | |||||||
SD/male [88] | High-caloric (NR) | 1×30 | 2 | m-von Frey (↓1) | |||
PWL (radiant heat) (↓1) | |||||||
STZ/NA models | |||||||
Wistar/male [33] | Nicotinamide: 1×50 mg/kg IP 15 min | 2 | TFL (radiant heat) (↓2) | Sciatic- axonal and myelin injury, haemorrhage, collagen deposition, vascular degeneration (2) | |||
Later STZ: 1×52.5 mg/mg IP | Hindpaw cold allodynia (cold water) (↓2) | ||||||
Tail cold allodynia (cold water) (↓2) | |||||||
Rotarod (latency to fall) (↓2) | |||||||
Wistar/male [34] | Nicotinamide: 1×50 mg/kg IP 15 min | 2 | TFL (radiant heat) (↓2) | Sciatic- axonal and myelin injury, haemorrhage, collagen deposition, vascular degeneration (2) | |||
Later STZ: 1×52.5 mg/kg IP | Hindpaw cold allodynia (cold water) (↓2) | ||||||
Tail cold allodynia (cold water) (↓2) | |||||||
Rotarod (latency to fall) (↓2) | |||||||
Wistar albino [32] | Nicotinamide: 1×110 mg/kg IP 15 min | 5 | PWL (hot plate) (↑1, 2, 3, 4, 5) | Sciatic-nerve cell degeneration (5) | |||
Later STZ: 1×65 mg/kg IP | Rotarod (latency to fall) (↓1, 2, 3, 4, 5) |
↑=significant increase, ↓=significant decrease, ↔=no change.
STZ, streptozotocin; HFD, high-fat diet; m-von Frey, manual von Frey; SD, Sprague-Dawley; PWL, paw withdrawal latency; e-von Frey, electronic von Frey; MNCV, motor nerve conduction velocity; R/S, Randal-Selitto; SNCV, sensory nerve conduction velocity; IENFD, intraepidermal nerve fiber density; CNFL, corneal nerve fiber length; TFL, tail flick latency; HFHS, high-fat high-sugar; NR, not reported; NCV, nerve conduction velocity; HFHFr, high-fat high-fructose; NA, nicotinamide; IP, intra-peritoneal.
Rat strain/sex |
Diabetic animal model details |
Neuropathy phenotype (age in wk) |
||||
---|---|---|---|---|---|---|
Age (start-end), wk | Diabetes established, wk | Behavioural assessment of nerve function | Nerve conduction | Peripheral nerve structure | ||
ZDF | ||||||
ZDF/male [105] | 5–16 | BGL measured, not diagnostic | m-von Frey (↓6, 12, 14, 16) | |||
PWL (radiant heat) (↓6, 12, 14, 16) | ||||||
ZDF/male [106] | 6–17 | BGL measured, not diagnostic | e-von Frey (↓7–8, 12–13, 16–17) | |||
PWL (Hargreaves) (↑16–17) | ||||||
ZDF/male [107] | 5–10 | Yes | R/S (↓8–9) | |||
ZDF/male [100] | 8–39 | BGL measured, not diagnostic | R/S (↓18, 24, 32, 36) | |||
TFL (↓8, ↑16, 20, 24, 28, 36) | ||||||
ZDF/male [108] | 8–14 | Yes | e-von Frey (↓10, 14) | MNCV (↓8, 10, 12, 14) | ||
PWL (radiant heat) (↓8, 14) | SNCV (↓8, 10, 12, 14) | |||||
ZDF/male [109] | 7–29 | Yes | m-von Frey (↔9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29) | |||
ZDF/male [110] | 4–30a | Yes | e-von Frey (↓14a) | MNCV (↓26a) | IENFD (↓30a) | |
PWL (Hargreaves) (↓18a) Grip-strength (↓16a) | SNCV (↓12.5a) | Sural nerve axonal atrophy (30) | ||||
Rotarod (latency to fall) (↓14a) | ||||||
ZDF/male [111] | 5–13 | NR | m-von Frey (↓11, 12, 13) | |||
PWL (Hargreaves) (↓13) | ||||||
ZDF/male [101] | 6–40 | BGL measured, not diagnostic | MNCV (↓12, 14, 16, 20, 24, 28, 32, 36, 40) | |||
ZDF/male [112] | 7–13 | Yes | R/S (↓12, 13) | |||
e-von Frey (↓12, 13) | ||||||
ZDF/male [113] | 8–NR | BGL measured, not diagnostic | MNCV (↓12a) | |||
ZDF/NR [114] | 8–16 | Yes | m-von Frey (↓14, 15) | SNCV (↓12, 14, 15) | ||
PWL (Hargreaves) (↓12, 14, 15) | ||||||
ZDF/male [115] | 6–14 | Yes | m-von Frey (↓13, 14) | |||
PWL (hot plate) (↓13, 14) | ||||||
ZDF/male [116] | 6–15 | BGL measured, not diagnostic | m-von Frey (↓13, 14, 15) | Spontaneous locomotor activity (↔13, 14, 15) | ||
PWL (Hargreaves) (↓13, 14) | ||||||
ZDF/male [117] | 7–16 | Yes | m-von Frey (↓13, 14, 15, 16) | |||
PWL (hot plate) (↓13, 14, 15, 16) | ||||||
ZDF/NR [118] | 8–16 | Yes | m-von Frey (↓13, 16) | SNCV (↓13, 16) | ||
PWL (radiant heat) (↓13, 16) | ||||||
ZDF/male [119] | NR | BGL measured, not diagnostic | R/S (↓13) | |||
ZDF/male [120] | 13 | NR | Sciatic-tibial nerve demyelination (↑13) | |||
ZDF/male [121] | 14–23 | BGL measured, not diagnostic | R/S (↓18, 20, 22) | MNCV (↓23) | IENFD (↓23) | |
TFL (↑14, 16,18, 20, 22) | SNCV (↓23) | Peroneal nerve myelinated fiber density (↑23) | ||||
Myelin area (↓23) | ||||||
ZDF/NR [122] | 6–38 | Yes | R/S (↓15) | |||
m-von Frey (↓15) | ||||||
Spontaneous locomotor activity (↓7, 15, 31) | ||||||
ZDF/male [123] | 4–19 | Yes | R/S (↓15, 16, 17, 18) | |||
PWL (hot plate) (↓15, 17, 18) | ||||||
Cold hyperalgesia (↑18) | ||||||
ZDF/male [97] | 5–20 | BGL measured, not diagnostic | MNCV (↓19) | |||
ZDF/male [124] | 9–19 | BGL measured, not diagnostic | m-von Frey (↓15, 19) | MNCV (↓15, 19) | IENFD (↓15/19) | |
R/S (↑15, 19) | SNCV (↓15, 19) | Tibial nerve myelin thickness (↓19) | ||||
PWL (Hargreaves) (↑15, 19) | G-ratio and axon diameter/myelin thickness (↑19) | |||||
ZDF/male [125] | 14–20 | BGL measured, not diagnostic | m-von Frey (↔16, 18, 20) | |||
ZDF/male [126] | 6–25 | BGL measured, not diagnostic | m-von Frey (↓25a) | MNCV (↔12a, ↓25a) | IENFD (↓25a) | |
PWL (Hargreaves) (↔25a) | SNCV (↔12a, ↓25a) | Sural nerve morphometry (↔25a) | ||||
ZDF/male [127] | 6–40 | Yes | R/S (↓17, 33) | MNCV (↓38–40) | IENFD (↓35) | |
m-von Frey (↑31, 38) | SNCV (↓38–40) | |||||
ZDF/male [128] | 7–17 | BGL measured, not diagnostic | MNCV (↓17) | |||
ZDF/female [129] | 8–18 | BGL measured, not diagnostic | MNCV (↓18) | Sciatic nerve DNA damage and neuronal injury (↑18) | ||
SNCV (↓18) | ||||||
ZDF/male [102] | 9–19 | NR | MNCV (↓18, 19) | Sciatic nerve histopathology (↔19) | ||
NCV (↓18, 19) | ||||||
ZDF/male [130] | 10–18 | Yes | R/S (↓18) | |||
PWL (Hargreaves) (↓18) | ||||||
ZDF/male [131] | 14–22 | BGL measured, not diagnostic | MNCV (↓21, 22) | |||
ZDF/male [132] | NR | BGL measured, not diagnostic | m-von Frey (↓18, 32) | MNCV (↓NR) | ||
PWL (Hargreaves) (↑NR) | SNCV (↓NR) | |||||
ZDF/male [133] | 7–21/27 | BGL measured, not diagnostic | MNCV (↓21/27) | |||
ZDF/male [134] | 6–24 | NR | PWL (Hargreaves) (↑24) | MNCV (↓24) | ||
SNCV (↓24) | ||||||
ZDF/male [135] | 6–28 | NR | PWL (Hargreaves) (↑28) | MNCV (↓28) | ||
SNCV (↓28) | ||||||
ZDF/male [99] | 6–35 | BGL measured, not diagnostic | e-von Frey (↔ up to 35) | NCV (↔up to 35) | ||
TFL (↓35) | ||||||
ZDSD | ||||||
ZDSD/male [103] | 16–34 | BGL measured, not diagnostic | PWL (Hargreaves) (↑34) | MNCV (↓34) | IENFD (↔34) | |
SNCV (↓34) | CNFL (↓34) | |||||
NGR | ||||||
African NGR/male [104] | 52–104 | Yes | m-von Frey ↑ | MNCV ↓ | IENFD ↓ | |
PWL (Hargreaves) ↑ |
For each rat strain, studies are listed according to age of earliest standardised neuropathic assessment. Number(s) in parentheses refer to the age of rats in weeks, except for where diabetes duration is used and clearly mentioned. ↑=significant increase, ↓=significant decrease, ↔=no change.
ZDF, Zucker diabetic fatty; BGL, blood glucose level; m-von Frey, manual von Frey; PWL, paw withdrawal latency; e-von Frey, electronic von Frey; R/S, Randal-Selitto; TFL, tail flick latency; MNCV, motor nerve conduction velocity; SNCV, sensory nerve conduction velocity; IENFD, intraepidermal nerve fiber density; NR, not reported; NCV, nerve conduction velocity; ZDSD, Zucker diabetic Sprague-Dawley; CNFL, corneal nerve fiber length; NGR, Nile grass rat.
a Values were converted to weeks of age, from months or weeks of diabetes, as reported in original study.
Model type | No. of articles included | Proportion of articles assessing three DPN endpoints |
Articles observing significant change in ≥2 DPN endpoints |
|||
---|---|---|---|---|---|---|
Pre-Neurodiab | Post-Neurodiab | Pre-Neurodiab | Post-Neurodiab | |||
Diet and chemically induced models | ||||||
SD rat (HFD+low dose STZ) | 51 | 7/18 | 12/33 | 10/18 | 13/33 | |
Wistar rat (HFD+low dose STZ) | 9 | - | 0/9 | - | 6/9 | |
Wistar rat (STZ-NA model) | 3 | 0/1 | 0/2 | 1/1 | 2/2 | |
Total | 63 | 7/19 | 12/44 | 11/19 | 21/44 | |
Transgenic/spontaneous models | ||||||
ZDF rat | 36 | 4/20 | 1/16 | 8/20 | 4/16 | |
BBZDR/Wor rat | 3 | 1/3 | - | 2/3 | - | |
GK rat | 10 | 0/8 | 1/ 2 | 2/8 | 1/2 | |
SDT fatty rat | 5 | 0/3 | 0/2 | 2/3 | 0/2 | |
OLETF rat | 6 | 0/5 | 1/1 | 2/5 | 1/1 | |
ZDSD-Pco | 1 | 1/1 | - | 1/1 | - | |
NGR | 1 | - | 1/1 | - | 1/1 | |
WDF | 1 | 0/1 | - | 0/1 | - | |
Total | 63-1 |
6/41-1 |
4/22 | 17/41-1 |
7/22 | |
Grand total | 125 | 13/59 | 16/66 | 28/59 | 28/66 |
Rat strain/sex | Diabetes induction paradigm |
Neuropathy phenotype (wk post-STZ) |
|||||
---|---|---|---|---|---|---|---|
Diet description | STZ Injection No. & dose, mg/kg | Diabetes duration, wk | Pain related behaviours | Nerve conduction | Peripheral nerve structure | ||
HFD | |||||||
SD/male & female [60] | HFD (58% fat) | 1×35 | 2 | m-von Frey (↔0.5, 1, 2) | |||
Needle-prick (↓0.5, 1, 2) | |||||||
PWL (radiant heat) (↔0.5, 1, 2) | |||||||
Cold latency (acetone test) (↔0.5, 1, 2) | |||||||
Wistar/male [48] | HFD (lard 310 g/kg) | 1×35 | 3 | e-von Frey (↓0, 1, 2, 3) | MNCV (↓3) | ||
PWL (Hargreaves) (↓0, 1, 2, 3) | |||||||
Cold water latency (↓0, 1, 2, 3) | |||||||
SD/male [62] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓3, 4) | |||
PWL (radiant heat) (↓3, 4) | |||||||
SD/male [63] | HFD (22% g fat) | 1×30 | 5 | m-von Frey (↓3–5) | |||
PWL (radiant heat) (↓3–5) | |||||||
SD/male [30] | HFD (24% g fat) | 4×30 (wkly 5–8 wk) | 4 | R/S (↓4) | |||
PWL (hot plate) (↑4) | |||||||
SD/male [64] | HFD (24% g fat, lard) | 1×30 | 4 | PWL (Hargreaves) (↑4) | MNCV (↓4) | IENFD (↓4) | |
SNCV (↓4) | CNFL (↓4) | ||||||
SD/male [65] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓1, 2, 3) | |||
PWL (radiant heat) (↓1, 2, 3) | |||||||
SD/male [66] | HFD (22% g fat) | 1×30 | 4 | m-von Frey (↓2, 3) | |||
PWL (radiant heat) (↓2, 3) | |||||||
SD/male [50] | HFD (45% kcal fat) | 1×30 | 4 | PWL (Hargreaves) (↑4) | MNCV (↓4) | IENFD (↓4) | |
SNCV (↓4) | CNFL (↓4) | ||||||
SD/male [67] | HFD (22% g fat) | 1×30 | 5 | R/S (↓1, 2, 3, 4, 5) | |||
PWL (radiant heat) (↓1, 2, 3, 4, 5) | |||||||
SD/male [68] | HFD (60% kcal fat) | 1×45 | 5 | m-von Frey (↓2, 3, 4, 5) | |||
Wistar/male [69] | HFD (58% fat) | 1×35 | 6 | TFL (radiant heat) (↓6) | |||
Wistar/male [70] | HFD (30% fat) | 1×30 | 7 | m-von Frey (↓5, 7) | Sciatic-axonal, myelin and Schwann cell injury (7) | ||
PWL (hot plate) (↓1, 5, 7) | |||||||
SD/male [49] | HFD (60% kcal fat) | 1×35 | 8 | PWL (hot plate) (↓5, 6, 7, 8) | |||
Cold water latency (tail-flick) (↓5, 6, 7, 8) | |||||||
Walking function test performance (↓8) | |||||||
SD/NR [27] | HFD (lard 310 g/kg) | 2×25 (1 wk apart) | 9 | R/S (↓5, ↑9) | MNCV (↓6) | Sciatic-axonal injury and increased Schwann cells (9) | |
TFL (hot water immersion) (↓5, ↑9) | |||||||
SD/male [71] | HFD (58% fat) | 1×35 | 9 | ↓ IENFD (8.5) | |||
SD/male [72] | HFD (58% fat) | 1×35 | 9 | m-von Frey (↔2, 4, 6.5, 8.5) | ↓ IENFD (8.5) | ||
Needle-prick (↔2, 4, 6.5, 8.5) | |||||||
PWL (radiant heat) (↔2, 4, 6.5, 8.5) | |||||||
Cold latency (acetone test) (↔2, 4, 6.5, 8.5) | |||||||
SD/female [40] | HFD (60% kcal fat) | 1×30 | 12 | m-von Frey (↓12) | MNCV (↓12) | IENFD (↓12) | |
PWL (Hargreaves) (↑12) | SNCV (↓12) | CNFL (↓12) | |||||
SD/male [61] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↓15) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | CNFL (↓16) | ||||||
SD/male [52] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [42] | HFD (45% kcal fat) | 1×30 | 16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [43] | HFD (24% g fat, soybean oil and lard) | 1×30 | 16 | ↑ PWL (Hargreaves) (16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [41] | HFD (58% kcal fat) | 1×35 | 17 | m-von Frey and R/S (↓17) | ↓ MNCV (17) | Sciatic-axonal injury, lymphocyte infiltration (17) | |
PWL (hot plate) (↓17) | |||||||
TFL (hot water immersion) (↓17) | |||||||
SD/male [56] | HFD (45% kcal fat) | 1×30 | 18 | m-von Frey (↓18) | MNCV (↓18) | IENFD (↓18) | |
PWL (Hargreaves) (↑18) | SNCV (↓18) | CNFL (↓18) | |||||
SD/male [57] | HFD (45% kcal fat) | 1×30 | 20 | PWL (Hargreaves) (↑8) | MNCV (↓8) | IENFD (↓20) | |
SNCV (↓8) | CNFL (↓20) | ||||||
SD/male [59] | HFD (45% kcal fat) | 1×30 | 20 | PWL (Hargreaves) (↑20) | MNCV (↓20) | IENFD (↓20) | |
SNCV (↓20) | |||||||
SD/male [55] | HFD (45% kcal fat) | 1×30 | 28 | PWL (Hargreaves) (↑16, 28) | MNCV (↓16, 28) | IENFD (↓16, 28) | |
SNCV (↓16, 28) | CNFL (↓16, 28) | ||||||
HFD measured at multiple time points, in different cohorts | |||||||
SD/male [51] | HFD (45% kcal fat) | 1×30 | 2-8-16 | PWL (Hargreaves) (↑8, 16) | MNCV (↓2, 8, 16) | IENFD (↓2, 8, 16) | |
SNCV (↓2, 8, 16) | CNFL (↓2, 8, 16) | ||||||
SD/male [73] | HFD (45% kcal fat) | 1×30 | 4/16 | PWL (Hargreaves) (↑4, 16) | MNCV (↓4, 16) | IENFD (↓4, 16) | |
SNCV (↓4, 16) | CNFL (↓4, 16) | ||||||
SD/male [74] | HFD (45% kcal fat) | 1×30 | 4/16 | PWL (Hargreaves) (↑16) | MNCV (↓16) | IENFD (↓16) | |
SNCV (↓16) | |||||||
SD/male [58] | HFD (45% kcal fat) | 1×30 | 8-18-32 | PWL (Hargreaves) (↑18, 32) | MNCV (↓8, 18, 32) | IENFD (↓8, 18, 32) | |
SNCV (↓8, 18, 32) | CNFL (↓8, 18, 32) | ||||||
SD/male [54] | HFD (45% kcal fat) | 1×30 | 24/36 | PWL (Hargreaves) (↑8, 24, 36) | MNCV (↓8, 24, 36) | IENFD (↓8, 24, 36) | |
SNCV (↓8, 24, 36) | CNFL (↓8, 24, 36) | ||||||
SD/male [75] | HFD (58% fat) | 1×35 | 2 wk/2 mo | m-von Frey (↔2, 4, 6.5, 8.5) | |||
Needle-prick (↔2, 4, 6.5, 8.5) | |||||||
PWL (radiant heat) (↔2, 4, 6.5, 8.5) | |||||||
Cold latency (acetone test) (↔2, 4, 6.5, 8.5) | |||||||
Wistar/male [76] | HFD | 1×40 | NR | MNCV (↓NR) | |||
HFHS | |||||||
SD/male [77] | HFHS (10% oil, 7% sugar) | 1×30 | 3 | m-von Frey (↓3) | |||
PWL (Hargreaves) (↓3) | |||||||
SD/male [45] | HFHS (10% lard, 10% sucrose) | 1×35 | 3 | e-von Frey (↓2) | Sciatic-axonal and myelin injury (3) | ||
SD/male [47] | HFHS (10% lard, 10% sucrose) | 1×35 | 3 | PWL (Hargreaves) (↓2, 3) | |||
SD/male [44] | HFHS (10% lard, 20% sucrose) | 1×35 | 4 | e-von Frey (↓2, 2.5, 3, 4) | |||
PWL (radiant heat) (↓2, 2.5, 3, 4) | |||||||
SD/male [31] | HFHS (10% lard, 20% sucrose) | 1× (30, 35, 40) | 4 | e-von Frey (↓2, 4) | |||
PWL (radiant heat) (↓2, 4) (only in 35 mg/kg group) | |||||||
SD/male [46] | HFHS (10% oil, 7% sugar) | 1×30 | 4 | m-von Frey (↓2, 3) | |||
PWL (Hargreaves) (↓1, 2, 3, 4) | |||||||
SD/male [78] | HFHS (20% sucrose) | 1×25 | 5 | m-von Frey (↓1, 2, 3, 4, 5) | |||
Albino/male [79] | HFHS (10% lard, 20% sucrose) | 1×30 | 5 | TFL (radiant heat) (↓5) | Sciatic-myelin injury, increased macrophage and mast cells (5) | ||
SD/male [37] | HFHS (10% lard, 20% sucrose) | 1×35 | 6 | MNCV (↓6) | |||
SNCV (↓6) | |||||||
Wistar/male [38] | HFHS (10% lard, 20% sucrose) | 1×30 | 6 | MNCV (↓6) | Sciatic-axonal and myelin injury (6) | ||
SNCV (↓6) | |||||||
SD/male [80] | HFHS (15% lard, 25% sucrose) | 1×25 | 8 | Sciatic-myelin injury (8) | |||
SD/male [81] | HFHS (10% fat, 70% carb) | 1×40 | 8 | ||||
SD/male [35] | HFHS (10% lard, 10% sucrose) | 1×30 | 11 | PWL (radiant heat) (↑8) | MNCV (↓11) | ||
SD/male [36] | HFHS (10% lard, 20% sucrose) | 1×35 | 12 | MNCV (↓12) | |||
SNCV (↓12) | |||||||
Wistar/female [82] | HFHS (10% lard, 20% sucrose) | 1×30 | 12 | m-von Frey (↓6) | |||
SD/male [28] | HFHS (15% lard, 10% white sugar) | 2×25 (1 wk apart) | 16 | MNCV (↓16) | Sciatic-myelinated fiber abnormality (16) | ||
SD/male [29] | HFHS (15% lard, 10% white sugar) | 2×25 (1 wk apart) | 16 | m-von Frey (↓16) | MNCV (↓16) | Sciatic-myelinated fiber abnormality (16) | |
PWL (hot plate) (↔16) | |||||||
SD/male [39] | HFHS (45% kcal as fat) | 1×35 | 2.5 | PWL (hot plate) (↓2.5) | NCV (↔2.5) | ||
HFHFr | |||||||
SD/male [83] | HFHFr (660 g fructose; 80 g fat/kg) | 1×35 | 8 | PWL (hot plate) (↓1–8) | Sciatic-axonal injury, reduced Schwann cells (8) | ||
TFL (hot water immersion) (↓1–8) | |||||||
SD/male [84] | HFHFr | 1×35 | 4 | e-von Frey (↓2, 3, 4) | |||
PWL (radiant heat) (↓2, 3, 4) | |||||||
SD/male [85] | HFHFr (660 g fruc- tose; 80 g fat/kg) | 1×35 | 8 | TFL (hot water immersion) (↓1–8) | Sciatic-axonal injury, reduced Schwann cells (8) | ||
Formalin-evoked hyperalgesia (tail-flinch) (↑8) | |||||||
Wistar/male & female [86] | HFHFr (10% fructose solution) | 1×35 | 12 | PWL (hot plate) (↓12) | Sciatic- (12) | ||
TFL (hot water immersion) (↓12) | |||||||
Cold water latency (↓12) | |||||||
Walking function test performance (↓12) | |||||||
Wistar/male [53] | HFHFr (25.7% g lard, 46.5% g fructose) | 4×25 (2, 8, 14, 20 wk diet) | 36 | m-von Frey (↓–2 to 36) | Sciatic- loss of small and large myelinated fibers (36) | ||
R/S (↓10–34) | |||||||
PWL (Hargreaves) (↔0–36) | |||||||
High caloric diet | |||||||
SD/male [87] | High-caloric (NR) | 1×30 | 2 | R/S (↓1) | |||
PWL (radiant heat) (↓1) | |||||||
SD/male [88] | High-caloric (NR) | 1×30 | 2 | m-von Frey (↓1) | |||
PWL (radiant heat) (↓1) | |||||||
STZ/NA models | |||||||
Wistar/male [33] | Nicotinamide: 1×50 mg/kg IP 15 min | 2 | TFL (radiant heat) (↓2) | Sciatic- axonal and myelin injury, haemorrhage, collagen deposition, vascular degeneration (2) | |||
Later STZ: 1×52.5 mg/mg IP | Hindpaw cold allodynia (cold water) (↓2) | ||||||
Tail cold allodynia (cold water) (↓2) | |||||||
Rotarod (latency to fall) (↓2) | |||||||
Wistar/male [34] | Nicotinamide: 1×50 mg/kg IP 15 min | 2 | TFL (radiant heat) (↓2) | Sciatic- axonal and myelin injury, haemorrhage, collagen deposition, vascular degeneration (2) | |||
Later STZ: 1×52.5 mg/kg IP | Hindpaw cold allodynia (cold water) (↓2) | ||||||
Tail cold allodynia (cold water) (↓2) | |||||||
Rotarod (latency to fall) (↓2) | |||||||
Wistar albino [32] | Nicotinamide: 1×110 mg/kg IP 15 min | 5 | PWL (hot plate) (↑1, 2, 3, 4, 5) | Sciatic-nerve cell degeneration (5) | |||
Later STZ: 1×65 mg/kg IP | Rotarod (latency to fall) (↓1, 2, 3, 4, 5) |
Rat strain/sex | Diabetic animal model details |
Neuropathy phenotype (age in wk) |
||||
---|---|---|---|---|---|---|
Age (start-end), wk | Diabetes established, wk | Behavioural assessment of nerve function | Nerve conduction | Peripheral nerve structure | ||
ZDF | ||||||
ZDF/male [105] | 5–16 | BGL measured, not diagnostic | m-von Frey (↓6, 12, 14, 16) | |||
PWL (radiant heat) (↓6, 12, 14, 16) | ||||||
ZDF/male [106] | 6–17 | BGL measured, not diagnostic | e-von Frey (↓7–8, 12–13, 16–17) | |||
PWL (Hargreaves) (↑16–17) | ||||||
ZDF/male [107] | 5–10 | Yes | R/S (↓8–9) | |||
ZDF/male [100] | 8–39 | BGL measured, not diagnostic | R/S (↓18, 24, 32, 36) | |||
TFL (↓8, ↑16, 20, 24, 28, 36) | ||||||
ZDF/male [108] | 8–14 | Yes | e-von Frey (↓10, 14) | MNCV (↓8, 10, 12, 14) | ||
PWL (radiant heat) (↓8, 14) | SNCV (↓8, 10, 12, 14) | |||||
ZDF/male [109] | 7–29 | Yes | m-von Frey (↔9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29) | |||
ZDF/male [110] | 4–30a | Yes | e-von Frey (↓14 |
MNCV (↓26 |
IENFD (↓30 |
|
PWL (Hargreaves) (↓18 |
SNCV (↓12.5 |
Sural nerve axonal atrophy (30) | ||||
Rotarod (latency to fall) (↓14 |
||||||
ZDF/male [111] | 5–13 | NR | m-von Frey (↓11, 12, 13) | |||
PWL (Hargreaves) (↓13) | ||||||
ZDF/male [101] | 6–40 | BGL measured, not diagnostic | MNCV (↓12, 14, 16, 20, 24, 28, 32, 36, 40) | |||
ZDF/male [112] | 7–13 | Yes | R/S (↓12, 13) | |||
e-von Frey (↓12, 13) | ||||||
ZDF/male [113] | 8–NR | BGL measured, not diagnostic | MNCV (↓12 |
|||
ZDF/NR [114] | 8–16 | Yes | m-von Frey (↓14, 15) | SNCV (↓12, 14, 15) | ||
PWL (Hargreaves) (↓12, 14, 15) | ||||||
ZDF/male [115] | 6–14 | Yes | m-von Frey (↓13, 14) | |||
PWL (hot plate) (↓13, 14) | ||||||
ZDF/male [116] | 6–15 | BGL measured, not diagnostic | m-von Frey (↓13, 14, 15) | Spontaneous locomotor activity (↔13, 14, 15) | ||
PWL (Hargreaves) (↓13, 14) | ||||||
ZDF/male [117] | 7–16 | Yes | m-von Frey (↓13, 14, 15, 16) | |||
PWL (hot plate) (↓13, 14, 15, 16) | ||||||
ZDF/NR [118] | 8–16 | Yes | m-von Frey (↓13, 16) | SNCV (↓13, 16) | ||
PWL (radiant heat) (↓13, 16) | ||||||
ZDF/male [119] | NR | BGL measured, not diagnostic | R/S (↓13) | |||
ZDF/male [120] | 13 | NR | Sciatic-tibial nerve demyelination (↑13) | |||
ZDF/male [121] | 14–23 | BGL measured, not diagnostic | R/S (↓18, 20, 22) | MNCV (↓23) | IENFD (↓23) | |
TFL (↑14, 16,18, 20, 22) | SNCV (↓23) | Peroneal nerve myelinated fiber density (↑23) | ||||
Myelin area (↓23) | ||||||
ZDF/NR [122] | 6–38 | Yes | R/S (↓15) | |||
m-von Frey (↓15) | ||||||
Spontaneous locomotor activity (↓7, 15, 31) | ||||||
ZDF/male [123] | 4–19 | Yes | R/S (↓15, 16, 17, 18) | |||
PWL (hot plate) (↓15, 17, 18) | ||||||
Cold hyperalgesia (↑18) | ||||||
ZDF/male [97] | 5–20 | BGL measured, not diagnostic | MNCV (↓19) | |||
ZDF/male [124] | 9–19 | BGL measured, not diagnostic | m-von Frey (↓15, 19) | MNCV (↓15, 19) | IENFD (↓15/19) | |
R/S (↑15, 19) | SNCV (↓15, 19) | Tibial nerve myelin thickness (↓19) | ||||
PWL (Hargreaves) (↑15, 19) | G-ratio and axon diameter/myelin thickness (↑19) | |||||
ZDF/male [125] | 14–20 | BGL measured, not diagnostic | m-von Frey (↔16, 18, 20) | |||
ZDF/male [126] | 6–25 | BGL measured, not diagnostic | m-von Frey (↓25 |
MNCV (↔12a, ↓25 |
IENFD (↓25 |
|
PWL (Hargreaves) (↔25 |
SNCV (↔12a, ↓25 |
Sural nerve morphometry (↔25 |
||||
ZDF/male [127] | 6–40 | Yes | R/S (↓17, 33) | MNCV (↓38–40) | IENFD (↓35) | |
m-von Frey (↑31, 38) | SNCV (↓38–40) | |||||
ZDF/male [128] | 7–17 | BGL measured, not diagnostic | MNCV (↓17) | |||
ZDF/female [129] | 8–18 | BGL measured, not diagnostic | MNCV (↓18) | Sciatic nerve DNA damage and neuronal injury (↑18) | ||
SNCV (↓18) | ||||||
ZDF/male [102] | 9–19 | NR | MNCV (↓18, 19) | Sciatic nerve histopathology (↔19) | ||
NCV (↓18, 19) | ||||||
ZDF/male [130] | 10–18 | Yes | R/S (↓18) | |||
PWL (Hargreaves) (↓18) | ||||||
ZDF/male [131] | 14–22 | BGL measured, not diagnostic | MNCV (↓21, 22) | |||
ZDF/male [132] | NR | BGL measured, not diagnostic | m-von Frey (↓18, 32) | MNCV (↓NR) | ||
PWL (Hargreaves) (↑NR) | SNCV (↓NR) | |||||
ZDF/male [133] | 7–21/27 | BGL measured, not diagnostic | MNCV (↓21/27) | |||
ZDF/male [134] | 6–24 | NR | PWL (Hargreaves) (↑24) | MNCV (↓24) | ||
SNCV (↓24) | ||||||
ZDF/male [135] | 6–28 | NR | PWL (Hargreaves) (↑28) | MNCV (↓28) | ||
SNCV (↓28) | ||||||
ZDF/male [99] | 6–35 | BGL measured, not diagnostic | e-von Frey (↔ up to 35) | NCV (↔up to 35) | ||
TFL (↓35) | ||||||
ZDSD | ||||||
ZDSD/male [103] | 16–34 | BGL measured, not diagnostic | PWL (Hargreaves) (↑34) | MNCV (↓34) | IENFD (↔34) | |
SNCV (↓34) | CNFL (↓34) | |||||
NGR | ||||||
African NGR/male [104] | 52–104 | Yes | m-von Frey ↑ | MNCV ↓ | IENFD ↓ | |
PWL (Hargreaves) ↑ |
The Neurodiab guidelines were published on the 17th of June, 2014. A 12-month window was included, and thus ‘pre-Neurodiab’ refers to articles published on or before 16th June 2015, and ‘post-Neurodiab’ refers to articles published from 17th June, 2015, to 3rd November 2020. DPN, diabetic peripheral neuropathy; SD, Sprague-Dawley; HFD, high-fat diet; STZ, streptozotocin; NA, nicotinamide; ZDF, Zucker diabetic fatty; BBZDR, Bio-Breeding Zucker diabetic rat; GK, Goto-Kakizaki; SDT, spontaneously diabetic Torii; OLETF, Otsuka Long-Evans Tokushima Fatty; ZDSD, Zucker diabetic Sprague-Dawley; NGR, Nile grass rat; WDF, Wistar diabetic fatty. One study was counted as both ZDF and WDF model and then subtracted from the total numbers. A dash (-) indicates no studies available. Note that in most cases, more studies reported neuropathy (at least 2 endpoints significantly different) than number of studies testing all 3 endpoints.
↑=significant increase, ↓=significant decrease, ↔=no change. STZ, streptozotocin; HFD, high-fat diet; m-von Frey, manual von Frey; SD, Sprague-Dawley; PWL, paw withdrawal latency; e-von Frey, electronic von Frey; MNCV, motor nerve conduction velocity; R/S, Randal-Selitto; SNCV, sensory nerve conduction velocity; IENFD, intraepidermal nerve fiber density; CNFL, corneal nerve fiber length; TFL, tail flick latency; HFHS, high-fat high-sugar; NR, not reported; NCV, nerve conduction velocity; HFHFr, high-fat high-fructose; NA, nicotinamide; IP, intra-peritoneal.
For each rat strain, studies are listed according to age of earliest standardised neuropathic assessment. Number(s) in parentheses refer to the age of rats in weeks, except for where diabetes duration is used and clearly mentioned. ↑=significant increase, ↓=significant decrease, ↔=no change. ZDF, Zucker diabetic fatty; BGL, blood glucose level; m-von Frey, manual von Frey; PWL, paw withdrawal latency; e-von Frey, electronic von Frey; R/S, Randal-Selitto; TFL, tail flick latency; MNCV, motor nerve conduction velocity; SNCV, sensory nerve conduction velocity; IENFD, intraepidermal nerve fiber density; NR, not reported; NCV, nerve conduction velocity; ZDSD, Zucker diabetic Sprague-Dawley; CNFL, corneal nerve fiber length; NGR, Nile grass rat. Values were converted to weeks of age, from months or weeks of diabetes, as reported in original study.