Intervertebral disc degeneration in mice with type II diabetes induced by leptin receptor deficiency

Abstract

Background: The leptin receptor-deficient knockout (db/db) mouse is a well-established model for studying type II diabetes mellitus (T2DM). T2DM is an important risk factor of intervertebral disc degeneration (IVDD). Although the relationship between type I diabetes and IVDD has been reported by many studies, few studies have reported the effects of T2DM on IVDD in db/db mice model. Methods: Mice were separated into 3 groups: wild-type (WT), db/db, and IGF-1 groups (leptin receptor-deficient mice were treated with insulin-like growth factor-1 (IGF-1). To observe the effects of T2DM and glucose-lowering treatment on IVDD, IGF-1 injection was used. The IVD phenotype was detected by H&E and safranin O fast green staining among db/db, WT and IGF-1 mice. The levels of blood glucose and weight in mice were also recorded. The changes in the mass of the trabecular bone in the fifth lumbar vertebra were documented by micro-computed tomography (micro-CT). Tunnel assays were used to detect cell apoptosis in each group. Results: The weight of the mice were 27.68 ± 1.6 g in WT group, which was less than 57.56 ± 4.8 g in db/db group, and 52.17 ± 3.7 g in IGF-1 injected group (P < 0.05). The blood glucose levels were also significantly higher in the db/db mice group. T2DM caused by leptin receptor knockout showed an association with significantly decreased vertebral bone mass and increased IVDD when compared to WT mice. The db/db mice induced by leptin deletion showed a higher percentage of MMP3 expression as well as cell apoptosis in IVDD mice than WT mice (P < 0.05), while IGF-1 treatment reversed this situation (P < 0.05). Conclusions: T2DM induced by leptin receptor knockout led to IVDD by increasing the levels of MMP3 and promoting cell apoptosis. IGF-1 treatment partially rescue the phenotype of IVDD induced by leptin receptor knockout.

The Relationship between Diabetes Mellitus Type II and Intervertebral Disc Degeneration in Diabetic Rodent Models: A Systematic and Comprehensive Review

“…We identified 9511 published studies related to the issue IVDD. Out of these 27 manuscripts were related to the topic IVDD in diabetic rodent models, which is our research field of interest [ 3 , 15 , 43 , 47 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], see Table 4 and Table 5 . By further evaluation another four publications were excluded; two of them discussed the diabetic animal models used in IVDD, including rodents, but they were not related to IVDD.…”

“…One study (8.7%) surveyed the physio-biomechanical properties of the diabetic degenerated IVD [ 15 , 54 ]. One study investigated the pathogenesis of the diabetic IVDD by carrying out a therapeutic trial using IGF-1 injection as an anti-DM drug [ 47 ], see Table 4 .…”

“…Nevertheless, there was a bulk of evidence deduced from the included in vitro studies. Molecular biological techniques were less often applied as a means to achieve evidence for IVDD caused by T2DM [ 47 , 59 , 69 ].…”

“…Looking at the in vitro studies when high glucose was used to mimic hyperglycemia conditions, the concentrations applied substantially differ (e.g., 25 mM [ 65 , 66 ]) versus 100, 200, or even 400 mM [ 54 , 55 , 56 , 59 , 60 ] or 5.5, 25, 50, 100, and 150 μM [ 58 ]. In this respect, one has to face the fact that the blood glucose levels in diabetic rats (ZDF rats, 4–8 weeks) or mice were between 20 and 30 mM [ 47 , 73 ].…”

“…The db/db mouse is a model of severe T2DM. Its musculoskeletal changes are not clearly addressed; however, disturbances in bone structure and reduction of the length of long bones are reported [ 47 ]. Diabetic manifestations are more obvious in males.…”