The chronic inflammation resultant from type 2 diabetes (T2D) causes many comorbidities, such as cardiovascular, renal, and neuropathic complications. T2D is also associated with several spinal pathologies, including intervertebral disc (IVD) degeneration and chronic neck and back pain. Although confounding factors, such as increased weight gain in obesity, increase the physiological loads experienced by the musculoskeletal system and subsequent mechanical damage, studies have shown that even after adjusting age, body mass index, and genetics (e.g. twins), patients with T2D suffer from disproportionately more IVD degeneration and back pain
despite this, the tissue-specific responses of the IVD during T2D remain relatively unknown. We hypothesize that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts disc homeostasis. To test this hypothesis, we evaluated two commonly used mouse models of T2D -the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). The db/db is a genetic model that spontaneous develop T2D through hyperphagia, while the STZ-HFD mouse first exhibits rapid obesity development under high-fat diet (HFD) and pronounced insulin resistance following streptozotocin (STZ) administration. Both animal models were allowed to develop sustained T2D for at least twelve weeks, as defined by elevated hemoglobin A1C, hyperglycemia, and glucose intolerance. Following the twelve-week period, the IVDs were extracted and evaluated for tissue-specific secreted cytokines, viscoelastic mechanical behavior, structural composition, and histopathologic degeneration. Although there were no differences in mechanical function or the overall structure of the IVD, the STZ-HFD IVDs were more degenerated. More notably, the STZ-HFD model shows a significantly higher fold increase for eight cytokines: CXCL2, CCL2, CCL3, CCL4, CCL12 (monocyte/macrophage associated), IL-2, CXCL9 (T-cell associated), and CCL5 (pleiotropic). Correlative network analyses revealed that the expression of cytokines is differentially regulated between the db/db and the STZ-HFD models. Moreover, the RNAseq analysis revealed vast transcriptional dysregulation of many pathways in the STZ-HFD but not in the db/db tissues. Taken together, the STZ-HFD may better recapitulates the complexities of the chronic inflammatory processes in the IVD during T2D.