Insulin-Stimulated Bone Blood Flow and Bone Biomechanical Properties Are Compromised in Obese, Type 2 Diabetic OLETF Rats

• Published in: JBMR plus 2017-10, Vol.1 (2), p.116-126
• Main Authors: Dirkes, Rebecca K, Ortinau, Laura C, Rector, R Scott, Olver, T Dylan, Hinton, Pamela S
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomechanics; Blood flow; Blood glucose; Body fat; Body weight; Bone blood flow; Bone strength; Cancellous bone; Cardiovascular disease; Cell adhesion & migration; Computed tomography; Cortical bone; Data analysis; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dietary restrictions; Endothelium; Epiphysis; Femur; Geometry; Hypotheses; Insulin; Insulin resistance; Laboratory animals; Mechanical properties; Metabolism; Obesity; Original; Oxidative stress; Pathogenesis; Rodents; Software; Studies; Vasodilation
• ISSN: 2473-4039; 2473-4039
• DOI: 10.1002/jbm4.10007

Type 2 diabetes (T2D) increases skeletal fragility and fracture risk; however, the underlying mechanisms remain to be identified. Impaired bone vascular function, in particular insulin-stimulated vasodilation and blood flow is a potential, yet unexplored mechanism. The purpose of this study was to determine the effects of T2D on femoral biomechanical properties, trabecular microarchitecture, and insulin-stimulated bone vasodilation by comparison of hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats with normoglycemic control OLETF rats. Four-week old, male OLETF rats were randomized to two groups: type 2 diabetes (O-T2D) or normoglycemic control (O-CON). O-T2D were allowed access to a rodent chow diet and O-CON underwent moderate caloric restriction (30% restriction relative to intake of O-T2D) to maintain normal body weight (BW) and glycemia until 40 weeks of age. Hyperphagic O-T2D rats had significantly greater BW, body fat, and blood glucose than O-CON. Total cross-sectional area (Tt.Ar), cortical area (Ct.Ar), Ct.Ar/Tt.Ar, and polar moment of inertia of the mid-diaphyseal femur adjusted for BW were greater in O-T2D rats versus O-CON. Whole-bone biomechanical properties of the femur assessed by torsional loading to failure did not differ between O-T2D and O-CON, but tissue-level strength and stiffness adjusted for BW were reduced in O-T2D relative to O-CON. Micro-computed tomography (μCT) of the distal epiphysis showed that O-T2D rats had reduced percent bone volume, trabecular number, and connectivity density, and greater trabecular spacing compared with O-CON. Basal tibial blood flow assessed by microsphere infusion was similar in O-T2D and O-CON, but the blood flow response to insulin stimulation in both the proximal epiphysis and diaphyseal marrow was lesser in O-T2D compared to O-CON. In summary, impaired insulin-stimulated bone blood flow is associated with deleterious changes in bone trabecular microarchitecture and cortical biomechanical properties in T2D, suggesting that vascular dysfunction might play a causal role in diabetic bone fragility. © 2017 The Authors. Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.