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

Abstract

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 ad libitum 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. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Obesity and bone health: key 2020–2022 highlights and implications

“…As well, the persistent impact of excess body weight, while possibly favoring bone mineral increases, may yet exceed the overall mechanical threshold of the bone, especially in females 20 if other obesity associated health conditions prevail that heighten fracture risk. 20,21 Rinonaploi et al, 22 who recently reviewed this issue concluded that despite the fact that an increase in body weight may induce a higher than normal bone mineral density, the risk of sustaining a fracture is higher in the obese individual than predicted. This greater risk of fracture in the obese subject may involve an array of complex metabolic factors as well as an increased falls risk.…”

“…As well, age and diabetes type 2 factors, having a lower than desirable vitamin D intake due to sedentary and nutritional practices, may confer an increased risk of non vertebral fractures among obese women with type 2 diabetes. 21 A strictly weightbearing explanation for some fractures must however be ruled out, because as observed by Franchesci et al, 23 forearm fractures in children and adolescents are often associated with the presence of an increased body mass index, but this bone site is non-weight-bearing and results of 12 key studies showed overweight children typically had normal or increased volumetric levels of bone mineral density and an inconsistent finding of an associated higher fat-to-lean mass ratio, and findings bone size and bone strength were not lower than those of their normal weight peers. However, it was concluded that the local higher fat-to-lean mass ratio in the muscles of the forearm may yield a mismatch between the prevailing bone strength and the load experienced by the distal forearm during a fall, thus resulting in increased forearm fracture risk.…”

Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model

“…These rats also display diabetic nephropathy [42]. This is an appropriate animal model to evaluate both disease progression and skeletal alterations observed in humans [43,44].…”