Bone Geometry and Trabecular and Cortical Microarchitecture are Altered by Type 2 Diabetes, but not Insulin Resistance, in the Hyperphagic OLETF Rat

Abstract

Recently, fragility fracture has been added to the list of type 2 diabetes (T2D) complications. The purpose of this study was to determine the effects of insulin resistance (IR) and T2D on bone outcomes using the hyperphagic Otsuka Long‐Evans Tokushima Fatty (OLETF) rat model of T2D. Long‐Evans Tokushima Otsuka (LETO) and calorically restricted (CR; ~30% reduction vs. OLETF) OLETF rats weight‐matched to the LETO controls were used as lean, normoglycemic controls. The skeletal effects of IR and T2D were evaluated in 20‐ and 40‐week old male OLETF rats. Femur geometry and trabecular and cortical microarchitecture were analyzed using mCT. Cortical bone strength was analyzed by torsional loading of the femur to failure. The effects of IR and T2D on bone outcomes were compared using a two‐way (group, age) ANOVA; body weight (BW) was included as a covariate for body‐size‐dependent outcomes. As expected, the hyperphagic OLETF rats had significantly greater BW than controls. Blood glucose and insulin confirmed that OLETF rats were hyperglycemic and hyperinsulinemic at 20 weeks and at 40 weeks were hypoinsulinemic due to β‐cell dysfunction. At 20 weeks, only the cortical‐to‐total area ratio (Ct.Ar/Tt.Ar) was greater in IR OLETF versus CR controls. However, at 40 weeks bone geometry, microarchitecture, and biomechanical properties differed between OLETF rats and LETO and CR controls. OLETF rats had significantly shorter femur length than LETO and CR controls. Total cross‐sectional area and cortical area were greater in T2D OLETF rats versus LETO and CR controls. Ct.Ar/Tt.Ar and polar moment of inertia were greater in OLETF compared with CR. OLETF rats showed a greater increase in trabecular spacing and greater decreases in connectivity density from 20 to 40 weeks compared with LETO and CR controls; at 40 weeks T2D OLETF rats had reduced percent bone volume. T2D OLETF rats did not show the age‐related decline in torsional stiffness (Ks) observed in controls. Relative to CR, OLETF rats had a greater decline in ultimate tensile strength (Su), and at 40 weeks OLETF rats had reduced shear modulus of elasticity (G). In summary, bone geometry, trabecular and cortical microarchitecture, and biomechanical properties are altered by T2D, but not IR, in the hyperphagic OLETF rat relative to lean controls. The results of this study suggest that early identification and treatment of T2D might reduce the skeletal complications associated with hyperglycemia and β‐cell dysfunction.Support or Funding InformationThis work was funded by the VA Career Development Award and the Department of Nutrition and Exercise Physiology at the University of Missouri.