title: Changes in the Fracture Resistance of Bone with the Progression of Type 2 Diabetes in the ZDSD Rat.
abstract: Individuals with type 2 diabetes (T2D) have a higher fracture risk compared to non-diabetics, even though their areal bone mineral density is normal to high. Identifying the mechanisms whereby diabetes lowers fracture resistance requires well-characterized rodent models of diabetic bone disease. Toward that end, we hypothesized that bone toughness, more so than bone strength, decreases with the duration of diabetes in ZDSD rats. Bones were harvested from male CD(SD) control rats and male ZDSD rats at 16 weeks (before the onset of hyperglycemia), at 22 weeks (5-6 weeks of hyperglycemia), and at 29 weeks (12-13 weeks of hyperglycemia). There were at least 12 rats per strain per age group. At 16 weeks, there was no difference in either body weight or glucose levels between the two rat groups. Within 2 weeks of switching all rats to a diet with 48 % of kcal from fat, only the ZDSD rats developed hyperglycemia (>250 mg/dL). They also began to lose body weight at 21 weeks. CD(SD) rats remained normoglycemic (<110 mg/dL) on the high-fat diet and became obese (>600 g). From micro-computed tomography (μCT) analysis of a lumbar vertebra and distal femur, trabecular bone volume did not vary with age among the non-diabetic rats but was lower at 29 weeks than at 16 weeks or at 22 weeks for the diabetic rats. Consistent with that finding, μCT-derived intra-cortical porosity (femur diaphysis) was higher for ZDSD following ~12 weeks of hyperglycemia than for age-matched CD(SD) rats. Despite an age-related increase in mineralization in both rat strains (μCT and Raman spectroscopy), material strength of cortical bone (from three-point bending tests) increased with age only in the non-diabetic CD(SD) rats. Moreover, two other material properties, toughness (radius) and fracture toughness (femur), significantly decreased with the duration of T2D in ZDSD rats. This was accompanied by the increase in the levels of the pentosidine (femur). However, pentosidine was not significantly higher in diabetic than in non-diabetic bone at any time point. The ZDSD rat, which has normal leptin signaling and becomes diabetic after skeletal maturity, provides a pre-clinical model of diabetic bone disease, but a decrease in body weight during prolonged diabetes and certain strain-related differences before the onset of hyperglycemia should be taken into consideration when interpreting diabetes-related differences.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Creecy
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave S., Suite 4200, Nashville, TN, 37232, USA.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Merkel
authors.affiliation: School of Medicine, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: O'Neal
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Makowski
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave S., Suite 4200, Nashville, TN, 37232, USA.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Granke
authors.affiliation: Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA. jeffry.s.nyman@vanderbilt.edu.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. jeffry.s.nyman@vanderbilt.edu.|Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. jeffry.s.nyman@vanderbilt.edu.|Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave S., Suite 4200, Nashville, TN, 37232, USA. jeffry.s.nyman@vanderbilt.edu.
authors.forename: Jeffry S
authors.identifier: 0000-0001-7403-7605
authors.initials: JS
authors.lastname: Nyman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000096:biosynthesis; D001835:Body Weight / Q000502:physiology; D015519:Bone Density / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051381:Rats; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D001786:Blood Glucose
keywords: Advanced glycation end products; Bone quality; Micro-computed tomography; Porosity; Raman spectroscopy; Type 2 diabetes