title: Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus.
abstract: Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+50.1%, p=0.001) and Ct.Po (+22.9%, p=0.004), as well as to reduced mechanical competence (max. stress: -14.2%, p=0.041, toughness: -29.7%, p=0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R(2)=0.41, p<0.001, Ct.Po: R(2)=0.34, p=0.003) and HbA1c (NEG: R(2)=0.42, p<0.001, Ct.Po: R(2)=0.28, p=0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R(2)=0.21, p=0.023, yield stress: R(2)=0.17, p=0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.
authors: Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany; Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany. Electronic address: graeme.campbell@tuhh.de.
authors: G M
authors: GM
authors: Campbell
authors: Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors: S
authors: S
authors: Tiwari
authors: Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany.
authors: A-K
authors: AK
authors: Picke
authors: Department of Orthopedics, Technische Universität Dresden Medical Center, Dresden, Germany.
authors: C
authors: C
authors: Hofbauer
authors: Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany.
authors: M
authors: M
authors: Rauner
authors: Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany.
authors: M M
authors: MM
authors: Morlock
authors: Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany; Center for Regenerative Therapies Dresden, Germany.
authors: L C
authors: LC
authors: Hofbauer
authors: Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors: C-C
authors: CC
authors: Glüer
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001786:Blood Glucose / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006031:Glycosylation; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008903:Minerals / Q000378:metabolism; D016062:Porosity; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D008903:Minerals
keywords: Biomechanics; Collagen; Diabetes; Insulin; Non-enzymatic glycation; Preclinical studies