title: Bone's responses to mechanical loading are impaired in type 1 diabetes.
abstract: Diabetes adversely impacts many organ systems including the skeleton. Clinical trials have revealed a startling elevation in fracture risk in diabetic patients. Bone fractures can be life threatening: nearly 1 in 6 hip fracture patients die within one year. Because physical exercise is proven to improve bone properties and reduce fracture risk in non-diabetic subjects, we tested its efficacy in type 1 diabetes. We hypothesized that diabetic bone's response to anabolic mechanical loading would be attenuated, partially due to impaired mechanosensing of osteocytes under hyperglycemia. Heterozygous C57BL/6-Ins2(Akita)/J (Akita) male and female diabetic mice and their age- and gender-matched wild-type (WT) C57BL/6J controls (7-month-old, N=5-7 mice/group) were subjected to unilateral axial ulnar loading with a peak strain of 3500 με at 2 Hz and 3 min/day for 5 days. The Akita female mice, which exhibited a relatively normal body weight and a mild 40% elevation of blood glucose level, responded with increased bone formation (+6.5% in Ct.B.Ar, and 4 to 36-fold increase in Ec.BFR/BS and Ps.BFR/BS), and the loading effects, in terms of changes of static and dynamic indices, did not differ between Akita and WT females (p ≥ 0.1). However, loading-induced anabolic effects were greatly diminished in Akita males, which exhibited reduced body weight, severe hyperglycemia (+230%), diminished bone formation (ΔCt.B.Ar: 0.003 vs. 0.030 mm(2), p=0.005), and suppressed periosteal bone appositions (ΔPs.BFR/BS, p=0.02). Hyperglycemia (25 mM glucose) was further found to impair the flow-induced intracellular calcium signaling in MLO-Y4 osteocytes, and significantly inhibited the flow-induced downstream responses including reduction in apoptosis and sRANKL secretion and PGE2 release. These results, along with previous findings showing adverse effects of hyperglycemia on osteoblasts and mesenchymal stem cells, suggest that failure to maintain normal glucose levels may impair bone's responses to mechanical loading in diabetics.
authors.affiliation: Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: parajuli.ashutosh@gmail.com.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Parajuli
authors.affiliation: Department of Mechanical and Industrial Engineering, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: wenli@udel.edu.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: davegu@udel.edu.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: laixhan@udel.edu.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Lai
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: shaopeng@udel.edu.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Pei
authors.affiliation: Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: cprice@udel.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Price
authors.affiliation: Department of Mechanical and Industrial Engineering, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada. Electronic address: youlidan@mie.utoronto.ca.
authors.forename: Lidan
authors.initials: L
authors.lastname: You
authors.affiliation: Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA; Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: xlu@udel.edu.
authors.forename: X Lucas
authors.initials: XL
authors.lastname: Lu
authors.affiliation: Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA; Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA. Electronic address: lywang@udel.edu.
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology*; D051381:Rats; D014457:Ulna / Q000378:metabolism* / Q000473:pathology; D016474:Weight-Bearing / Q000502:physiology*
keywords: Akita diabetic mouse; Bone formation; Fluid flow; Osteocyte mechanosensitivity; Ulnar mechanical loading