Preserving and restoring bone with continuous insulin infusion therapy in a mouse model of type 1 diabetes

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24 Scopus citations

Abstract

Those with type 1 diabetes (T1D) are more likely to suffer a fracture than age- and sex-matched individuals without diabetes, despite daily insulin therapy. In rodent studies examining the effect of bone- or glucose-targeting therapies on preventing the T1D-related decrease in bone strength, insulin co-therapy is often not included, despite the known importance of insulin signaling to bone mass accrual. Therefore, working toward a relevant pre-clinical model of diabetic bone disease, we assessed the effect of continuous subcutaneous insulin infusion (CSII) therapy at escalating doses on preserving bone and the effect of delayed CSII on rescuing the T1D-related bone deterioration in an established murine model of T1D. Osmotic minipumps were implanted in male DBA/2 J mice 2 weeks (prevention study) and 6 weeks (rescue study) after the first injection of streptozotocin (STZ) to deliver insulin at 0, 0.0625, 0.125, or 0.25 IU/day (prevention study; n = 4–5 per dose) and 0 or 0.25 IU/day (rescue study; n = 10 per group). CSII lasted 4 weeks in both studies, which also included age-matched, non-diabetic DBA/2 J mice (n = 8–12 per study). As the insulin dose increased, blood glucose decreased, body weight increased, a serum maker of bone resorption decreased, and a serum marker of bone formation increased such that each end-point characteristic was linearly correlated with dose. There were insulin dose-dependent relationships (femur diaphysis) with cross-sectional area of cortical bone and cortical thickness (micro-computed tomography) as well as structural strength (peak force endured by the mid-shaft during three-point bending). Likewise, trabecular bone volume fraction (BV/TV), thickness, and number (distal femur metaphysis) increased as the insulin dose increased. Delayed CSII improved glycated hemoglobin (HbA1c), but blood glucose levels remained relatively high (well above non-diabetic levels). Interestingly, it returned the resorption and formation markers to similar levels as those seen in non-T1D control mice. This apparent return after 4 weeks of CSII translated to a partial rescue of the structural strength of the femur mid-shaft. Delayed CSII also increased Tb.Th to levels seen in non-T1D controls but did not fully restore BV/TV. The use of exogenous insulin should be considered in pre-clinical studies investigating the effect of T1D on bone as insulin therapy maintains bone structure without necessarily lowering glucose below diabetic levels.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalBone Reports
Volume7
DOIs
StatePublished - Dec 2017

Bibliographical note

Funding Information:
Support for this work was provided by the Children's University Medical Group Fund of the Arkansas Children's Hospital Research Institute (KMT), the Arkansas Biosciences Institute (JLF), National Institutes of Health (1R01DK084045 to JLF and 1R01AR063157 to JSN), Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (1I01BX001018 to JSN). The micro-computed tomography scanner was supported by the National Center for Research Resources (1S10RR027631) and matching funds from the Vanderbilt Office of Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies.

Publisher Copyright:
© 2017 The Authors

Keywords

  • Bone strength
  • Cortical structure
  • Diabetes
  • Insulin
  • Trabecular architecture

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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