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The Journal of Bone and Joint Surgery (American) 83:1537-1544 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.

Scientific Article

Insulin Secretory Response Is Positively Associated with the Extent of Ossification of the Posterior Longitudinal Ligament of the Spine

Toru Akune, MD, Naoshi Ogata, MD, Atsushi Seichi, MD, Isao Ohnishi, MD, Kozo Nakamura, MD and Hiroshi Kawaguchi, MD

Investigation performed at the Department of Orthopaedic Surgery, University of Tokyo, Tokyo, Japan
Toru Akune, MD
Naoshi Ogata, MD
Atsushi Seichi, MD
Isao Ohnishi, MD
Kozo Nakamura, MD
Hiroshi Kawaguchi, MD
Department of Orthopaedic Surgery, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail address for H. Kawaguchi: kawaguchi-ort{at}h.u-tokyo.ac.jp

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were a Grant-in-Aid from the Investigation Committee on the Ossification of Spinal Ligaments, Japanese Ministry of Public Health and Welfare; a Grant-in-Aid (#11470301) for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture; the Bristol-Myers Squibb/Zimmer Unrestricted Research Grant; and the Uehara Memorial Foundation.

Background: Glucose intolerance is frequently found in patients with ossification of the posterior longitudinal ligament of the spine. This study was undertaken to examine the relationship between glucose intolerance and the extent of ossification in patients with ossification of the posterior longitudinal ligament.

Methods: A total of 100 patients with ossification of the posterior longitudinal ligament (the overall study group), including fifty-two inpatients who were scheduled to have an operation (the inpatient group) and forty-eight outpatients who had undergone an operation, were analyzed. Indices of glucose metabolism—fasting plasma glucose and serum insulin levels, hemoglobin A1c level, and insulinogenic index (a ratio of the increment of the serum level of insulin to that of glucose)—as well as age and body-mass index were correlated with the extent of ossification, as determined by the number of vertebral levels affected with ossification of the posterior longitudinal ligament (extent of ossification), in the inpatient group. In addition, a similar analysis was performed in twenty-eight inpatients (the selected inpatient group) whose ages and body-mass indices were within one standard deviation of the mean values of those of the inpatient group. Association of a polymorphism in the gene of insulin receptor substrate-1, an essential substrate in insulin signaling, with the extent of ossification was evaluated with genomic DNA extracted from the overall study group.

Results: Multiple-regression analysis revealed direct correlations of age (p = 0.038), body-mass index (p = 0.006), and insulinogenic index (p = 0.0003) with the extent of ossification of the posterior longitudinal ligament in the inpatient group. The fasting plasma glucose level, the hemoglobin A1c level, and the stage of glucose tolerance were not associated with the extent of ossification. In the analysis of the selected inpatient group, only the insulinogenic index was correlated with the extent of ossification (p = 0.002). However, no significant association was seen between the insulin receptor substrate-1 polymorphism and the extent of ossification.

Conclusions: The insulin secretory response was associated with the extent of ossification of the posterior longitudinal ligament. Since insulin receptor substrate-1 is expressed both in the spinal ligament and in the tissues regulating glucose metabolism, we speculate that some other molecules related to insulin signaling that are impaired only in the tissues regulating glucose metabolism may be responsible for the progression of ossification. We also speculate that the upregulation of insulin production due to the impairment of insulin action may stimulate osteoprogenitor cells in the ligament to induce ossification.

Clinical Relevance: The insulinogenic index may be useful as a serum marker for the prediction of progression of ossification of the posterior longitudinal ligament. This study may serve as a stimulus for evaluation of the use of various drugs that may improve the response to insulin in the tissues regulating glucose metabolism to prevent the progression of ossification.


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