Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. Exercise training ameliorates glucosamine-induced insulin resistance in ovariectomized rats Chung-Hwan Chen, MD, PhD, 1,2,3,4 Tsang-Hai Huang, PhD, 5 Tsung-Lin Cheng, PhD, 3,6 Chi-Fen Chang, PhD, 7 Chau-Zen Wang, PhD, 3,6,8 Meng-Hsing Wu, MD, PhD, 9 and Lin Kang, MD, PhD 9 Abstract Objective: Glucosamine (GlcN), which has been reported to induce insulin resistance (IR), is a popular nutritional supplement used to treat osteoarthritis in menopausal women. We previously demonstrated that GlcN treatment caused IR in ovariectomized rats by reducing the expression of glucose transport protein subtype 4 (GLUT-4) in skeletal muscle. In the present study, we hypothesized that endurance exercise training can reverse GlcN-induced IR. Methods: Fifty female rats were randomly divided into five groups with 10 rats in each group: (1) sham-operated group; (2) sham-operated group with GlcN treatment for 14 days; (3) ovariectomy (OVX) group; (4) OVX with GlcN treatment; and (5) OVX with GlcN treatment followed by exercise training (running program) for 8 weeks. Results: Fasting plasma glucose increased in the OVX þ GlcN group, and fasting plasma insulin and the homeostasis model assessment-insulin resistance (HOMA-IR) were significantly higher only in this group. After the rats received exercise training for 8 weeks, no increase in the fasting plasma glucose, insulin, or HOMA-IR was observed. In an intraperitoneal glucose tolerance test, the plasma glucose, plasma insulin, HOMA-IR, and glucose- insulin index were significantly elevated only in the OVX with GlcN treatment group. However, the plasma glucose, plasma insulin, HOMA-IR, and glucose-insulin index decreased after exercise training for 8 weeks, implying that GlcN-induced IR in OVX rats could be reversed through exercise. A histological analysis revealed that exercise training can reduce islet hypertrophy and maintain GLUT-4 in skeletal muscle. Conclusions: Exercise training can alleviate IR in OVX rats treated with GlcN. Islet hyperplasia was subsequently prevented. Preserving GLUT-4 expression may be one of the mechanisms by which exercise prevents IR. Key Words: Exercise – Glucosamine – Glucose transport protein subtype 4 (GLUT-4) – Insulin resistance – Menopause. K nee osteoarthritis is a common disease among post- menopausal women. 1 Glucosamine (GlcN) is widely used as a nutritional supplement for osteoarthritis. 2 GlcN leads to glucose intolerance and insulin resistance (IR) 3,4 and impairs insulin production from pancreatic b-cells. 3,5 Detrimental effects of GlcN on glucose metabolism have been reported 6,7 ; however, some studies have reported no effect of GlcN on glucose metabolism. 8,9 In male rodent studies, GlcN impaired insulin production in pancreatic b-cells. 10 In vitro studies have demonstrated that GlcN hampered glycogen syn- thesis and reduced glucose uptake in adipocytes and skeletal muscle. 3,11 In addition, GlcN reduced insulin secretion and induced b-cell apoptosis. 12,13 In postmenopausal women, estrogen deficiency causes IR. 14,15 Theoretically, GlcN supple- ments exert an additional burden on glucose metabolism. Our previous study revealed that GlcN reduced insulin secretion from b-cells by prohibiting Ca 2þ influx and increased b-cell apoptosis by raising endoplasmic reticulum stress-related protein expression. 16 O-linked N-acetyl-GlcN levels are altered during postnatal retinal vascular development and neovascula- rization. Dysregulation under hyperglycemia or ischemia may contribute to the pathogenesis of diabetic retinopathy and Received July 7, 2016; revised and accepted October 26, 2016. From the 1 Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung City, Taiwan; 2 Department of Orthopedics, Kaoh- siung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 3 Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4 Departments of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaoh- siung, Taiwan; 5 Institute of Physical Education, Health and Leisure Studies, National Cheng Kung University, Tainan, Taiwan; 6 Department Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 7 Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan; 8 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical Univer- sity, Kaohsiung, Taiwan; and 9 Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. C.-H.C. and T.-H.H contributed equally. Funding/support: This study was supported in part by the National Cheng Kung University Hospital (NCKUH-10203008), Kaohsiung Medical University Hospital (KMUH103-3R38), Kaohsiung Medical University (KMU-TP104B09, KMU-DK105009), and Taiwan and Ministry of Sci- ence and Technology (MOST 103-2314-B-006-072-) (MOST 104-2314- B-037-032-MY3) (104-2314-B-006-071-MY2) of Taiwan. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Lin Kang, MD, PhD, Department of Obstet- rics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan 70428, Taiwan. E-mail: kanglin@mail.ncku.edu.tw Menopause, Vol. 24, No. 6, 2017 617 Menopause: The Journal of The North American Menopause Society Vol. 24, No. 6, pp. 617-623 DOI: 10.1097/GME.0000000000000811 ß 2016 by The North American Menopause Society