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17β-Estradiol protects against glucosamine-induced pancreatic β-cell dysfunction

Kang, Lin MD1,2; Chen, Chung-Hwan MD, PhD3,4,5,6,7; Wu, Meng-Hsing MD, PhD2; Chang, Je-Ken MD3,4,5,7; Chang, Fong-Ming MD, PhD1,2,8; Cheng, Juei-Tang PhD, FCP1,9

doi: 10.1097/GME.0000000000000232
Original Articles
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Objective Glucosamine (GlcN) is a popular supplement for osteoarthritis in postmenopausal women. Although GlcN possibly induces insulin resistance, the effects of GlcN on β-cell dysfunction are still obscure.

Methods In the present study, we investigated changes in insulin production and β-cell apoptosis in pancreatic islets after GlcN treatment in rats with or without ovariectomy and used MIN-6 cells to investigate the protective effects and molecular mechanisms of 17β-estradiol (E2) in GlcN-induced β-cell dysfunction. The rats were divided into four groups: (1) sham operation (SHAM; n = 8); (2) SHAM with 750 mg/kg/day GlcN injected intraperitoneally for 14 days (SHAM + GlcN; n = 10); (3) ovariectomy (OVX; n = 9); and (4) OVX with 750 mg/kg/day GlcN injected intraperitoneally for 14 days (OVX + GlcN; n = 9).

Results Both GlcN and ovariectomy reduced the expression of insulin, determined by the staining intensity of insulin and reverse polymerase chain reaction. GlcN alone also induced β-cell apoptosis, and this adverse effect was aggravated after ovariectomy. In addition, we found that GlcN decreased calcium influx and insulin secretion by decreasing the protein levels of inwardly rectifying potassium in the ATP-sensitive potassium channel. GlcN decreased the protein levels of endoplasmic reticulum (ER) stress–associated proteins, including C/EBP homologous protein, phospho-protein kinase-like endoplasmic reticulum kinase, phospho-eukaryotic initiation factor 2α, and phospho-c-Jun N-terminal kinase. Finally, GlcN decreased cell viability. E2 counteracted GlcN-mediated attenuation in intracellular calcium concentration, extracellular insulin secretion, protein levels of inwardly rectifying potassium, cell viability, and protein levels of ER stress–associated proteins. ICI182.780 inhibited these beneficial effects of E2.

Conclusions GlcN impairs insulin secretion of β-cells by inhibiting Ca2+ influx and enhancing β-cell apoptosis with increases in ER stress–related proteins, whereas E2 counters these adverse effects of GlcN.

From the 1Graduate Institute of Clinical Medicine and 2Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 3Department of Orthopedics and 4Orthopedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 6Department of Orthopedics, Kaohsiung Municipal Hsiao-Kang Hospital, and 7Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Clinical Medicine, Da-An Women Children Hospital, Tainan, Taiwan; and 9Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.

Received December 3, 2013; revised and accepted February 12, 2014.

L.K. and C.-H.C. contributed equally to this work.

Funding/support: This study was supported, in part, by grants from the National Cheng Kung University Hospital (NCKUH-1013004 and NCKUH-10203008), National Science Council (NSC97-2314-B-006-022-MY3, NSC101-2314-B-006-044-MY3, and NSC 100-2314-B-037-012), Kaohsiung Medical University Hospital (KMUH100-0R39), and National Health Research Institute (NHRI-EX101-9935EI) of Taiwan.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Fong-Ming Chang, MD, PhD, Department of Clinical Medicine, Da-An Women Children Hospital, Tainan City, Taiwan. E-mail: fchang@mail.ncku.edu.tw; Juei-Tang Cheng, PhD, FCP, Department of Medical Research, Chi-Mei Medical Center, No. 901 Zhonghua Road, Yong Kang District, Tainan City 710, Taiwan. E-mail: m980103@mail.chimei.org.tw

© 2014 by The North American Menopause Society.