17β-estradiol protects against glucosamine-induced pancreatic β-cell dysfunction.
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 Ca 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.
Lin
L
Kang
Chung-Hwan
CH
Chen
Meng-Hsing
MH
Wu
Je-Ken
JK
Chang
Fong-Ming
FM
Chang
Juei-Tang
JT
Cheng
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004965:Estrogen Antagonists; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D005944:Glucosamine / Q000008:administration & dosage*; D007328:Insulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010052:Ovariectomy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D004965:Estrogen Antagonists; D007328:Insulin; D012333:RNA, Messenger; D000077267:Fulvestrant; D004958:Estradiol; D005944:Glucosamine; D002118:Calcium