Hexosamine pathway but not interstitial changes mediates glucotoxicity in pancreatic β-cells as assessed by cytosolic Ca2+ response to glucose.
Hyperglycemia impairs insulin secretion as well as insulin action, being recognized as the glucotoxicity that accelerates diabetes. However, the mechanism underlying the glucotoxicity in pancreatic β-cells is not thoroughly understood. Hyperglycemia alters glucose metabolism within β-cells and interstitial conditions around β-cells, including elevated osmolarity and increased concentrations of insulin and ATP released from overstimulated β-cells. In this study, to explore direct effects of these alterations on β-cells, single β-cells isolated from rat islets were cultured for 3 days with high (22.3 mM) glucose (HG), compared with control 5.6 mM glucose, followed by their functional assessment by measuring cytosolic Ca2+ concentration ([Ca2+]i). The [Ca2+]i response to a physiological rise in glucose concentration to 8.3 mM was impaired in b-cells following culture with HG for 3 days, while it was preserved in β-cells following culture with non-metabolizable L-glucose and with elevated osmolarity, insulin and ATP. This HG-induced impairment of [Ca2+]i response to 8.3 mM glucose was prevented by adding azaserine, a hexosamine pathway inhibitor, into HG culture. Conversely, culture with glucosamine, which increases the hexosamine pathway flux, impaired [Ca2+]i response to 8.3 mM glucose, mimicking HG. These results suggest that the HG-associated abnormal glucose metabolism through hexosamine pathway, but not elevated osmolarity, insulin and ATP, plays a major role in the glucotoxicity to impair the secretory function of pancreatic β-cells.
2nd Department of Internal Medicine, Kagoshima University School of Medicine, Kagoshima, Japan.
Kazuhiro
K
Yanagida
Yuko
Y
Maejima
Putra
P
Santoso
Zesemdorj
Z
Otgon-Uul
Yifei
Y
Yang
Kazuya
K
Sakuma
Kenju
K
Shimomura
Toshihiko
T
Yada
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000633:toxicity*; D006595:Hexosamines / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar
D006595:Hexosamines; D007328:Insulin; D000255:Adenosine Triphosphate; D005947:Glucose