Hexosamine pathway but not interstitial changes mediates glucotoxicity in pancreatic ß-cells as assessed by cytosolic Ca2+ response to glucose.
Aging (Albany NY)
; 6(3): 207-14, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24704640
ABSTRACT
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 ß-cells is not thoroughly understood. Hyperglycemia alters glucose metabolism within ß-cells and interstitial conditions around ß-cells, including elevated osmolarity and increased concentrations of insulin and ATP released from overstimulated ß-cells. In this study, to explore direct effects of these alterations on ß-cells, single ß-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 ß-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 ß-cells.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sinalização do Cálcio
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Células Secretoras de Insulina
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Glucose
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Hexosaminas
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article