Glucose-modulated tyrosine nitration in beta cells: targets and consequences.
Hyperglycemia, key factor of the pre-diabetic and diabetic pathology, is associated with cellular oxidative stress that promotes oxidative protein modifications. We report that protein nitration is responsive to changes in glucose concentrations in islets of Langerhans and insulinoma beta cells. Alterations in the extent of tyrosine nitration as well as the cellular nitroproteome profile correlated tightly with changing glucose concentrations. The target proteins we identified function in protein folding, energy metabolism, antioxidant capacity, and membrane permeability. Nitration of heat shock protein 60 in vitro was found to decrease its ATP hydrolysis and interaction with proinsulin, suggesting a mechanism by which protein nitration could diminish insulin secretion. This was supported by our finding of a decrease in stimulated insulin secretion following glycolytic stress in cultured cells. Our results reveal that protein tyrosine nitration may be a previously unrecognized factor in beta-cell dysfunction and the pathogenesis of diabetes.
Koeck
Thomas
T
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. koeckt@ccf.org
Corbett
John A
JA
Crabb
John W
JW
Stuehr
Dennis J
DJ
Aulak
Kulwant S
KS
D000818:Animals; D018834:Chaperonin 60 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007340:Insulinoma / Q000473:pathology / Q000503:physiopathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology; D009566:Nitrates / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D011236:Prediabetic State / Q000473:pathology / Q000503:physiopathology*; D014443:Tyrosine / Q000378:metabolism*
D018834:Chaperonin 60; D007328:Insulin; D009566:Nitrates; D014443:Tyrosine; D005947:Glucose