Streptozotocin, an O-GlcNAcase inhibitor, blunts insulin and growth hormone secretion.
Type 2 diabetes mellitus results from a complex interaction between nutritional excess and multiple genes. Whereas pancreatic beta-cells normally respond to glucose challenge by rapid insulin release (first phase insulin secretion), there is a loss of this acute response in virtually all of the type 2 diabetes patients with significant fasting hyperglycemia. Our previous studies demonstrated that irreversible intracellular accumulation of a glucose metabolite, protein O-linked N-acetylglucosamine modification (O-GlcNAc), is associated with pancreatic beta-cell apoptosis. In the present study, we show that streptozotocin (STZ), a non-competitive chemical blocker of O-GlcNAcase, induces an insulin secretory defect in isolated rat islet cells. In contrast, transgenic mice with down-regulated glucose to glucosamine metabolism in beta-cells exhibited an enhanced insulin secretion capacity. Interestingly, the STZ blockade of O-GlcNAcase activity is also associated with a growth hormone secretory defect and impairment of intracellular secretory vesicle trafficking. These results provide evidence for the roles of O-GlcNAc in the insulin secretion and possible involvement of O-GlcNAc in general glucose-regulated hormone secretion pathways.
Liu
Kan
K
Department of Medicine/Endocrinology, Cell Biology, University of Alabama at Birmingham, 1808 7th Avenue South, Rm 756, Birmingham, AL 35294, USA.
Paterson
Andrew J
AJ
Konrad
Robert J
RJ
Parlow
A F
AF
Jimi
Shiro
S
Roh
Meejeon
M
Chin
Edward
E
Kudlow
Jeffrey E
JE
D000117:Acetylglucosamine / Q000378:metabolism / Q000502:physiology; D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors*; D000818:Animals; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000187:drug effects* / Q000378:metabolism; D051548:Histone Acetyltransferases; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes; D051381:Rats; D017207:Rats, Sprague-Dawley; D022142:Secretory Vesicles; D013311:Streptozocin / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases
D007328:Insulin; D007329:Insulin Antagonists; D009097:Multienzyme Complexes; D013311:Streptozocin; D013006:Growth Hormone; D051548:Histone Acetyltransferases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D005947:Glucose; D000117:Acetylglucosamine