Abstract
Type 2 diabetes mellitus results from a complex interaction between nutritional excess and multiple genes. Whereas pancreatic β-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 β-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 β-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.
Original language | English (US) |
---|---|
Pages (from-to) | 135-146 |
Number of pages | 12 |
Journal | Molecular and Cellular Endocrinology |
Volume | 194 |
Issue number | 1-2 |
DOIs | |
State | Published - Aug 30 2002 |
Keywords
- Diabetes mellitus
- Glucose
- Insulin
- Pituitary
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Endocrinology