The pancreatic beta cell can respond in the long term to
hyperglycemia both with an increased capacity for
insulin production and, in susceptible individuals, with apoptosis. When
glucose-induced apoptosis offsets the increasing beta cell capacity,
type 2 diabetes results. Here, we tested the idea that the pathway of
glucose metabolism that leads to the modification of intracellular
proteins with the O-linked
monosaccharide N-acetylglucosamine (O-GlcNAc) is involved in the
glucose-induced apoptosis. This idea is based on two recent observations. First, the beta cell expresses much more
O-GlcNAc transferase than any other known cell, and second, that the beta cell-specific toxin,
streptozotocin (STZ), itself a GlcNAc analog, specifically blocks the
enzyme that cleaves O-GlcNAc from intracellular
proteins. As a consequence, we now show that
hyperglycemia leads to the rapid and reversible accumulation of O-GlcNAc specifically in beta cells in vivo. Animals pretreated with STZ also accumulate O-GlcNAc in their beta cells when hyperglycemic, but this change is sustained upon re-establishment of euglycemia. In concert with the idea that STZ toxicity results from the sustained accumulation of O-GlcNAc after a hyperglycemic episode, we established a low-dose STZ protocol in which the beta cells' toxicity of STZ was manifest only after
glucose or
glucosamine administration. Transgenic mice with impaired beta cell
glucosamine synthesis treated with this protocol are resistant to the diabetogenic effect of STZ plus
glucose yet succumb to STZ plus
glucosamine. This study provides a causal link between apoptosis in beta cells and
glucose metabolism through
glucosamine to O-GlcNAc, implicating this pathway of
glucose metabolism with beta cell
glucose toxicity.