Besides being degraded to glucose-6-phosphate and to free glucose, glycogen is degraded by alpha-1,4-glucan lyase to 1, 5-anhydro-D-fructose. We examined the influence of 1, 5-anhydro-D-fructose on glucose-stimulated insulin secretion in vivo and in vitro in mice. When administered together with i.v. glucose (1 g/kg), 1,5-anhydro-D-fructose did not affect (at 0.2 g/kg) or inhibited (at 1 g/kg) insulin secretion without affecting glucose elimination. When incubated with isolated islets, 1, 5-anhydro-D-fructose at <16.7 mmol/l, did not affect glucose (11.1 mM)-stimulated insulin secretion but inhibited insulin secretion at 16.7 mmol/l. When given through a gastric gavage (150 mg/mouse) together with glucose (150 mg/mouse), 1,5-anhydro-D-fructose increased glucose tolerance and insulin secretion. Furthermore, 1, 5-anhydro-D-fructose potentiated the increase in plasma levels of the gut hormone, glucagon-like peptide-1 (GLP-1). We therefore conclude that when given enterally, but not parenterally, 1, 5-anhydro-D-fructose increases glucose tolerance in mice by increasing insulin secretion due to increased plasma levels of GLP-1. The sugar may therefore be explored for increasing endogenous GLP-1 secretion in the treatment of type 2 diabetes.