EFFECTS OF GLP-1 AND 2,5-ANHYDRO-D-MANNITOL ON INSULIN-SECRETION AND PLASMA-GLUCOSE IN MICE

The truncated glucagon-like peptide-1 (GLP-1((7.36))amide or GLP-1) stimulates insulin secretion, enhances glucose elimination and is of potential interest in diabetes treatment. We studied the hypoglycemic action of GLP-1 in normal mice when given alone or together with the fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), which inhibits glycogenolysis and gluconeogenesis. GLP-1 (32 nmol/kg iv) lowered plasma glucose levels after 25 min to 4.6+/-0.2 mmol/l compared with 7.3+/-0.4 mmol/l in controls (P<0.001). Also 2,5-AM (0.5 mu mol/kg iv) reduced plasma glucose levels, to 5.6+/-0.3 mmol/l (P<0.01). When given together, the glucose lowering action of GLP-1 and 2,5-AM was additive, since the 25 min glucose level was 2.8+/-0.2 mmol/l. At 5 min after injection, GLP-1 had increased plasma insulin levels to 693+/-68 pmol/l compared with 342+/-42 pmol/l in controls (P<0.01). 2,5-AM abolished this increase. Furthermore, GLP-1 (32 nmol/kg) did not affect the glycogen content, neither in the liver nor in the gastrocnemic muscle in samples taken at 30 min after injection. Moreover, in isolated islets incubated at 3.3 and 8.3 mmol/l glucose, 2,5-AM at 75 mmol/l inhibited glucose-stimulated insulin secretion (P<0.05) showing that 2,5-AM inhibits insulin secretion both in vivo and in vitro. We conclude that GLP-1 may reduce plasma glucose levels also to levels below the basal levels under normal conditions, and that an insulin- and liver-independent action of the peptide contributes to its hypoglycemic action in normal animals.