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) st imulates insulin secretion, enhances glucose elimination and is of pot ential interest in diabetes treatment. We studied the hypoglycemic act ion of GLP-1 in normal mice when given alone or together with the fruc tose analogue, 2,5-anhydro-D-mannitol (2,5-AM), which inhibits glycoge nolysis and gluconeogenesis. GLP-1 (32 nmol/kg iv) lowered plasma gluc ose levels after 25 min to 4.6+/-0.2 mmol/l compared with 7.3+/-0.4 mm ol/l in controls (P<0.001). Also 2,5-AM (0.5 mu mol/kg iv) reduced pla sma 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 t he 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 compare d with 342+/-42 pmol/l in controls (P<0.01). 2,5-AM abolished this inc rease. Furthermore, GLP-1 (32 nmol/kg) did not affect the glycogen con tent, neither in the liver nor in the gastrocnemic muscle in samples t aken 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 ins ulin secretion both in vivo and in vitro. We conclude that GLP-1 may r educe plasma glucose levels also to levels below the basal levels unde r normal conditions, and that an insulin- and liver-independent action of the peptide contributes to its hypoglycemic action in normal anima ls.