GLUCAGON-LIKE PEPTIDE-1 (7-36)AMIDE IMPROVES GLUCOSE SENSITIVITY IN BETA-CELLS OF NOD MICE

The effect of the insulinotropic gut hormone glucagon-like-peptide-1 ( GLP-1) was studied on the residual insulin capacity of prediabetic non obese diabetic (NOD) mice, a model of insulin-dependent diabetes melli tus (type 1). This was done using isolated pancreas per fusion and dyn amic islet perifusion. Prediabetes was defined by insulitis and fastin g normoglycemia. Insulitis occurred in 100% of NOD mice beyond the age of 12 weeks. K values in the intravenous glucose tolerance test were reduced in 20-week-old NOD mice compared with age-matched non-diabetes -prone NOR (nonobese resistant) mice (2.4+/-1.1 vs 3.8+/-1.5% min(-1), P<0.05). Prediabetic NOD pancreases were characterized by a complete loss of the glucose-induced first-phase insulin release. In perifused NOD islets GLP-1, at concentrations already effective in normal islets , left the insulin release unaltered. However, a significant rise of g lucose-dependent insulin secretion occurred for GLP-1 concentrations > 0.1 nM. This was obtained with both techniques, dynamic islet perifusi on and isolated pancreas perfusion, indicating a direct effect of GLP- 1 on the beta-cell. Analysis of glucose-insulin dose-response curves r evealed a marked improvement of glucose sensitivity of the NOD endocri ne pancreas in the presence of GLP-1 (half-maximal insulin output with out GLP-1 15.2 mM and with GLP-1 9.4 mM, P<0.002). We conclude that GL P-1 can successfully reverse the glucose sensing defect of islets affe cted by insulitis.