To investigate the effect of glucagon-like peptide (GLP)-1 receptor agonist (exendin-4) on the structure and function of pancreatic α cells in impaired glucose tolerance (IGT) rats.

A total of 54 male Wistar rats aged 4-5 weeks (150-170 g) were randomly divided into normal glucose tolerance (NGT) group (n=18) and IGT group (n=36). Rats in NGT group were administrated with routine diet and rats in IGT group were administrated with high-sugar, high-fat diet. 32 rats which were successfully established IGT models (the modeling success rate was 88%) were randomly divided into the IGT group (IGT group, n=16) and the Exendin-4 intervention group (Ex group, n=16). Levels of plasma glucagon, the percentage of α cells area and the glucagon protein expression in half rats of each group were detected by radioimmunoassay, immunohistochemical staining and immunofluorescence respectively. The ultrastructure of α cells were observed under transmission electron microscope. Rats in Ex group received Exendin-4 5 μg/kg subcutaneously, twice daily, while rats in the NGT and IGT group both received saline 5 μg/kg instead. Indicators were detected and collected after intervention for 4 weeks. One-way analysis of variance and least-significant difference was used for multigroup comparison.

(1) Before intervention, the plasma levels of glucagon, the area percentage of α cells, the glucagon protein expression and the secretory granules level of α cells in IGT group and Ex group were higher than those in the NGT group respectively [glucagon: (118.89±3.53), (116.12±3.37) vs (88.18±6.94) pg/ml; the area percentage of α cells: (26.91±7.77)%, (24.00±9.88)% vs (11.01±6.33)%; the glucagon protein expression: (307.44±71.85), (321.71±105.65) vs (71.74±12.10); the secretory granules level of α cells: (135.32±16.31), (129.64±12.78) vs (74.60±6.55); all P<0.05]. After intervention, the plasma levels of glucagon, the area percentage of α cells, the glucagon protein expression and the secretory granules levels of rat islet α cells were less in Ex group than those in the IGT group and the pre-intervention Ex group [glucagon: (86.89±6.23) vs (116.12±3.37), (118.39±4.36) pg/ml (t=11.67, 11.72, all P<0.05); the area percentage of α cells: (15.09±3.35)% vs (24.00±9.88)%, (29.21±5.66)%; the glucagon protein expression: (102.10±26.28) vs (321.71±105.65), (327.55±155.53); the secretory granules level of α cells: (75.79±8.23) vs (129.64±12.78), (133.39±4.36) (t=10.02, 17.49, all P<0.05]. There were no significant differences of above indicators between the NGT group and the post-intervention Ex group (all P>0.05); (2) Compared with the NGT group, the ultrastructural changes under electron microscopy in the IGT group showed: the nuclear membrane of α cells shrank and the nuclear chromatin was condensed; the mitochondria and endoplasmic reticulum were irregularly arranged, the mitochondria were swollen and deformed, and the cristae became shorter and shallower; the granula of endoplasmic reticulum fell off, the secretory granules increase, and the gap between dense core and boundary membrane narrowed or even disappeared. After intervention, compared with the IGT group before and during the intervention, the ultrastructural changes under electron microscopy in Ex group showed: the shrinkage of nuclear membrane and chromatin decreased, the abnormal proliferation and edema of mitochondria improved, the degranulation of rough endoplasmic reticulum was alleviated, the number of secretory particles decreased, and the gap between dense core and boundary membrane returned to near normal.

The number, ultrastructure and function of α cells have changed in the IGT stage. Exendin-4 can improve the number, ultrastructure and dysfunction of α cells in IGT rats.

Glucagon-like peptide-1; Glucagon; Ultrastructure; Impaired glucose tolerance; Alpha cell