Estudio de la expresión de la hormona incretínica glp-1 en dos modelos animales de diabetes mellitus tipo 1 (ratones nod y ratones balb/c tratados con estreptozotocina)

Resumen

GLP-1 expression in two models of type 1 diabetes mellitus (NOD mice and streptozotocin-treated Balb/c mice). Raquel Alcaraz Ortega, School of Sciences, University of Navarra (Spain), 2012. Type 1 diabetes mellitus is characterized by loss of insulin-producing beta cells of the islets of Langerhans in the pancreas, mediated by an autoimmune attack that leading to insulin deficiency. Glucagon-like peptide 1 (GLP-1) is a gut derived incretin hormone. This peptide is mainly synthesized by L cells of the small and large bowel. GLP-1 is produced as an inactive 37 amino-acid long peptide, whose N-terminal six amino acids are cleaved to generate the form GLP-1 (7-37). The generation of this molecule is contingent on the expression of the prohormone convertase enzyme PC1/3 in the enteroendocrine cells. The most important action of GLP-1 is the enhancement of glucose-stimulated insulin secretion in pancreatic beta cells, mediated by activation of its receptor. In addition to its insulinotropic actions GLP-1 exerts islet trophic effects by stimulating replication as well as decreasing beta¿s cell apoptosis. The aim of this study was to relate diabetes development to changes in L cells population and the rate of beta cell replication. In addition, we studied the ultrastructure of the intestinal barrier in healthy and diabetic mice. This study has demonstrated the expected global increase with age of GLP-1 serum levels and GLP-1 immunoreactive cells in the intestine of NOD mice. The increase of GLP-1 cellular density was found only at intermediate ages (20 weeks), but it was not observed in older animals (32 weeks). Therefore our results suggest that active GLP-1 gut expression is higher in prediabetic and diabetic NOD mice. These results were also observed in the streptozotocin (stz) treated mice, in which animals treated with the highest dose (160 mg/kg) showed the highest GLP-1 cellular density. Several studies have confirmed that in NOD mice, -cell replication is increased in the early stages of the diabetes. This study suggests that animals that reached a critical loss of β mass, due to autoimmune attack or drugs, present a higher rate of β cell replication which may be related to an increase of GLP-1 expression. The rate of β-cell replication, in NOD strain and stz treated Balb /c mice, was related to a percentage of endocrine area close to 0.3%. However, this rate was not correlated to GLP-1 cellular density. The alteration of intestinal barrier function in type I diabetes mellitus, are frequently associated with mucosal ultra-structural alterations. Many enterocytes of the diabetic animals exhibited a cytoplasm characterized by the presence of large and complex vacuoli and swollen mitochondria with alterations of the cristae mostly localized in the sub-apical region. The baso-lateral inter-cellular spaces between adjacent enterocytes appeared to be enlarged in most cases.