Abstract

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate insulin secretion, promote beta cell proliferation, and reduce apoptosis. To test the hypothesis that GLP-1 would preserve beta cell function and improve glycemic control in a murine model of neonatal diabetes, we examined the effects of a GLP-1 agonist (exendin-4) on Akita mice, which are characterized by severe and progressive hyperglycemia. Upon weaning, wild type and Akita littermates were given daily intraperitoneal injections of exendin-4 or PBS for a four-week period. Random blood glucose (BG) was measured twice per week, and fasting BG, plasma insulin, and plasma glucagon were measured at the end of the treatment period following a six-hour fast. In pancreatic cryosections, beta cell proliferation was assessed by Ki67 labeling and apoptosis by TUNEL staining. Prior to treatment, there was no significant difference in BG between mice assigned to receive control vs. GLP-1. Three to four days after initiation of treatment, BG further increased in the control group but was reduced in GLP-1 treated mice. After four weeks of treatment, the random and fasting BG were lower in the GLP-1 treated group. GLP-1 treated mice had higher fasting plasma insulin (corrected for glucose) than the control group, but fasting glucagon levels were similar. Beta cell proliferation, but not apoptosis, was greater in the GLP-1 treated group. The abnormal islet morphology that characterizes the Akita mouse was not improved by GLP-1 treatment. The initial reduction in BG and the maintenance of reduced BG levels suggest both an acute and chronic effect of GLP-1 in improving glycemic control, including acute stimulation of insulin secretion and stimulation of beta cell proliferation. These findings suggest some therapeutic benefit of a GLP-1 agonist in preserving beta cell function and reducing hyperglycemia in neonatal diabetes.