The Biological Role of Optimized Recombinant Oral Long-Acting Glucagon Like Peptide-1 and Its Impact on the Expression of Genes Associated with Glucose Metabolism of Diabetes

Abstract

Previously published studies have described optimized rolGLP-1 (Opt-rolGLP-1) exhibited good hypoglycemic efficacy. As such, additional studies were conducted aimed at exploring the therapeutic utility of Opt-rolGLP-1 in a murine model of diabetes and examining the mechanistic basis for such efficacy. A murine model of type 2 diabetes was constructed via a combination of an intraperitoneal STZ injection (STZ) together with a high fat/sugar diet. These model mice were then orally administered Opt-rolGLP-1. Treatment was associated with a reduction in average food and water intake. Notably, diabetic model animals tended to exhibit a reduction in overall body weight that was not evident in mice treated using Opt-rolGLP-1. Treatment with this compound was additionally associated with significant decreases in fasting plasma glucose, cholesterol, triglycerides, and glycosylated hemoglobin levels, whereas oral glucose tolerance and hyperinsulinemia improved significantly. At the gene expression level, we found that Opt-rolGLP-1 treatment increased the expression of GLUT2, INSR, and GCK in the liver, whereas the expression of PGC-1α fell significantly. These changes in gene expression may be associated with the mechanistic benefits of Opt-rolGLP-1 in this model of type 2 diabetes. Together these results highlight the value of further studying the potential clinical utility of Opt-rolGLP-1.