Type 2 diabetes mellitus is 1 of the leading causes of death and disability in the world. While current treatments prevent some of diabetes' more damaging complications, they can neither restore normoglycemia nor eliminate all the harmful effects caused by long term diabetes. Recent studies have shown that the continuous intravenous (i.v.) administration of Glucagon-like peptide 1 (GLP-1) can lower plasma glucose significantly in a majority of patients with Type 2 diabetes. However, due to the need for the continuous infusion of GLP-1 and the failure of oral GLP-1 peptide to lead to an increase in serum GLP-1 levels, current approaches using GLP-1 are not suitable for long term diabetes treatment. Advanced controlled release systems provide an alternative approach to the standard oral, intravenous or intramuscular delivery of pharmaceutical agents. This application proposes a non-invasive diabetes therapy through the oral administration of GLP-1 encapsulated in biodegradable nanoparticles. Encapsulation of labile biologicals such as GLP-1 into biodegradable polymers provides protection from the acidic environment and proteases of the stomach and allows safe passage into the lumen of the Gl tract for uptake. This proposal is designed to determine whether orally delivered, nano-encapsulated GLP-1 are superior to systemic bolus delivery in reducing blood glucose levels in experimental animals. To this end, 3 aims are proposed.
In Aim 1, different bioadhesive formulations of encapsulated GLP-1 are analyzed for release kinetics (ELISA) and post-release peptide bioactivity (INS-1 cell insulin release / proliferation) in vitro. The goal of Aim 2 is to determine in vivo dosing and kinetics. In this aim, control mice are treated with a intra-peritoneal injection of glucose followed by the oral administration of GLP-1 nanoparticle formulations selected from the release and bioactivity studies in Aim 1. In the final Aim, the therapeutic efficacy of GLP-1 nanoparticles is examined in fasting and post-prandial diabetic mice. Type II diabetes mellitus and its long term complications affect 18.2 million people in the United States alone. Deaths due to the long-term complications of this disease make diabetes the third leading cause of death in the US. The orally delivered form of GLP-1 proposed here could have a profound effect on public health due to its potential to reduce the illness and death associated with long term diabetes. ? ? ?
