Biomarker of IAPP dysfunction in prediabetes and early type 2 diabetes mellitus (T2DM)

Project Summary Type 2 diabetes mellitus (T2DM) is a major unmet public health concern with an annual cost in the United States of over 300 billion dollars, according to the American Diabetes Association. Approximately 25% of the U.S. population is considered prediabetic, or at high risk of developing T2DM. Human islet amyloid polypeptide (hIAPP, or amylin) is a pancreatic hormone co-expressed and secreted with insulin in response to high glucose concentrations. hIAPP has a strong propensity to misfold and aggregate, causing amyloid formation in the islets which results in pancreatic β-cell death and decreased insulin secretion. A significant unmet challenge associated with early detection of hIAPP aggregates is the ability to detect misfolded hIAPP protein versus the natively folded and functional monomeric peptides. In this Phase I application we will develop a first in-kind assay derived from our innovative ‘cap and trap’ technology that provides the capacity to discriminate between misfolded hIAPP and native functional amylin. From this platform we will identify the top 3 highest affinity monoclonal antibodies that will be utilized for an ELISA-based diagnostic in order allow early detection of amyloidogenic hIAPP prior to complete amyloid- dependent β-cell toxicity and insulin-dependent T2DM. The assay will be designed to specifically recognize and quantitate levels of protofibril as opposed to native hIAPP in blood samples of prediabetic and diabetic patients. The immediate impact on the patient population will be the early detection of pathogenic β-cell-derived amyloid protofibrils as a new indicator of prediabetes or early signs of T2DM, as well as a valuable assay for monitoring the effectiveness of drug or dietary interventions.NARRATIVE Type 2 diabetes mellitus (T2DM) is a chronic and progressive condition that affects 10 to 25% of the U.S. population. In prediabetics, when the pancreas secretes insulin in response to high glucose, it can also secrete misfolded copies of human islet amyloid polypeptide (hIAPP) which then cause destruction of the insulin-producing pancreatic beta cells. We propose to develop a novel assay for the detection of early hIAPP misfolding, to provide an entirely new approach that can predict T2DM risk before the onset of overt damage to the pancreas and thereby guide early treatment that will decrease damage to the pancreas.