2015 Poll Visiting Scientist Lecture
Kevan C. Herold, MD
Professor of Immunology and of Medicine (Endocrinology)
Director, Yale Diabetes Center
Deputy Director for Translational Science, YCCI
Yale School of Medicine
Sakeneh Zraika, Ph.D.
Research Associate Professor
Metabolism, Endocrinology, & Nutrition
The proposed studies will examine whether the peptidase, neprilysin (NEP), modulates glucose-stimulated insulin secretion (GSIS) by degrading the insulinotropic peptide, glucagon-like peptide-1 (GLP-1). Findings may have significant implications for development of therapeutics to treat pancreatic ß-cell dysfunction in diabetes.
NEP is a widely expressed plasma membrane peptidase that we have shown is increased in pancreatic islets under conditions associated with type 2 diabetes. This increased NEP activity in islets is associated with impaired GSIS, while NEP deficiency protects against fat-induced impairments in GSIS both in vitro and in vivo. Since NEP is capable of degrading and inactivating the insulinotropic peptide GLP-1, we will test the hypothesis that increased NEP activity limits the beneficial effects of GLP-1 on insulin secretion and glucose homeostasis.
To date, we have preliminary data to demonstrate that under conditions of increased dietary fat, NEP ablation in mice enhances active GLP-1 levels thereby contributing to increased GSIS and improved glucose tolerance. Our goal is to examine the contribution of NEP that is expressed not only in the islet but also in the gut, given that the major source of GLP-1 is the intestine. Studies will involve pharmacological and genetic approaches to inhibit NEP activity in cell culture (in vitro) and whole body (in vivo) models.
Like NEP, dipeptidyl peptidase-4 (DPP-4) also inactivates GLP-1. DPP-4 inhibitors are used clinically in order to prolong the half-life of GLP-1 and thereby improve GSIS in type 2 diabetes. Patients with type 2 diabetes exhibit additive glycemic improvement when DPP-4 inhibition is combined with other therapies, such as metformin. Thus, DPP-4 inhibition alone is frequently insufficient to achieve maximal glycemic control. We will examine whether combining NEP and DPP-4 inhibition under conditions relevant to type 2 diabetes, is beneficial for ß-cell function.
Together, our proposed studies will determine whether islet and/or intestinal NEP inhibition, with or without concurrent DPP-4 inhibition, increases levels of endogenous GLP-1 and thereby enhances GSIS. Our findings have implications for development of therapies to improve ß-cell function in diabetes; specifically, a dual NEP and DPP-4 inhibitor could be more beneficial than a DPP-4 inhibitor alone in augmenting the insulinotropic action of GLP-1.