This application addresses Broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-DK-106: Preservation/Recovery of endogenous insulin secretion. Diabetes is a serious and common metabolic disorder that afflicts 18 million Americans with an annual estimated cost of approximately $170 billion per year. The prevalence and incidence are increasing worldwide and this disease threatens to overwhelm the health care systems in the United States and other countries. Type 2 diabetes mellitus (T2DM) is the commonest form of diabetes accounting for well over 80% of cases. Current therapies for T2DM have significant limitations. Efficacy is frequently short lived and potentially serious side effects particularly in the cardiovascular system have been reported. Only a small proportion of diabetics achieve treatment targets and as a result, complications of T2DM are a major cause of morbidity and mortality. It has been known for some time that peptides produced and secreted by endocrine cells in the intestine play a major role in glucose metabolism in part by enhancing the insulin secretory response to glucose. Modulating the action or plasma concentrations of Glucagon- Like Peptide-1 (GLP-1), an intestinal peptide produced by intestinal L cells, is the basis for the action of two novel treatments of T2DM that have recently been approved and are now in widespread clinical use. There is thus considerable interest in determining whether other intestinal peptides could play a similar role. Although Glucose-dependent Insulinotropic Polypeptide increases glucose-stimulated insulin release in healthy individuals, this peptide product of the intestinal K cells is inactive in persons with T2DM. In the course of studies in transgenic mice engineered to lack K cells, we have determined that xenin-25, a second peptide product of the K cell, regulates insulin secretion specifically by enhancing insulin secretory responses to Glucose-Dependent Insulinotropic Polypeptide (GIP). The mechanism of xenin-25 action is also novel because preliminary results indicate that xenin-25 does not act directly on the pancreatic -cell. Rather, xenin-25 stimulates acetylcholine release from parasympathetic neurons that innervate the islets and this neurotransmitter then activates muscarinic receptors on the pancreatic islet -cell. This unexpected finding is not only of interest and importance for understanding the physiology of insulin secretion, but suggests a role for xenin-25 in the treatment of T2DM by enhancing endogenous insulin secretion. Based on these preliminary data, the present application proposes to conduct a proof-of-concept clinical trial in humans with T2DM and matched controls with normal glucose tolerance to determine whether xenin-25 either alone or in combination with GIP increases endogenous insulin secretion in T2DM.
In Specific Aim 1 we will determine whether xenin-25 enhances the insulin secretory response to exogenously infused GIP and in Specific Aim 2 we will determine whether xenin-25 enhances the insulin secretory response to endogenously secreted GIP. The specific deliverables that will result from the Challenge Award include: 1. Definition of the role of xenin-25 in regulation of insulin secretion in normal subjects;2. Definition of the role of xenin-25 in regulating insulin secretion in persons with T2DM;3. Determination of the potential for xenin-25 or compounds that mimic its mode of action to be used in the treatment of T2DM.

Public Health Relevance

The American Diabetes Association [Diabetes Care, 31:1-2, (2008)] points out that in the United States alone, greater than 17.5 million persons have been diagnosed with type 2 diabetes mellitus (T2DM) with an associated yearly economic burden exceeding $174 billion. The incidence of the disease is increasing rapidly on a worldwide basis with staggering impact on cost of healthcare and quality of life. Thus, there is an urgent need to develop new and improved approaches to the prevention and treatment of T2DM. The proposed studies will determine whether an intestinal peptide called xenin-25 could be used to treat T2DM. If so, this would have a dramatic positive impact on human health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Challenge Grants and Partnerships Program (RC1)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-C (58))
Program Officer
Staten, Myrlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Sterl, Karin; Wang, Songyan; Oestricker, Lauren et al. (2016) Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery. Peptides 82:76-84
Zhang, Sheng; Wang, Songyan; Puhl, Matthew D et al. (2015) Global biochemical profiling identifies ?-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans. Diabetes 64:1383-94
Chowdhury, Sara; Reeds, Dominic N; Crimmins, Dan L et al. (2014) Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes. Am J Physiol Gastrointest Liver Physiol 306:G301-9
Chowdhury, Sara; Wang, Songyan; Patterson, Bruce W et al. (2013) The combination of GIP plus xenin-25 indirectly increases pancreatic polypeptide release in humans with and without type 2 diabetes mellitus. Regul Pept 187:42-50
Wice, Burton M; Reeds, Dominic N; Tran, Hung D et al. (2012) Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes 61:1793-800
Wice, Burton M; Wang, Songyan; Crimmins, Dan L et al. (2010) Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem 285:19842-53