The dual epidemics of obesity and type II diabetes represent an enormous challenge to our health care system. The staggering human and monetary costs of these disorders are the direct result of having inadequate treatment options that both lower glucose levels and reduce body weight. Over the last decade, novel pharmacological strategies have become available that target the GLP-1 system. Glucagon-like-peptide- 1 (GLP-1), a regulatory peptide with a broad role in the regulation of nutrient ingestion and disposition, is produced in the intestine as well as in a small cluster of neurons in the hindbrain. Plasma GLP-1 originates from the gut, but is rapidly inactivated by the ubiquitous protease DPP-4. GLP-1's very short half-life challenges the dogma that under normal circumstances endogenous GLP-1 released by the gut acts on distant receptors in the pancreas or brain. Emerging GLP-1-based therapies use two distinct strategies: 1) Long- acting GLP-1 receptor (GLP-1R) agonists that are resistant to the actions of DPP-4;and 2) Inhibitors of DPP-4 that reduce GLP-1 inactivation, effectively prolonging the activity of endogenous GLP-1. Both classes of medication are hypothesized to stimulate GLP-1R signaling, and consequently to control hyperglycemia via a common mechanism of action. However, this cannot be the case since there are clinically important yet still unexplained differences in their spectrum of effects. Most notably, while both classes of compounds improve glucose tolerance, GLP-1R agonists additionally cause weight loss while DPP-4 inhibitors do not. Given the efficacy of GLP-1R-based therapies and the growing numbers of patients being treated with them, understanding endogenous GLP-1 and how it relates to the pharmacological action(s) of GLP-1-based therapies has immediate clinical relevance. The overarching goal of the proposed research is to identify the underlying mechanisms that mediate the effects of these novel treatments for diabetic patients, and to explain their important differences. The research will use state-of-the-art mouse genetic technologies to inactivate the only identified GLP-1 receptor selectively in pancreas, visceral sensory nerves and/or the central nervous system. Genetically modified mice will be treated with both GLP-1R agonists and DPP-4 inhibitors to determine which populations of GLP-1R are necessary for specific actions of these drugs on multiple aspects of glucose metabolism and body weight regulation. We will thus be able to identify the key receptor populations that mediate the important and varied effects of these GLP-1-based therapies. Our ability to deploy second generations of these medicines and to maximize their clinical benefit depends on identifying the key underlying mechanisms. The result of the this proposal will be to simultaneously drive new insights on the role of the endogenous GLP-1 system AND to refine and optimize current and future GLP-1-based therapies to better treat patients with type 2 diabetes.

Public Health Relevance

Effective treatments for individuals with diabetes remain elusive but among the most effective treatments currently available are those based on augmenting a hormone made in our intestines called GLP-1. This proposal aims to determine just how these effective therapies exert their positive effects. In this way, we can maximize their clinical benefit and develop a second generation of even more potent therapies for diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093848-03
Application #
8618900
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2012-03-05
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$370,478
Indirect Cost
$134,505
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Sisley, Stephanie R; Arble, Deanna M; Chambers, Adam P et al. (2016) Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight. Diabetes 65:2732-41
Arble, Deanna M; Holland, Jenna; Ottaway, Nickki et al. (2015) The melanocortin-4 receptor integrates circadian light cues and metabolism. Endocrinology 156:1685-91
Seeley, Randy J; Chambers, Adam P; Sandoval, Darleen A (2015) The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metab 21:369-78
Arble, Deanna M; Sandoval, Darleen A; Seeley, Randy J (2015) Mechanisms underlying weight loss and metabolic improvements in rodent models of bariatric surgery. Diabetologia 58:211-20
Gutierrez-Aguilar, Ruth; Thompson, Abigail; Marchand, Nathalie et al. (2015) The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids. Physiol Behav 150:38-42
Arble, D M; Sandoval, D A; Turek, F W et al. (2015) Metabolic effects of bariatric surgery in mouse models of circadian disruption. Int J Obes (Lond) 39:1310-8
Pressler, Josh W; Haller, April; Sorrell, Joyce et al. (2015) Vertical sleeve gastrectomy restores glucose homeostasis in apolipoprotein A-IV KO mice. Diabetes 64:498-507
Li, B; Matter, E K; Hoppert, H T et al. (2014) Identification of optimal reference genes for RT-qPCR in the rat hypothalamus and intestine for the study of obesity. Int J Obes (Lond) 38:192-7
Habegger, Kirk M; Heppner, Kristy M; Amburgy, Sarah E et al. (2014) GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats. Diabetes 63:505-13
Ryan, Karen K; Tremaroli, Valentina; Clemmensen, Christoffer et al. (2014) FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509:183-8

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