The prevalence of Type 2 diabetes has risen dramatically in the United States and globally for the past few decades and has now reached epidemic proportions. The etiology of this disease involves both insulin resistance and decreased ? cell function, and one typically needs both defects (2 hit hypothesis) in order to develop the full hyperglycemic diabetic state. Current anti-diabetic therapeutics is available, but is inadequate to control the disease in most patients and there is a large unmet medical need for better methods of treating diabetes to prevent morbidity and mortality. Our recent work has led to the discovery that Fractalkine (FKN) (CX3CL1) working exclusively by signaling through its cognate receptor CX3CR1 in ? cells, leads to enhanced glucose, arginine, and GLP-1 stimulated insulin secretion with markedly improved glucose tolerance in obese and diabetic mouse models. Thus, CX3CR1 KO mice are glucose intolerant due to decreased insulin secretion. Furthermore, neutralization of circulating FKN by administration of anti-FKN antibodies leads to an abrupt decrease in insulin secretion with glucose intolerance in WT mice. Furthermore, in vivo FKN administration leads to increased insulin secretion with improved glucose tolerance in WT mice, but is completely without effect in CX3CR1 KO animals. In vitro, FKN administration directly causes increased insulin secretion in ? cell lines, isolated islets and perfused islets, but it is without any effect when CX3CR1 is deleted from the ? cells. This led to the conclusion that FKN is a novel potentiator of ? cell insulin secretion. This proposal seeks to build on this newly identified FKN/CX3CR1 ? cell regulatory system to identify the underlying cellular and molecular mechanisms of FKN-induced insulin secretion. We will also test the hypothesis that long-term FKN treatment will have beneficial effects on glucose metabolism and insulin secretion in a series of hyperglycemic mouse models. In addition, we will test the overall hypothesis that FKN will have beneficial effects on ? cell "health". This is based on our current findings that FKN inhibits ? cell apoptosis and stimulates the ? cell differentiation gene program. Finally, we will test the additional hypothesis that FKN administration in vivo will inhibit the development of atherosclerosis in the LDLR KO mouse model. If the ideas incorporated into this application are supported by the proposed experiments, then this would strongly support the concept that a FKN-based biotherapeutic could be administered in vivo to potentiate glucose stimulated insulin secretion in man. This therapeutic strategy could be used for the treatment of patients with Type 2 diabetes mellitus to augment their ability to secrete insulin in response to nutrients and other stimuli and to prevent the decline in ? cell mass which characterizes this disease. This would lead to improved glycemic control adding a new component in our therapeutic armamentarium for the treatment of this widespread disease.

Public Health Relevance

This project builds on our recent discovery that Fractalkine (FKN) binds to its receptor CX3CR1 on cells to enhance insulin secretion. Our studies are designed to elucidate underlying mechanisms for FKN-mediated insulin secretion and also determine whether in vivo FKN treatment inhibits apoptosis in a variety of rodent models and identify the mechanisms of this effect. An improved understanding of the effects of this novel insulin secretagogue has substantial potential to lead to a new therapeutic opportunity in Type 2 diabetes mellitus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK101395-01A1
Application #
8813806
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2014-09-19
Project End
2018-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093