Graham, Timothy E., MD
RBP4 receptor-2 (RBPR2) in tissue-specific regulation of whole body insulin-glucose homeostasis
General Research Subject: Type 2 Diabetes
Focus: Insulin Action, Insulin Action\Transgenic Models, Integrated Physiology, Integrated Physiology\Insulin Resistance, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transgenic Models
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes Type: Type 2 diabetes
Type 2 diabetes is characterized by "insulin resistance", an impaired ability of tissues to respond to insulin. Serum Vitamin A/retinol binding protein (RBP4) has been identified as a possible cause of insulin resistance. Circulating RBP4 produced by fat is elevated in insulin-resistant humans with obesity and type 2 diabetes. Certain genetic variants of RBP4 are associated with Type 2 diabetes in humans, and elevated RBP4 levels cause insulin resistance in mice. Therefore, lowering RBP4 or blocking its actions in tissues may be beneficial. Little is known about how RBP4 interacts with tissues to cause insulin resistance. We identified "RBP4 receptor-2" (RBPR2) as a new receptor that binds RBP4 on cell surfaces and regulates Vitamin A uptake. RBPR2 is present in liver and fat, where we hypothesize RBP4 interacts with it to cause insulin resistance.
To test this, we developed mice that lack a functional RBPR2 gene (total body knockout mice). When made obese by feeding high fat diet, RBPR2 total body knockout mice are protected from developing insulin resistance or high blood sugar. Our project goals are to define specific functions of RBPR2 in liver and fat by studying mice with RBPR2 impaired selectively in each tissue. We will also determine whether RBPR2 is a target of the insulin-sensitizing drug, fenretinide, by studying effects of fenretinide in RBPR2 knockout mice and mice with increased RBPR2 in liver. These studies will provide mechanistic insight regarding insulin resistance in Type 2 diabetes and further refine approaches to targeting RBP4 action with drugs.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
In prior work, we had determined that the fat-secreted protein, RBP4, is increased in blood of individuals with obesity, Type 2 diabetes, and other conditions associated with insulin resistance. Lowering RBP4 in rodents improves insulin sensitivity and enhances glucose tolerance, suggesting RBP4 may play a causal role in Type 2 diabetes. Consistent with that, specific polymorphisms in the human RBP4 gene that increase RBP4 protein production confer increased risk for developing Type 2 diabetes. Nevertheless, little is known about the specific mechanism by which RBP4 interacts with tissues to regulate insulin action and glucose levels. The goal of this project is define the metabolic functions of a recently discovered RBP4-binding receptor protein, RBPR2, expressed in liver and in adipose tissue.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Obesity and inactivity are major risk factors for Type 2 diabetes -- both of these conditions cause insulin resistance, which is an inability of cells in the body to respond to insulin produced by the pancreas. In addition, certain individuals have a family tendency to develop insulin resistance. The purpose of this project is to gain a better understanding about the connection between fat tissue and insulin resistance; specifically to understand how a protein called RBP4 produced in fat may cause insulin resistance in other tissues involved in regulation of glucose levels. By understanding the function of this protein, we hope to develop new ways to prevent or treat Type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My father developed Type 2 diabetes in the 1960s, about two years before I was born. He was 35 years old. Some of my strongest early childhood memories are of my Dad measuring his blood sugar with a new invention called the "home glucometer", and injecting himself throughout the day with different types of insulin. Despite what seemed like an enormous amount of attention on his part to taking care of his blood sugar, he still went on to develop the usual complications of neuropathy, nephropathy, and retinopathy by the time he reached his 60s.
In addition, like many patients with Type 2 diabetes, he had accelerated cardiovascular disease, suffering a minor stroke and requiring a carotid endarterectomy around age 50, an occipital stroke that caused partial blindness at age 60, a myocardial infarction at age 65. He also required a slew of surgeries: ileofemoral and ileopopliteal bypass surgeries at age 63, a below the knee amputation at age 66, and a cardiac bypass surgery at age 69. He finally succumbed to the combination of congestive heart failure and chronic kidney disease at the early age of 73. It is still hard for me to express the feeling of helplessness in watching my father's body slowly, literally fall apart, piece-by-piece, starting in his early 50s, a time that should have been the prime of his adult life.
This experience played a key role in my decision to become a physician, and I made up my mind early in my career that I would work in academic medicine to stop diabetes, especially Type 2 diabetes. Toward that end I sought the best possible training in Endocrinology and Diabetes, studying under my mentor, Barbara Kahn, at Harvard Medical School and Beth Israel Deaconess Medical Center. Today I am clinically active as Director of the University of Utah Diabetes and Heart Disease Prevention Program -- in addition to developing a statewide screening program, I run a clinic in which we use cutting edge protein, lipid, and metabolomics biomarkers to identify patients with very early stages of prediabetes (essentially "pre-prediabetes").
Our goal is to provide these patients with the earliest possible interventions via lifestyle modification (education and physician-supervised diet and exercise programs), along with early cardiovascular risk assessment and treatment, well before the appearance of the hyperglycemia that marks the clinical onset of prediabetes or diabetes. When I'm not running this clinical program, I oversee several active research programs aimed at understanding the causes of insulin resistance and Type 2 diabetes at the cellular and molecular level. This ADA Basic Science Award will provide the majority of funding for a specific project dealing with the interactions between a fat-secreted molecule and a new receptor for the molecule found in both liver and fat. We hope that understanding this interaction will provide new strategies for developing therapies to prevent and/or treat Type 2 diabetes. During a time of intense nationwide funding competition in the NIH, this ADA award enables important, potentially life-saving research to move forward at the pace it deserves.
In what direction do you see the future of diabetes research going?
Advances in systems biology, including next generation sequencing, proteomics, and metabolomics, will dramatically increase our ability to perform basic diabetes discovery science in humans, through the help of our patient volunteers. Even so, we will still rely heavily on bench, animal, and translational methods to formally test hypotheses spawned by these human discoveries. To do this optimally, it will be necessary for basic science to achieve new levels of efficiency, allowing it to more directly interface with the "data pipelines" of systems biology-based discoveries. Innovations in high throughput screening methods, rapid development of mouse models using engineered ESC libraries, use of expert metabolic phenotyping core facilities, and "therapeutomics" approaches for accelerated design and testing of prototype drug compounds will all play key roles in this necessary next-stage evolution of basic diabetes research.
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