Research Description
Critical to treating diabetes is the development of “precision medicine” strategies that account for variability in individual patients to optimize prevention and treatments. Human studies have identified an association between body mass index (BMI) and several genetic variations that implicate the central nervous system in obesity susceptibility including a variant near the gene Cell Adhesion Molecule1, which encodes a membrane protein mediating intercellular contact. We showed that one genetic variant that correlates with increased CADM1 expression. The identification of this CADM1-associated variant suggests that this genetic information may be leveraged as part of a ‘precision medicine’ strategy to identify individuals at potential risk for obesity and its co-morbidities including inflammation, insulin resistance, and glucose intolerance. We observed that elevated expression of Cadm1 in mice expedited diet-induced obesity and insulin resistance illustrating its role in metabolic dysfunction. Conversely, genetic deletion of Cadm1 protected mice from diet-induced obesity, insulin resistance, and glucose intolerance. From these results, we hypothesize that blocking Cadm1 function will alleviate diet-induced obesity and metabolic dysfunction. To test this idea, we administered a monoclonal ‘blocking’ antibody against Cadm1 in mice and our results showed that antibody-treated animals exhibited improved insulin sensitivity and glucose tolerance. From these observations, the goals of this proposal are to test whether delivery of the Cadm1 monoclonal antibody prevents Cadm1-mediated cell-to-cell contact in mice to reverse diet-induced obesity, inflammation, insulin resistance, and glucose intolerance. This work would constitute an important step towards developing a precision medicine approach for reversing metabolic dysfunction in the clinical setting.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?This project aims to address several complications associated with diabetes including insulin resistance, obesity, and pancreatic beta-cell dysfunction. Numerous studies link obesity and insulin resistance to activation of the innate immune system and macrophages have been shown to play a critical role in the chronic inflammation that underlies metabolic dysfunction. During obesity, macrophages in adipose tissue release pro-inflammatory cytokines contributing to local and systemic inflammation as well as insulin resistance. Our previous work showed increased expression of the gene CADM1 (referred to as human CADM1 and mouse Cadm1) associates with increased body weight in human subjects. As a cell adhesion protein, CADM1 mediates interaction between different cell types including immune cells, neurons, and endocrine cells. Here we hypothesize increased levels of Cadm1 in macrophages in multiple tissues including adipose mediate systemic inflammation, insulin resistance, and weight gain. This project will test whether a monoclonal antibody raised against the extracellular domain of Cadm1 can prevent macrophage binding and function that leads to inflammation in critical metabolic tissues that maintain proper systemic insulin sensitivity and energy metabolism. Successful outcomes of these preclinical studies will lay the foundation for the development of CADM1 ‘neutralizing’ antibodies that could be used to prevent or potentially treat and cure individuals with diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?The goal of our project is to demonstrate that a monoclonal ‘neutralizing’ antibody raised against the membrane protein Cadm1 can prevent obesity, insulin resistance, and glucose intolerance in high-fat diet fed mice. Successful outcomes of this study would illustrate the potential for pursuing CADM1 as a therapeutic target for either preventing disease in individuals at high risk or to possibly treat individuals already living with diabetes. This preclinical study is an important step to determine whether a CADM1 ‘neutralizing’ antibody would be an effective therapeutic strategy before or after metabolic complications arise. Furthermore, as additional study continues to demonstrate that blocking CADM1 function can prevent the tissue inflammation that contributes to metabolic disorders, future work would entail the development of additional CADM1 'neutralizing' antibodies that could optimize effective combinatorial antibody strategies for treating individuals with diabetes.
Why important for you, personally, to become involved in diabetes research? What role will this award play?Diabetes is a disease that could affect anyone and at any time and everyone should be conscious of its causes as well as the factors that can render one susceptible. In addition, the continuous increase in the number of individuals affected worldwide is without dispute; therefore, it is essential to develop therapeutic strategies to curtail the incidence of this disease. This award is important for us to enable the preclinical testing of a monoclonal ‘neutralizing’ antibody targeting the membrane protein Cadm1 and this will help us validate our approach as being viable for the continued development of therapeutic strategies designed to inhibit CADM1 function as a potential treatment for diabetes.
In what direction do you see the future of diabetes research going?Diabetes research is an increasingly collaborative endeavor moving into the future. As research strategies evolve with the development of new technologies, diabetes investigators are increasingly engaged in cross-disciplinary projects that integrate the expertise of individuals with backgrounds in computational and molecular biology, protein biochemistry, as well as cell biology. To facilitate the development of new treatments, modern approaches also emphasize translational studies to further elucidate the pathogenesis of human disease. Furthermore, diabetes research often bridges the study of cell and molecular physiology with endocrinology, neuroscience and immunology. This has helped to expand research into how diabetes and other metabolic diseases overlap with other disorders including various cancers, neurodegenerative disorders, and autoimmune diseases. These developments have come with advances in single cell technologies, mass spectrometry, and metabolomics and have helped to further our understanding of how specific disorders can predispose individuals to multiple complications. Importantly, each advance in technology will continue to enhance our ability to resolve disease mechanisms and help researchers in designing strategies that could either reverse specific disease outcomes or aid in developing treatments that can prevent the complications that lead to disease.