Genomics Approach to Study Molecular Heterogeneity in the Pathogenesis of Type 2 Diabetes and Its Complications
Abstract
This proposal is designed to address the Congressionally Directed Medical Research Programs? (CDMRP?s) vision to ?find and fund the best research to eradicate diseases and support the warfighter for the benefit of the American public.? This year, type 2 diabetes (T2D) has been identified as a priority because it affects almost 30 million Americans. T2D affects up to one in seven patients in the TRICARE Military Health Care System and approximately 1 in 4 older Veterans cared for by Medicare. T2D impacts quality of life and cost of living, requiring regular medical monitoring and shortening life expectancy, despite the best available treatments. While current treatments reduce the cardiovascular, kidney, neurologic, and vision disorders that occur with T2D, these problems are still more frequent than in people without diabetes. In fact, most patients with T2D will die from heart disease that is directly caused by their diabetes, despite the best care available. Patients develop T2D because of ?insulin resistance? (the inability of insulin to work properly in muscle and other tissues) and the progressive decline of insulin secretion from specialized cells in the pancreas that become overworked trying to compensate for insulin resistance. It is very clear that genes and their actions in the body are involved in the metabolic changes that cause T2D. Though many of these genes have been identified, a gap remains between identifying them and understanding how they cause disease; which is critical for developing clinical treatments to reverse their effects. A new commentary in Diabetes states that ?recent analysis of a commercial drug pipeline ... reported that drug development projects were more likely to succeed if biomarkers of efficacy were available at the start of phase 2 studies or if there was genetic evidence linking the drug target to the targeted disease.? By studying needle biopsies of muscle from people with T2D, we identified a factor (NG1B) that is associated with promoting the healthy state of insulin sensitivity. Genetic changes (present in some, but not all people) near the NG1B gene, which appear to decrease its levels in muscle, are linked to increased chances of developing T2D. We will study NG1B in muscle cells to understand how it works and how insulin resistance develops. We will also identify other factors (genes, proteins, hormones, and biomarkers) that are affected by NG1B, to understand how they work together to influence the risk of developing T2D. This will be done through a combination of functional studies in human cell culture models (grown in the lab), physiological studies comparing patients with and without T2D, and by harnessing the power of genetics to test our findings in large groups of patients. Our metabolomics analyses of large numbers of relevant molecules will potentially reveal new biomarkers for the abnormalities. ?Metabolomic signatures? consisting of several biomarkers together can point to the underlying causes and consequences of T2D. Different metabolomic patterns between individuals with T2D can also explain some of the differences in severity or manifestation of T2D that they experience, one of the stated Department of Defense priorities. This work will thereby provide ways to understand how and why T2D develops, why it develops differently in different people, and how best to treat each individual patient based on these differences. In our project, we propose using these and other state-of-the-art approaches to support the CDMRP Mission to ?provide hope by promoting innovative research, recognizing untapped opportunities, creating partnerships, and guarding the public trust.? Our proposal to establish this research partnership will broaden our previous collaboration between McGill and Harvard to advance T2D research. It will provide an exceptional opportunity for early-career researchers, including clinician-scientists to learn new approaches to conduct
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710348
Entities
People
- James B. Meigs
Organizations
- Massachusetts General Hospital
- United States Army