Functional Genetics for Predisposition to Development of Type 2 Diabetes in Obese Individuals
Abstract
Topic Area: Diabetes. Overview: Type 2 diabetes (T2D) is the most common endocrine disease in adults, defined mainly by high blood sugar. In the United States, T2D is rising at an alarming rate in both civilians and military Veterans. It is one of the most costly and deadly diseases, and it kills yearly more Americans than breast cancer and AIDS combined. T2D is continuing to be a major healthcare problem for military Veterans, a group where the disease propensity exceeds 2.5-fold that in the general population. In 2014, the US Department of Veterans Affairs alarmed that one in four men and women who served the country, or 25%, have diabetes compared to 16% in year 2004. According to the Centers for Disease Control and Prevention, in year 2050 one in three Americans will be diabetic if the present trend continues. Notably, current medications are generally unable to stop disease progression, resulting in poor blood-sugar control and degenerative complications, such as heart attack, blindness, amputation, and kidney disease. Changing the status quo demands tackling all causes that render obese individuals, both civilians and military Veterans, susceptible to T2D. Critical Question Addressed in This Study: T2D frequently occurs together with obesity. In fact, the vast majority (85%) of T2D individuals from both civilian and Veteran populations are or have been overweight or obese. Therefore, it is not a surprise that with the increased obesity rate in both the general adult population and Veterans in the United States, T2D has also climbed. Intriguingly, however, a puzzling fact is that most obese subjects (~70%), both Veterans and non-Veterans, will never develop T2D. Obese individuals with or without T2D share causative lifestyle factors, such as excessive food intake and sedentary lifestyle. But because only a minor fraction of obese Veterans and civilian adults will develop T2D, the critical importance of the genetic susceptibility and predisposition to T2D development in obesity now becomes recognized. This project addresses the fundamental but overlooked question, i.e., why some obese individuals have the prerogative to never be struck by the devastating T2D whereas others do not. We address this question by assessing, for the first time, genetic causes triggering T2D in obesity, focusing on three genes whose role in T2D has been inferred from genetically modified mouse models. The Principal Investigator (PI) and the Co-PI of this proposal were creative to design their study around the available abdominal fat from extremely obese human volunteers without and with T2D, who undergo elective laparoscopic bariatric surgery at a local hospital. Innovation: The innovation of this project lies in its clinical focus, which capitalizes on characterizing, for the first time, genetic predisposition to T2D development in obese adult individuals. Indeed, thus far, research efforts on the genetic causes in T2D have been typically centered on the lean population. Because obese populations, both civilian and military Veterans, are the ones prone to T2D, performing studies focused on T2D-causing genetic variations in obesity is a more adequate approach and a highly innovative one. Identification of T2D-causing mutations within the three genes that have been implicated in development of pre-diabetes in experimental animal models may turn out to be key predictors of whether or not an obese non-Veteran or Veteran will develop T2D. Applicability and Impact: The proposed high-risk/high-reward research will advance the understanding of the genetic mechanisms triggering development of T2D in obesity. The knowledge gathered from this work will accelerate the progress towards T2D prevention by providing novel therapeutic targets for drug discovery to foster innovative therapies. T2D-causing mutations in obesity within the genes proposed to be studied herein will provide better understanding of the hetero
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710060
Entities
People
- Assia Shisheva
Organizations
- United States Army
- Wayne State University