Title: Advancing the Use of Exercise Testing as a Tool to Assess Whole-Body Substrate Selectivity and Metabolic Function in Individuals at Risk for Developing Type 2 Diabetes
Description: Type 2 diabetes is a metabolic disease marked by an abnormally high level of glucose (sugar) in the blood. Type 2 diabetes is now reaching an epidemic level with more than 30 million adults in the United States afflicted and 1.5 million new cases documented every year. Type 2 diabetes is linked with obesity, heart disease, hypertension, and liver disease, and individuals with type 2 diabetes are at an increased risk for heart failure, stroke, blindness, kidney failure, and amputation. According to the Centers for Disease Control and Prevention, more than $245 billion was spent in the United States in 2012 on medical expenses related to diabetes and despite that, nearly a quarter of a million Americans are losing their lives due to this disease each year. Indeed, type 2 diabetes is one of the leading causes of death in the United States and worldwide; its prevalence has almost doubled in the last 35 years, from 4.7% of the total population in 1980 to 8.5% in 2014. Consequently, more than 400 million people are at high risk for severe health problems and complications, poor quality of life, and early death.

Research such as the Diabetes Prevention Program (DPP), the Finnish Diabetes Prevention Study (DPS), the Vesterbotten Intervention Program (VIP), and the Diabetes Prevention Program Outcome Study (DPPOS) suggests that type 2 diabetes can be delayed, and even prevented, with a lifestyle behavioral modification program that includes healthy eating and/or exercise. Therefore, focus has been shifted from management to prevention. An early manifestation of dysfunction in the progression of type 2 diabetes is insulin resistance, a metabolic impairment associated with obesity. Indeed, it is estimated that ~90% of people with type 2 diabetes also are obese. The link between insulin resistance and obesity is well-established; however, the mechanistic basis(es) underpinning this link is/are still debated with multiple candidate molecules, systems, and pathways potentially involved. One theory that has gained traction in recent years suggests that type 2 diabetes, and the insulin-resistant state that predates it, are rooted in dysfunctional lipid metabolism (i.e., a reduced capacity to use lipid for energy production in circumstances where lipid would be preferred, such as in the basal fasting condition, after a high-fat meal, and during light- and moderate-intensity exercise).

However, there are conflicting findings regarding the degree to which the ability to oxidize lipid during these circumstances is compromised for individuals with the overweight/obesity that is associated with the disease progression. The reason(s) for this ambiguity is/are unclear but might have to do with a number of factors that were poorly controlled when substrate selectivity (i.e., lipid vs. carbohydrate oxidation rates) were compared between normal-weight individuals and those with the overweight/obese condition. These include: (a) acute energy balance and macronutrient composition of the diet; (b) the intensity and duration of the exercise bout; and (c) subject characteristics including the amount of muscle tissue they possess, their cardiorespiratory fitness level, and, perhaps most importantly, their insulin-sensitivity state. The purpose of this dissertational work is to: (a) help to resolve this ambiguity by identifying the degree to which conflicting results that have been reported might be explained by factors that were left unaccounted for and/or inadequately controlled in previous research; and (b) compare substrate selectivity in normal-weight individuals and those with the overweight/obesity condition during a physiologically-equivalent exercise challenge with the aforementioned factors rigidly controlled.