Clinical Trials

The investigators' prior research has focused on defining the changes in expression of nuclear encoded mitochondrial genes that predict changes in insulin sensitivity in skeletal muscle, with the goal of defining the molecular mechanisms underlying the connection between mitochondrial dysfunction and insulin resistance in skeletal muscle. The purpose of this study is to determine whether experimental lipid oversupply decreases mitochondrial respiratory function. We will use mitochondrial respiration studies in vitro and mass spectrometry and proteomics analysis to test the hypothesis that experimental lipid oversupply: 1. Decreases mitochondrial respiration in response to lipid fuels. 2. Reduces abundance of mitochondrial proteins. 3. Alters phosphorylation of proteins in the electron transport chain. Three groups of subjects will be studied: lean, healthy control subjects (n=12), obese non-diabetic subjects (n=12) and patients with type 2 Diabetes Mellitus (n=12) for a total of 36 subjects. Twenty subjects have completed the study at Arizona State University; the remaining 16 subjects will be accrued at the Mayo Clinic in Arizona. Subjects will come to the Mayo Clinic 2 times. On study Day 1 subjects will be screened with a medical history and physical exam, and a 75 g oral glucose tolerance test, measure body fat percentage, and an electrocardiogram (EKG). On Study Day 2, subjects will report to the clinic after an overnight fast. Female subjects will take a urine pregnancy test. A muscle biopsy will be performed to take a small sample from one thigh. A lipid infusion will be performed for 5 hours (60 ml/hr), with blood samples taken at 8 intervals during the infusion. At the end of the 5 hour period, a second muscle biopsy will be taken from the other thigh. The fat infusion will stop, subjects will be given lunch and allowed to leave the clinic.

Type 2 Diabetes and cardiovascular disease are closely linked. A common abnormality in both conditions is insulin resistance. The primary cause of insulin resistance in not known. A significant question is what dietary components contribute to the development of insulin resistance. Based on epidemiologic data, it seems that the type of dietary fat is a significant contributor to the development of insulin resistance. However, some researchers argue that the main determinant is total amount of fat, not the composition. This study is intended to determine if the main types of fat (saturated, monounsaturated and polyunsaturated) ingested over a short time can cause insulin resistance in lean, healthy people. It has been demonstrated that 6 hours of intravenous fat infused into lean, healthy subjects can result in insulin resistance, as well as blood pressure elevation and endothelial dysfunction. Whether this is so with oral fat is not known. The question is important because there is debate about whether the type of fat is as important as the quantity of fat in a person's daily diet. Settling this debate will enhance the ability of health care personnel to determine the optimal dietary recommendations. This study will make use of a high fat diet consisting of vegetable oils high in the 3 main fatty acids in plasma (palmitate, oleate and linoleate). Because large fat loads can cause intestinal discomfort, a feeding tube will be used to bypass the stomach. The 3 oils will be assigned randomly following a base line study with saline 2 weeks prior to the intervention. Our primary endpoint is insulin resistance, which will be measured by a euglycemic, hyperinsulinemic clamp. Secondary measures will include changes in blood pressure and in vascular reactivity as measured by ultrasound after brief occlusion of a forearm vessel. The changes will be compared to baseline and to the other 2 groups.

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will compare Somalians and NE Americans who are matched for age, BMI, and sex. The investigators will measure ROS production in skeletal muscle following high fat/high glycemic diet vs. healthy diet. The investigators will compare the oxidative damage to proteins, DNA, and lipids in these two populations following 10 days of high fat/high glycemic index diet in comparison with low fat diet. The investigators will determine if elevated levels of oxidative damage in Somali immigrant populations is accompanied by high mitochondrial capacity, higher ROS-emitting potential, and lower insulin sensitivity than NE. The proposed study will be performed utilizing the state-of-the-art proteomic and metabolomic methods many of which were recently developed in our laboratory. The investigators expect the results from this study to provide seminal insights into the underlying mechanism of insulin resistance and type 2 diabetes, in addition to demonstrating mechanisms by which a functional proteome is maintained in vivo.

The investigators' prior research has focused on defining the changes in expression of nuclear encoded mitochondrial genes that predict changes in insulin sensitivity in skeletal muscle, with the goal of defining the molecular mechanisms underlying the connection between mitochondrial dysfunction and insulin resistance in skeletal muscle. Three groups of subjects will be studied: lean, healthy control subjects (n=12) obese non-diabetic subjects (n=12) and patients with type 2 Diabetes Mellitus (n=12) for a total of 36 subjects. Twenty subjects have completed the study at Arizona State University; the remaining 16 subjects will be accrued at the Mayo Clinic in Arizona. Subjects will come to the Mayo Clinic 4 times. On Study Day 1 Subjects will be screened with a medical history & physical and a 75 g oral glucose tolerance test to determine if they are eligible for the study. On Study Day 2, subjects will report to the clinic after an overnight fast, undergo a euglycemic clamp (using deuterated glucose) to determine insulin sensitivity, and in addition have a muscle biopsy (basal biopsy for comparison). On Study Day 3, subjects will report to the clinic after an overnight fast, and undergo a Volume Oxygen Maximum (VO_2 max) determination. On Study Day 4, subjects will report to the clinic after an overnight fast to perform an exercise bout with muscle biopsy 30 minutes after the end of exercise. This will be followed by an overnight fast, and an additional muscle biopsy at 24 hours post exercise.