Insulin Resistance Clinical Trials

Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. In this study, the investigators hypothesize that metformin treatment in subjects free of type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects. Further, the investigators hypothesize that long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. The investigators will use a dual-site, 12- week drug intervention trial performed in a double-blind, placebo-controlled manner on 148 subjects recruited from two separate sites (Oklahoma Medical Research Foundation (OMRF) and University of Wisconsin-Madison (UWM)). After consent and initial subject screening for chronic disease, subjects will be stratified to insulin sensitive (IS) or insulin resistant (IR) groups. Over a 12- week intervention, half of each group will take metformin and half will take a placebo. Pre- and post--intervention, subjects will complete a series of procedures to assess insulin sensitivity, glucose regulation, and biomarkers of aging. The same subjects will provide a skeletal muscle biopsy pre-- and post-intervention to assess the change in mitochondrial function and mitochondrial remodeling with and without metformin treatment. By completion of this project, the investigators expect to provide evidence that helps further delineate who may benefit from metformin treatment to slow aging. Read Less

In this study, we investigate the impact of insulin resistance on the acceleration of brain aging, and test whether increased neuron insulin resistance can be counteracted by utilization of alternate metabolic pathways (e.g., ketones rather than glucose). This study has three Arms, which together provide synergistic data. For all three Arms, subjects are tested in a within-subjects design that consists of 2-3 testing sessions, 1-14 days apart, and counter-balanced for order. During each session we measure the impact of fuel (glucose in one session, ketones in the other) on brain metabolism and associated functioning. For Arms 1-2, our primary experimental measure is functional magnetic resonance imaging (fMRI), which we will use to trace the self-organization of functional networks following changes in energy supply and demand. Arm 1 tests the impact of endogenous ketones produced by switching to a low carbohydrate diet, while Arm 2 tests the impact of exogenous ketones consumed as a nutritional supplement. For Arm 3, we use simultaneous magnetic resonance spectroscopy/positron-emission tomography (MR/PET) to quantify the impact of exogenous ketones on production of glutamate and GABA, key neurotransmitters. Subjects will be given the option to participate in more than one of the Arms, but doing so is not expected nor required. Prior to scans, subjects will receive a clinician-administered History and Physical (H&P), which includes vital signs, an oral glucose tolerance test (OGTT), and the comprehensive metabolic blood panel. These will be used to assess diabetes, kidney disease, and electrolytes. If subjects pass screening, they will be provided the option to participate in one or more Arms, which include neuroimaging. To provide a quantitative measure of time-varying metabolic activity throughout the scan, based upon quantitative models of glucose and ketone regulation, as well as to be able to implement safety stopping rules (see below), we will obtain pin-prick blood samples three times: prior to the scan, following consumption of the glucose or ketone drink, and following completion of the scan. To assess effects of increased metabolic demand, we measure brain response to cognitive load, transitioning from resting-state to spatial reasoning through a Tetris task. To assess effects of increased metabolic supply, we measure brain response to glucose or ketone bolus. Read Less

The purpose of this study is to examine the hypothesize that 4 weeks of sympathetic nerve activity (SNA) inhibition (oral clonidine) will cause a significant reduction in circulating blood concentrations and endothelial cell expression of inflammatory markers (e.g., TNF-α, IL-6). Our study is a prospective study using a randomized, double-blinded design to test 4 weeks of SNA blockade (oral clonidine) compared with a BP-lowering control condition (diuretic, hydrochlorothiazide) or a placebo. Read Less