Determination of Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Recent-Onset Type 1 Diabetes

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PROJECT SUMMARY/ABSTRACT Insulin resistance (IR) is consistently found in patients with type 1 diabetes (T1DM) and pathophysiologically links T1DM with atherosclerotic disease. IR and nascent atherosclerosis, as characterized by endothelial dysfunction, are present early in T1DM. Although atherosclerosis leads to excess cardiovascular disease (CVD) death in T1DM, its early cardiometabolic processes are not well-characterized currently. People with T1DM have high plasma insulin levels because they must inject insulin directly into the peripheral circulation, which bypasses hepatic extraction. Hyperinsulinemia is an independent risk factor for IR, endothelial dysfunction, and CVD in the nondiabetic population. Thus, we will test the hypothesis that iatrogenic hyperinsulinemia independently correlates with IR and endothelial function in T1DM and healthy individuals. To test this hypothesis, the study will determine how strongly short and long-term hyperinsulinemia exposure (quantified by average basal insulin concentration [INSbasal] and total daily dose of insulin, TDDinsulin, respectively) are related to insulin sensitivity (Aim 1) and endothelial dysfunction (Aim 2). In a T1DM substudy, we will study patients during three phases over the 12 months following diagnosis: initial diagnosis, partial clinical remission (PCR), and post-PCR. Each phase has distinct insulin exposure: 1) soon after diagnosis (TDDinsulin≈0.5 units/kg/day), 2) during PCR, a.k.a. “Honeymoon phase” (TDDinsulin<0.4 units/kg/day), and 3) following PCR (TDDinsulin>0.6 units/kg/day). In a Control Substudy, we will study euglycemic, healthy participants under four fixed conditions for hyperinsulinemia: short-term hyperinsulinemia, long-term hyperinsulinemia, a combination of both short and long-term hyperinsulinemia, and euinsulinemia. The hyperinsulinemic, euglycemic clamp technique will quantify insulin sensitivity at each study visit (Aim 1). For Aim 2, endothelial function will be determined in a variety of vascular beds. As a primary outcome, this investigation will quantify brachial artery endothelium-dependent flow-mediated vasodilation. As a secondary outcome, contrast enhanced ultrasound will quantify insulin-induced microvascular recruitment. The proposed studies will provide a focus for mentored research training. The primary investigator (PI) seeks to become an independent physician-scientist with the expertise to investigate the relationship between metabolic dysregulation and endothelial dysfunction in T1DM. A comprehensive, mentored training program has been devised for the PI to transition from his background in canine physiology research to translational human subjects research (goal 1) and develop proficiency applying advanced cardiovascular research techniques to study preclinical vascular dysfunction (goal 2). This training will prepare the PI to use state-of-the-art techniques to quantify the metabolic and cardiovascular benefit of future therapies to lessen iatrogenic hyperinsulinemia.