Peripheral Insulin Delivery's Contribution to Insulin Resistance in Type 1 Diabetes

The goal of this pilot and feasibility proposal is to determine the pathophysiologic mechanisms underpinning insulin resistance (IR) in type 1 diabetes (T1DM), a consistent but under-recognized problem in this condition and a major predisposing factor to macrovascular disease, the leading cause of death in these patients. My research will test the hypothesis that IR in T1DM is predominantly a consequence of iatrogenic hyperinsulinemia in the peripheral circulation (as opposed to an effect of chronic hyperglycemia, as is commonly thought). I will test this hypothesis using a novel cross-sectional study design evaluating IR in 3 groups: subjects with T1DM, glucokinase mutations, and non-diabetic controls. I will utilize the hyperinsulinemic, euglycemic clamp to exploit key metabolic differences between these 3 groups and determine the etiology of T1DM IR at whole-body and tissue-specific levels. These studies will increase our understanding of IR in T1DM and how novel therapeutic approaches could alleviate this obstacle to optimal cardiovascular health for patients who live with this condition.