Reducing Hyperinsulinemia and Insulin Resistance in Type 1 Diabetes Using Adjunctive Therapies - PROJECT SUMMARY/ABSTRACT Peripheral insulin administration and impaired insulin clearance lead to hyperinsulinemia and insulin resistance in individuals with type 1 diabetes (T1D). As independent risk factors for cardiovascular disease (CVD), hyperinsulinemia and insulin resistance contribute to the high burden of CVD experienced by this population. The long-term goal is to develop approaches to reduce the excess risk of CVD in T1D. As the next step toward this goal, the overall objective of this proposal is to quantify the ability of combination adjunct-to-insulin therapy to reduce hyperinsulinemia and insulin resistance in T1D. The central hypothesis is that combination adjunctive therapy will (1) mitigate peripheral hyperinsulinemia via decreased insulin dosing and increased insulin clearance and (2) improve insulin resistance in muscle, adipose, and liver tissues. The rationale for this work is that gaining insight into the relationship between hyperinsulinemia and insulin resistance will inform new treatment strategies to mitigate the risk of CVD in T1D. The central hypothesis will be tested in a double-blind, placebo-controlled, crossover study in which participants with T1D will receive combination adjunct-to-insulin therapy and double placebo treatment, in random-order. The following specific aims will be pursued: (1) Quantify the reduction in hyperinsulinemia induced by combination adjunctive therapy and (2) Quantify the effect of reducing hyperinsulinemia on tissue-specific insulin resistance. For the first aim, ambulatory insulin dosing and circulating insulin concentrations will be measured, and the metabolic clearance rate of insulin will be calculated to determine the relative contribution of insulin dosing and insulin clearance in reducing hyperinsulinemia. For the second aim, insulin sensitivity will be measured in adipose, hepatic, and skeletal muscle tissue using hyperinsulinemic-euglycemic clamps with stable isotope tracer. This research is innovative because it leverages a unique therapeutic intervention (combination adjunct-to-insulin therapy) to achieve meaningful improvements in insulin clearance, hyperinsulinemia, and insulin resistance in T1D. This research is significant because it is expected to demonstrate a novel treatment approach and justify the study of adjunctive therapies to mitigate hyperinsulinemia, insulin resistance, and potentially CVD risk in T1D. The proposed studies will also provide a framework for mentored research training. The principal investigator (PI) seeks to gain expertise in advanced human metabolic research techniques to study insulin clearance, insulin resistance, and CVD in T1D. The PI has established a comprehensive training plan and a multidisciplinary mentorship team with diverse but complementary expertise to achieve the research and career development goals and transition to independence. This training will prepare the PI to pursue high impact research using novel therapies to mitigate hormonal and metabolic imbalances in T1D, with the mission of improving the health and wellbeing of people living with the disease.
