This single-center, double-blind, placebo-controlled, multi-dose study is designed to evaluate the effects of glucagon antagonism on insulin sensitivity, cardiovascular risk and ketogenesis in individuals with Type 1 Diabetes. To accomplish the specific aims proposed, a single clinical trial will be conducted in which a maximum of 30 subjects with T1D, who are otherwise healthy, will be treated with REMD-477 or matching placebo for up to 12 weeks at a dose of 70mg (administered subcutaneously each week) with assessments done pre- and post-therapy. Subjects will be randomized on a 1:1 basis to either the REMD-477 group or placebo group and all subjects will remain on their standard of care insulin therapy throughout the study. There will be 19 study visits as outlined below:~Screening - Complete consenting process, complete medical history and physical exam, review of current medications, collect height/weight, vital signs, and fasting laboratory (blood and urine) tests.~Baseline Visit 1 - Participants that meet screening criteria will complete cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.~Baseline Visit 2 - Participants will complete a 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.~Baseline Visit 3 - Insulin withdrawal challenge and injection #1 of REMD-477 or placebo. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.~Visit 4 - Injection #2 of REMD-477 or placebo and blood collection for safety labs.~Visit 5 - Injection #3 of REMD-477 or placebo.~Visit 6 - Injection #4 of REMD-477 or placebo and blood collection for safety labs.~Visit 7 - Injection #5 of REMD-477 or placebo.~Visit 8 - Injection #6 of REMD-477 or placebo and blood collection for safety labs.~Visit 9 - Injection #7 of REMD-477 or placebo.~Visit 10 - Injection #8 of REMD-477 or placebo and blood collection for safety labs.~Visit 11 - Injection #9 of REMD-477 or placebo.~Visit 12 - Injection #10 of REMD-477 or placebo and blood collection for safety labs.~Visit 13 - Injection #11 of REMD-477 or placebo.~Visit 14 - Injection #12 of REMD-477 or placebo and blood collection for safety labs.~Visit 15 - Repeat cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.~Visit 16 - Repeat 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.~Visit 17 - Repeat Insulin withdrawal challenge. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.~Visit 18 - Safety follow-up visit that includes physical exam, vitals, blood and urine sample collection.
This study will examine the effects a Glucagon Receptor Antagonist (GRA), has on Insulin Sensitivity, Cardiovascular risks (CVD), and Ketone body formation in participants with Type 1 diabetes. The participants will complete blood tests, tests to measure energy expenditure, CVD risks, and insulin resistance. These tests will be performed prior to start of treatment and again after 12-weeks of treatment with the GRA (called REMD-477).