GLP-1Ra Impact on Metabolic Outcomes in Stage 2 T1DM While Receiving Teplizumab

The goal of this study is to determine how a drug class called glucagon-like peptide-1 receptor agonists (GLP-1Ra) affects people during an early stage of Type 1 Diabetes undergoing clinical teplizumab treatment. This study involves giving participants a liquid meal under three different conditions and observing how their bodies respond, focusing on blood sugar levels, insulin effectiveness, and blood vessel function. The first meal test is pre-teplizumab, followed by two post-treatment tests, one with the GLP-1Ra drug and the other with a placebo. Each test involves blood draws before and during the meal test, GLP-1Ra or placebo administration, and an ultrasound to measure blood vessel function. The goal is to see if GLP-1Ra can help manage blood sugar levels and improve cardiovascular health in this population.

The long-term goal is to determine whether repurposing GLP-1Ra for stage 2 T1DM in combination with immunotherapy can modify the disease course, reducing the need for exogenous insulin therapy and leading to improved cardiometabolic outcomes and quality of life. The immediate objective is to investigate the impact of GLP-1Ra's insulinotropic and glucagonostatic effects on dysmetabolism in stage 2 T1DM patients treated with teplizumab. The study hypothesizes that these effects will each delay the need for exogenous insulin by improving three key aspects of dysmetabolism: 1) postprandial glycemia, 2) disposition index (i.e., the ability of the islet cells to compensate for a given insulin sensitivity), and 3) endothelial function. The rationale for this hypothesis is based on two observations: first, GLP-1Ra combined with immunomodulatory therapy sustains endogenous secretion in response to a mixed meal tolerance test (MMTT) during the first year of stage 3; and second, GLP-1Ras mitigate postprandial hyperglucagonemia in longer-duration T1DM. To test the hypothesis, studies will be conduct in individuals with stage 2 T1DM treated with teplizumab using a crossover design structured around the following specific aims:

Aim 1: Investigate the impact of GLP-1Ra on postprandial glycemia in a pilot study. The study team will measure postprandial glycemia during an MMTT before teplizumab treatment. After teplizumab the study team will compare the effects of placebo versus semaglutide (a GLP-1Ra).

Aim 2: Study the impact of GLP-1Ra on the disposition index (DI) in a pilot study. The study team will use the oral glucose minimal model to measure DI during an MMTT before and after teplizumab treatment, comparing the effects of placebo versus semaglutide. As an exploratory outcome, β-cell endoplasmic reticulum dysfunction will be quantified by measuring the proinsulin-to-C-peptide ratio during the MMTT.

Aim 3: Determine the impact of GLP-1Ra on endothelial function in a pilot study. The stud team will use B-mode ultrasound to measure flow mediated vasodilation (FMD), a bioassay of endothelial function, during each MMTT. Because endothelial cells are often among the first affected by hyperglycemia and insulin resistance, the study aims to illuminate how GLP-1Ra may mitigate early vascular disease progression.

Eligibility Criteria:
Inclusion Criteria:

* Age: 12-50 years
* BMI: 18-31 kg/m2 (adults) or 5-95th %ile (pediatric)
* Stage 2 T1DM (i.e., ≥ 2 islet auto-antibodies and:
* fasting glucose ≥ 100 mg/dL and \< 126 mg/dL OR
* 2-hr OGTT /MMTT ≥ 140 mg/dL and \< 200 mg/dL OR
* During an OGTT having a glucose of \> 199 mg/dL at 30, 60, or 90 minutes)

Exclusion Criteria:

* Comorbidities:
* SBP \> 140 mmHg and DBP \> 100 mmHg
* eGFR by MDRD equation of \< 60 mL/min/1.73m2
* AST or ALT \> 2.5 times ULN
* Family history of medullary thyroid carcinoma
* Diagnosis of pancreatitis or gastroparesis within the past 3 years
* Medications: Any diabetes medication, any antioxidant vitamin supplement (\<2 weeks before a study), any systemic glucocorticoid, antipsychotic, atenolol, metoprolol, propranolol, niacin, any thiazide diuretic, any OCP with \> 35 mcg ethinyl estradiol, growth hormone, any immunosuppressant, antihypertensive, any antihyperlipidemic
* Other: pregnancy, peri- or post-menopausal women, active smoker