GLP-1 RA for Stage 1 Type 1 Diabetes

Leveraging Semaglutide for Preservation of Beta Cell Function and Restoration of Alpha Cell Function

This study seeks to evaluate the hormone responses of insulin, c-peptide, glucagon, and incretins to semaglutide, a GLP-1 receptor agonist therapy, in individuals with stage 1 type 1 diabetes. The goal of this study is to see if semaglutide can protect beta cell function in this group of people and delay the progression to stage 2 type 1 diabetes.

This study aims to evaluate the effects of semaglutide on pancreatic beta and alpha cell function in individuals with stage 1 type 1 diabetes (T1D). Despite having euglycemia, individuals with stage 1 T1D may already exhibit loss of the first phase insulin response (FPIR). Incretins play a significant role in FPIR through their effects on insulin secretion and sensitivity, offering a potential therapeutic target for restoration of FPIR. Furthermore, prior studies have demonstrated that individuals with T1D exhibit inappropriate glucagon release in response to glucose, worsening glycemic control. Not only do incretins affect beta cells, but they can also inhibit glucagon secretion, potentially attenuating this dysregulated glucagon response. Studies have shown safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T1D and their beneficial effects on reducing inflammation and preserving beta cell function. However, no studies have evaluated the effects of GLP-1 RAs on beta cell function and glucagon secretion in stage 1 type 1 diabetes to date. As incretins can inhibit glucagon secretion, we hypothesize that semaglutide may attenuate dysregulated glucagon responses, thereby improving glycemic control and potentially altering disease progression. To evaluate the effects of semaglutide in stage 1 T1D, we propose the following aims:

1. Define the effect of semaglutide on beta cell function. We hypothesize that semaglutide may restore FPIR and preserve beta cell function. A 2 hour, 7-point oral glucose tolerance test (OGTT) at baseline and after 12 months of semaglutide will be used to evaluate FPIR and beta cell function through serial measurements of insulin, pro-insulin, C-peptide, glucose, GLP-1, and GIP.
2. Identify the effect of semaglutide on glucagon secretion in response to glucose. We hypothesize that semaglutide will suppress glucose-stimulated glucagon release. We will evaluate this by measuring stimulated glucagon levels via a 2 hour, 7-point OGTT and by measuring pre and post OGTT liver glycogen content via liver MRI at baseline and after 12 months of semaglutide therapy.

Inclusion Criteria:

• Stage 1 Type 1 Diabetes
• Screening OGTT with impaired or loss of first phase insulin secretion but no dysglycemia to suggest stage 2 or stage 3 type 1 diabetes

Exclusion Criteria:

• History of anaphylaxis or allergies to GLP-1 receptor agonists
• Already on a GLP-1 receptor agonist
• History of bariatric surgery
• Personal or family history of cancer such as medullary thyroid cancer
• Personal history of pancreatitis or pathogenic variants associated with increased risk of pancreatitis
• Severe hypoglycemia within 3 months of study enrollment
• Pregnant, breastfeeding, or the intention of becoming pregnant or not using adequate contraceptive measures
• Adult individuals with BMI < 18.5 kg/m2 and pediatric participants with BMI < 5th percentile