The Effect of Glycemic Control and of GLP-1 Receptor Agonism on Islet GLP-1 in People With Type 1 and Type 2 Diabetes

Phase 2

Not yet recruiting

• Conditions: Type 1 Diabetes; Type 2 Diabetes
• Interventions: Other: Saline Injections; Drug: Liraglutide Pen Injector

• Registration Number: NCT06976619
• Lead Sponsor: Mayo Clinic

Brief Summary

The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets. However, its regulation is at present unknown. There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell3. It is unclear if the effects of GLP1R agonism on islet GLP-1 differ in Type 1 diabetes (T1DM) compared to T2DM. This experiment will examine the effect of glycemic control ± a GLP1R agonist on islet GLP-1 in people with (T2DM) and without (T1DM) β-cells.

Detailed Description

The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. This supports other evidence (rodents and humans) that through the (inducible) expression of a prohormone convertase (PC-1/3), the α-cell can process proglucagon to intact GLP-15,6. 'Islet' or 'pancreatic' GLP-1 acts in a paracrine fashion to regulate insulin (basal and 1st phase) and glucagon secretion. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets.

There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell. β-cell secretion of the signaling peptide 14-3-3-Zeta is decreased by GLP1R agonism (Fig.1), stimulating α-cell production of GLP-1. This is a testable hypothesis in humans; people with type 1 diabetes (T1DM) have dysregulated glucagon secretion and evidence of islet GLP-1. It is unclear if the effects of GLP1R agonism on islet GLP-1 differ compared to T2DM. This experiment will examine the effect of glycemic control ± a GLP1R agonist on islet GLP-1 in people with (T2DM) and without (T1DM) β-cells.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-05
• Study First Submitted QC: 2025-05-13
• Last Update Submitted: 2025-05-13
• Study First Posted: 2025-05-16
• Last Update Posted: 2025-05-16
• Study Start: 2025-09-01
• Primary Completion: 2028-10-30
• Study Completion: 2029-03-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Type 1 or type 2 diabetes treated with insulin

Exclusion Criteria

1. Age < 25 or > 70 years.
2. HbA1c > 10.0%
3. For female subjects: positive pregnancy test at the time of enrollment or study
4. History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
5. Prior use of GLP-1 receptor agonists in the previous year.
6. Active systemic illness or malignancy.
7. Symptomatic macrovascular or microvascular disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Type 1 diabetes - Placebo arm	Saline Injections	Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase
Type 1 diabetes - Liraglutide arm	Liraglutide Pen Injector	Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase
Type 2 diabetes - Placebo arm	Saline Injections	Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase
Type 2 diabetes - Liraglutide arm	Liraglutide Pen Injector	Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase

Primary Outcome Measures

Name	Time	Method
Effect of exendin 9-39 on fasting glucagon secretion rate before and after liraglutide treatment	The change in fasting glucagon secretion rate (saline vs. exendin 9-39) in the baseline study will be compared with the change in fasting glucagon secretion rate (saline vs. exendin 9-39) after 30 days of treatment with liraglutide (post-liraglutide)	Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during fasting (-30 to 0 min) of each study day.
Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia before and after liraglutide	The change in glucagon secretion rate during hyperglycemia (saline vs. exendin 9-39) in the baseline study will be compared with the change (saline vs. exendin 9-39) after 30 days of treatment with liraglutide (post-liraglutide)	Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during hyperglycemia (150 to 180 min) of each study day.

Secondary Outcome Measures

Name	Time	Method
Effect of exendin 9-39 on fasting glucagon secretion rate in people with type 1 diabetes vs type 2 diabetes	The change in fasting glucagon secretion (saline vs. exendin 9-39) in the baseline studies will be compared in people with type 1 diabetes vs type 2 diabetes	Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during fasting (-30 to 0 minutes) during the baseline studies
Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia in people with type 1 diabetes vs type 2 diabetes	The change in glucagon secretion during hyperglycemia (saline vs. exendin 9-39) in the baseline studies will be compared in people with type 1 diabetes vs type 2 diabetes	Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during hyperglycemia (150 to 180 minutes) during the baseline studies

Trial Locations

Locations (1)

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States