Clinical trial NCT06976619: The Effect of Glycemic Control and of GLP-1 Receptor Agonism on Islet GLP-1 in People With Type 1 and Type 2 Diabetes
Official title: The Effect of Glycemic Control and of GLP-1 Receptor Agonism on Islet GLP-1 in People
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Type 1 Diabetes
Type 2 Diabetes
Keywords: Islet Function
Glucose Toxicity
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2025-05-16
Enrollment: 60
Sex: ALL
Minimum age (years): 25
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Effect of exendin 9-39 on fasting glucagon secretion rate before and after liraglutide treatment
timeFrame: 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)
measure: Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia before and after liraglutide
timeFrame: 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)
Secondary outcomes:
measure: Effect of exendin 9-39 on fasting glucagon secretion rate in people with type 1 diabetes vs type 2 diabetes
timeFrame: 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
measure: Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia in people with type 1 diabetes vs type 2 diabetes
timeFrame: 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
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adrian Vella, MD
role: PRINCIPAL_INVESTIGATOR
References: