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

Mayo Clinic

Status and phase: Enrolling; Phase 2

Conditions: Type 1 Diabetes; Type 2 Diabetes

Treatments: Drug: Liraglutide Pen Injector; Other: Saline Injections

Study type: Interventional

Funder types: Other

Identifiers

NCT06976619

24-007682

Details and patient eligibility

About

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.

Full 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.

Enrollment: 60 estimated patients

Sex: All

Ages: 25 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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60 participants in 4 patient groups, including a placebo group

Type 1 diabetes - Placebo arm

Placebo Comparator group

Description:

Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase

Treatment:

Other: Saline Injections

Type 1 diabetes - Liraglutide arm

Active Comparator group

Description:

Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase

Treatment:

Drug: Liraglutide Pen Injector

Type 2 diabetes - Placebo arm

Placebo Comparator group

Description:

Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase

Treatment:

Other: Saline Injections

Type 2 diabetes - Liraglutide arm

Active Comparator group

Description:

Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase

Treatment:

Drug: Liraglutide Pen Injector