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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Type 1 diabetes - Placebo arm | Placebo Comparator | Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase |
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| Type 1 diabetes - Liraglutide arm | Active Comparator | Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase |
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| Type 2 diabetes - Placebo arm | Placebo Comparator | Subjects will receive syringes loaded with saline to self-administer daily during the intervention phase |
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| Type 2 diabetes - Liraglutide arm | Active Comparator | Subjects will receive 0.6mg Liraglutide syringes to self-administer daily during the intervention phase |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Liraglutide Pen Injector | Drug | Liraglutide 0.6mg |
|
| Measure | Description | Time Frame |
|---|---|---|
| Effect of exendin 9-39 on fasting glucagon secretion rate before and after liraglutide treatment | Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during fasting (-30 to 0 min) of each study day. | 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) |
| Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia before and after liraglutide | Glucagon secretion rate will be estimated by deconvolution from glucagon concentrations during hyperglycemia (150 to 180 min) of each study day. | 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of exendin 9-39 on fasting glucagon secretion rate 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 | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Adrian Vella, MD | Contact | 507-255-6515 | vella.adrian@mayo.edu |
| Name | Affiliation | Role |
|---|---|---|
| Adrian Vella, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Recruiting | Rochester | Minnesota | 55905 | United States |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000069450 | Liraglutide |
| ID | Term |
|---|---|
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
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Intervention will be assigned in single-blind fashion (Placebo pens for liraglutide are unavailable). A placebo syringe created by Research Pharmacy in addition to 'masked' liraglutide pens will be used over 4-weeks
| Saline Injections | Other | Saline in syringes to serve as placebo for single blind study |
|
|
| Effect of exendin 9-39 on glucagon secretion rate during hyperglycemia 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 | 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 |
| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |