Type 1 Diabetes, Type 2 Diabetes
Conditions
Keywords
Islet Function, Glucose Toxicity
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.
Interventions
Liraglutide 0.6mg
OTHERSaline Injections
Saline in syringes to serve as placebo for single blind study
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
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
Eligibility
Sex/Gender
ALL
Age
25 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Contacts
Primary ContactAdrian Vella, MD
Outcome results
None listed