Insulin SecretionPhase 1NCT04347252
Glucagon Regulation of Glucose Metabolism
A Phase 1 study testing Glucagon in people with Insulin Secretion, run by David D'Alessio, M.D. at 1 site in United States.
Trial summary
Glucagon is a 30 amino acid peptide hormone that is produced exclusively in alpha-cells of the pancreatic islets. Glucagon binds to a G-protein coupled receptor and activates intracellular signaling by increasing the synthesis of cyclic AMP by adenylate cyclase. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Insulin Secretion
- What is being tested?
- Glucagon
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Sep 2019to 16 Apr 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy, fasting glucose values ≤ 95 mg/dL or A1c ≤ 5.9%, and no first degree family members with T2DM.
Who cannot join
- Active infectious, malignant or inflammatory conditions; unstable angina or uncompensated heart failure; pulmonary disorders including COPD and asthma; malabsorptive GI disease; significant hepatic disease; renal insufficiency (eGFR < 60 ml/kg/min); anemia (hematocrit < 34%); pregnancy; and uncontrolled hypertension. Subjects will be excluded if they require daily medications that alter glucose metabolism or GI function (glucocorticoids, psychotropics, narcotics, metoclopramide).
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke Center for Living
Durham, North Carolina, 27705
About this study
Official title: Incretin Action in Physiology and Diabetes
Glucagon is a 30 amino acid peptide hormone that is produced exclusively in alpha-cells of the pancreatic islets. Glucagon binds to a G-protein coupled receptor and activates intracellular signaling by increasing the synthesis of cyclic AMP by adenylate cyclase. The glucagon receptor is most prominently expressed by hepatocytes and the cardinal action of glucagon is to stimulate hepatic glucose output by increasing glycogenolysis and gluconeogenesis. A deep body of literature supports physiologic actions of glucagon to maintain fasting blood glucose and counter-regulate hypoglycemia, and the current view of glucose metabolism is that insulin and glucagon have opposing and mutually balancing effects on glycemia. However, it has long been appreciated that glucagon actually stimulates insulin secretion and islet β-cells express the glucagon receptor and respond to its activation by increasing cAMP.
The most potent stimulus for glucagon release is hypoglycemia and both low glucose per sé, as well as sympathetic nervous system activity are potent activators of the alpha-cell. However, glucagon is also stimulated by elevations of circulating amino acids, including after protein containing meals; this setting is one in which the release of glucagon during a period of elevated glycemia could contribute to postprandial insulin secretion. In fact, we have demonstrated that normal mice injected with glucagon while fasting (BG 75 mg/dl) have a prompt rise in blood glucose, whereas mice given glucagon while feeding (BG 150 mg/dl) increase insulin output 3 fold and have a decrease in glycemia. Moreover, in studies with isolated mouse and human islets we have demonstrated that glucagon stimulates insulin release by activating both the glucagon and GLP-1 receptors. This counter-intuitive observation has been reported by several other groups as well as ours.
In the studies proposed herein we wish to extend our novel observations to humans. The possibility that glucagon acts in the fed state to promote insulin secretion and glucose disposal would change current views of physiology in both healthy and diabetic persons. Moreover, since one of the more promising area of drug development is the creation of peptides that activate multiple receptors (GLP-1 + glucagon, GLP-1 + GIP + glucagon) the results of our studies have potential implications for therapeutics as well.
Read the detailed description
Subjects will have a screening visit for history, medication usage, and blood work; those who qualify will be offered participation. Subjects will be instructed to consume their usual diet, including at least 200 g carbohydrate, and not to engage in strenuous physical activity for the 3 days prior to a study. After an overnight fast they will present to the CRU at the Stedman Building on the Center for Living campus and have intravenous catheters placed in both forearms, one for infusion of test substances and the other for blood sampling; the sampling arm will be warmed with a heating pad to improve venous blood flow. All studies will start following withdrawal of several basal samples over an extended period:
- Glucagon infusion in fasting and hyperglycemic subjects: dose finding. Subjects receive graded doses of intravenous glucagon after a 12-14 hour fast. Doses will start at 10 ng/kg/min and be increased to 50 and 100 ng/kg/min at 30 minute intervals. Glucose concentrations will be measured at the bedside using a YSI glucose analyzer. Plasma samples will be collected at 10 minute intervals for assay of insulin, C-peptide, and glucagon. These pilot studies will provide insight into the relative sensitivity of hepatic glucose production (fasting study) and insulin secretion (glucose infusion study) to glucagon. These studies will include up to 10 volunteers each.
- Effects of glycemia to mediate glucagon-stimulated hepatic glucose production (HGP) and insulin secretion. Following placement of intravenous catheters subjects will have an infusion of saline with a tracer dose of deuterated glucose for the remainder of the 300 minute protocol. [6, 6]2H2 glucose will be started as a 4 mg/kg bolus over 5 minutes followed by a continuous infusion of 0.020-0.4 mg/kg/min. After a 2 hour equilibration period to label the glucose pool, subjects will have A) saline infusion, B) initiation of a hyperglycemic clamp, C) infusion of exendin-(9-39) 750 pmol/kg/min and a hyperglycemic clamp. The clamp will be generated with the infusion of a 20% solution of dextrose enriched to 2% with deuterated glucose. The infusion rate will be started at 30 mg/kg/h and adjusted every 5 minutes until the blood glucose reaches ~150 mg/dl; the infusion will be adjusted thereafter to maintain this level of glycemia. Blood samples will be taken at 10 minute intervals throughout the study to measure: enrichment with [6, 6]2H2 glucose, insulin, glucagon and C-peptide. After 120 minutes of A) tracer alone, B) hyperglycemia, or C) exendin-9 plus hyperglycemia, subjects will receive glucagon as an infusion of 10-100 ng/kg/min for 30 or 60 minutes.
The primary outcome variables from these experiment will be HGP and insulin secretion. The hypothesis to be tested is that glucagon given at fasting glucose levels will cause a rapid rise in HGP and blood glucose (50-150 mg/dl over basal) with a secondary rise of insulin secretion that follows the change in glycemia; and that glucagon given at mild hyperglycemia will promptly stimulate insulin secretion and limit the response of HGP. The protocol and predictions of results are depicted below.
- Conditions
- Insulin Secretion
- Being tested
- Glucagon
- Keywords
- glucagon, GLP-1 receptor, insulin secretion, glucose tolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlucagonDrug
Also called exendin-(9-39); hyperglycemia
Intravenous infusion of glucagon at fasting or elevated glycemia. Blockade of the GLP-1 receptor during hyperglycemia with and without glucagon.
| Study group | Role | What they receive |
|---|---|---|
| Glucagon at basal glycemia | Experimental | Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. Receives: Drug: Glucagon |
| Glucagon at hyperglycemia | Experimental | Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. Receives: Drug: Glucagon |
| Glucagon at hyperglycemia with GLP-1R blockade | Experimental | Subjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study; concurrently exendin-(9-39) will be infused at 750 pmol/kg/min, also for the remaining 180 minutes. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. Receives: Drug: Glucagon |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in insulin secretion
Derived from plasma insulin and C-peptide concentrations
Measured: before and after glucagon administration, up to 1 hour
hepatic glucose production
Derived from isotope dilution based on deuterated glucose enrichment
Measured: before and after glucagon administration, up to 1 hour
Secondary outcomes (2)
Change in Glucagon concentrations
Assay of plasma concentrations
Measured: before and after glucagon administration, up to 1 hour
Change in Beta-hydroxybutyrate concentrations
Assay of plasma concentrations
Measured: before and after glucagon administration, up to 1 hour
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2020
- Study start24 Sep 2019
- Primary completion16 Apr 2021
- Study completion16 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Insulin SecretionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Within-subject design with each subject receiving 3 separate single day interventions.
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- David D'Alessio, M.D.
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, David D'Alessio, M.D., Duke University
- Investigators
- David D'Alessio, MD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04347252
- Sponsor's protocol ID
- Pro00065698_1
- Other IDs
- R01DK101991
- Status last verified
- May 2021
- First submitted
- 31 Mar 2020
- Last updated
- 14 May 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Incretin Action in Physiology and Diabetes
- ClinicalTrials.gov ID
- NCT04347252
- Acronym / sponsor ID
- Pro00065698_1
- Conditions
- Insulin Secretion
- Keywords
- glucagon, GLP-1 receptor, insulin secretion, glucose tolerance
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- David D'Alessio, M.D.University, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- 24 Sep 2019 (actual)
- Primary completion
- 16 Apr 2021 (actual)
- Study completion
- 16 Apr 2021 (actual)
- First posted
- 15 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Glucagon is a 30 amino acid peptide hormone that is produced exclusively in alpha-cells of the pancreatic islets. Glucagon binds to a G-protein coupled receptor and activates intracellular signaling by increasing the synthesis of cyclic AMP by adenylate cyclase. The glucagon receptor is most prominently expressed by hepatocytes and the cardinal action of glucagon is to stimulate hepatic glucose output by increasing glycogenolysis and gluconeogenesis. A deep body of literature supports physiologic actions of glucagon to maintain fasting blood glucose and counter-regulate hypoglycemia, and the current view of glucose metabolism is that insulin and glucagon have opposing and mutually balancing effects on glycemia. However, it has long been appreciated that glucagon actually stimulates insulin secretion and islet β-cells express the glucagon receptor and respond to its activation by increasing cAMP.
The most potent stimulus for glucagon release is hypoglycemia and both low glucose per sé, as well as sympathetic nervous system activity are potent activators of the alpha-cell. However, glucagon is also stimulated by elevations of circulating amino acids, including after protein containing meals; this setting is one in which the release of glucagon during a period of elevated glycemia could contribute to postprandial insulin secretion. In fact, we have demonstrated that normal mice injected with glucagon while fasting (BG 75 mg/dl) have a prompt rise in blood glucose, whereas mice given glucagon while feeding (BG 150 mg/dl) increase insulin output 3 fold and have a decrease in glycemia. Moreover, in studies with isolated mouse and human islets we have demonstrated that glucagon stimulates insulin release by activating both the glucagon and GLP-1 receptors. This counter-intuitive observation has been reported by several other groups as well as ours.
In the studies proposed herein we wish to extend our novel observations to humans. The possibility that glucagon acts in the fed state to promote insulin secretion and glucose disposal would change current views of physiology in both healthy and diabetic persons. Moreover, since one of the more promising area of drug development is the creation of peptides that activate multiple receptors (GLP-1 + glucagon, GLP-1 + GIP + glucagon) the results of our studies have potential implications for therapeutics as well.
Detailed description
Subjects will have a screening visit for history, medication usage, and blood work; those who qualify will be offered participation. Subjects will be instructed to consume their usual diet, including at least 200 g carbohydrate, and not to engage in strenuous physical activity for the 3 days prior to a study. After an overnight fast they will present to the CRU at the Stedman Building on the Center for Living campus and have intravenous catheters placed in both forearms, one for infusion of test substances and the other for blood sampling; the sampling arm will be warmed with a heating pad to improve venous blood flow. All studies will start following withdrawal of several basal samples over an extended period:
- Glucagon infusion in fasting and hyperglycemic subjects: dose finding. Subjects receive graded doses of intravenous glucagon after a 12-14 hour fast. Doses will start at 10 ng/kg/min and be increased to 50 and 100 ng/kg/min at 30 minute intervals. Glucose concentrations will be measured at the bedside using a YSI glucose analyzer. Plasma samples will be collected at 10 minute intervals for assay of insulin, C-peptide, and glucagon. These pilot studies will provide insight into the relative sensitivity of hepatic glucose production (fasting study) and insulin secretion (glucose infusion study) to glucagon. These studies will include up to 10 volunteers each.
- Effects of glycemia to mediate glucagon-stimulated hepatic glucose production (HGP) and insulin secretion. Following placement of intravenous catheters subjects will have an infusion of saline with a tracer dose of deuterated glucose for the remainder of the 300 minute protocol. [6, 6]2H2 glucose will be started as a 4 mg/kg bolus over 5 minutes followed by a continuous infusion of 0.020-0.4 mg/kg/min. After a 2 hour equilibration period to label the glucose pool, subjects will have A) saline infusion, B) initiation of a hyperglycemic clamp, C) infusion of exendin-(9-39) 750 pmol/kg/min and a hyperglycemic clamp. The clamp will be generated with the infusion of a 20% solution of dextrose enriched to 2% with deuterated glucose. The infusion rate will be started at 30 mg/kg/h and adjusted every 5 minutes until the blood glucose reaches ~150 mg/dl; the infusion will be adjusted thereafter to maintain this level of glycemia. Blood samples will be taken at 10 minute intervals throughout the study to measure: enrichment with [6, 6]2H2 glucose, insulin, glucagon and C-peptide. After 120 minutes of A) tracer alone, B) hyperglycemia, or C) exendin-9 plus hyperglycemia, subjects will receive glucagon as an infusion of 10-100 ng/kg/min for 30 or 60 minutes.
The primary outcome variables from these experiment will be HGP and insulin secretion. The hypothesis to be tested is that glucagon given at fasting glucose levels will cause a rapid rise in HGP and blood glucose (50-150 mg/dl over basal) with a secondary rise of insulin secretion that follows the change in glycemia; and that glucagon given at mild hyperglycemia will promptly stimulate insulin secretion and limit the response of HGP. The protocol and predictions of results are depicted below.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Within-subject design with each subject receiving 3 separate single day interventions.
| Arm | Type | Receives |
|---|---|---|
| Glucagon at basal glycemia | Experimental | Drug: GlucagonSubjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. |
| Glucagon at hyperglycemia | Experimental | Drug: GlucagonSubjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. |
| Glucagon at hyperglycemia with GLP-1R blockade | Experimental | Drug: GlucagonSubjects will present after an overnight fast and at time 0 an infusion of deuterated glucose will be started and continued for the remainder of the 5 hour study (4 mg/kg bolus followed by 0.04 mg/kg/min infusion). Blood will be sampled at 10 minute intervals throughout the study for measurement of substrates and hormones. At time 120 an infusion of 20% glucose, labeled to 2% with deuterated glucose, will be started and adjusted to raise the blood glucose to 8.3 mM for the remainder of the study; concurrently exendin-(9-39) will be infused at 750 pmol/kg/min, also for the remaining 180 minutes. At time 240 an intravenous infusion of glucagon (10-100 ng.kg.min) will be started and continued for 30 or 60 minutes. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Healthy, fasting glucose values ≤ 95 mg/dL or A1c ≤ 5.9%, and no first degree family members with T2DM.
Key exclusion criteria (1 listed)
- Active infectious, malignant or inflammatory conditions; unstable angina or uncompensated heart failure; pulmonary disorders including COPD and asthma; malabsorptive GI disease; significant hepatic disease; renal insufficiency (eGFR < 60 ml/kg/min); anemia (hematocrit < 34%); pregnancy; and uncontrolled hypertension. Subjects will be excluded if they require daily medications that alter glucose metabolism or GI function (glucocorticoids, psychotropics, narcotics, metoclopramide).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlucagonAlso: exendin-(9-39); hyperglycemiaIntravenous infusion of glucagon at fasting or elevated glycemia. Blockade of the GLP-1 receptor during hyperglycemia with and without glucagon. | Drug | Glucagon at basal glycemia, Glucagon at hyperglycemia, Glucagon at hyperglycemia with GLP-1R blockade |
Primary outcome
Change in insulin secretion
Time frame: before and after glucagon administration, up to 1 hour
Derived from plasma insulin and C-peptide concentrations
hepatic glucose production
Time frame: before and after glucagon administration, up to 1 hour
Derived from isotope dilution based on deuterated glucose enrichment
2 secondary outcomes
Change in Glucagon concentrations
Time frame: before and after glucagon administration, up to 1 hour
Change in Beta-hydroxybutyrate concentrations
Time frame: before and after glucagon administration, up to 1 hour
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David D'Alessio, MD principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Glucagon in people with Insulin Secretion, run by David D'Alessio, M.D. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in insulin secretion (time frame: before and after glucagon administration, up to 1 hour). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2021.