Healthy
Conditions
Keywords
insulin secretion, GLP-1, alpha cell, paracrine effect, Glucagon-Like Peptide 1
Brief summary
This study is being done to determine the role of a hormone, glucagon-like peptide 1 (GLP-1), on insulin secretion and to study how GLP-1 works in in diabetic individuals as compared to non-diabetic individuals, under fasting conditions. GLP-1 is a naturally occurring hormone made in the intestines. It is released into the circulating blood after eating and helps to control the blood glucose levels by increasing insulin secretion by cells in the pancreas. However, the exact method by which GLP-1 causes insulin secretion and how GLP-1 activity is changed in diabetic persons remain unclear. This research is being done to address these questions and better understand the function of GLP-1. In this research, the investigators will use a synthetic form of Exendin-9 to determine the effects of GLP-1 on insulin secretion in diabetic and non-diabetic persons. Exendin-9 acts as a blocker of GLP-1 action, allowing us to study the specific effects of the GLP-1 hormone. Exendin-9 is an investigational compound, which means it is still being tested in research studies and is not approved by the U.S. Food and Drug Administration (FDA). In this study, the investigators will also use the drug Sitagliptin, which is an FDA-approved drug for the treatment of type 2 diabetes mellitus. In this study, use of Sitagliptin is considered investigational since it is not being used for treatment of diabetes but is instead being used to understand how GLP-1 works and to better understand how medications like Sitagliptin work in patients with type 2 diabetes mellitus.
Interventions
DRUGActive Comparator: Sitagliptin
Subjects will receive sitagliptin prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time).
DRUGPlacebo Comparator - No Sitagliptin
Subjects will receive Placebo (instead of sitagliptin) prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time).
Sponsors
Merck Sharp & Dohme LLC
David D'Alessio, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Diabetic cohort: adults age 35-70 years with Type 2 diabetes managed by an oral medication or diet and exercise * Non-diabetic cohort: healthy adults age 35-70 years * Male or female * Ability to speak and understand English * Diabetic cohort: HbA1c ≤ 8.0% * Non-diabetic cohort: HbA1c ≤ 6.2%
Exclusion criteria
* Rheumatoid arthritis * Inflammatory bowel disease * Unstable angina or uncompensated heart failure * Pulmonary disorders, including COPD and asthma * Malabsorptive GI disease, such as celiac disease, or gastric bypass * Significant hepatic disease * Renal insufficiency (eGFR \< 60 mL/kg/min) * Anemia (hematocrit \< 34%) as measured at screening visit * Uncontrolled hypertension * Pregnant females * Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide) * Consumption or injection of insulin * Apparent sensitivity to any of the study peptides as determined by the skin test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | 30 minutes | The investigators will use the mean increment of insulin secretion rate above baseline in the 30 minutes after Arginine stimulation to integrate insulin secretion, the primary outcome measure, and 2-way ANOVA with and without Sitagliptin and Ex-9/saline at the two factors. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited by advertisement from March 2017 to March 2018.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin and Non-Sitagliptin Recipients The infusion procedures performed during study visits 2 and 3 are identical except that the oral medicine Sitagliptin will only be administered at one of the two visits, with order of Sitagliptin administration determined at random by study staff.
Active Comparator: Sitagliptin: Subjects will receive sitagliptin prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time).
Placebo Comparator - No Sitagliptin: Subjects will receive Placebo (instead of sitagliptin) prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time). | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Failed IV access | 3 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Sitagliptin and Non-Sitagliptin Recipients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants |
| Age, Continuous | 51 years STANDARD_DEVIATION 10 |
| Diabetes Type No Diabetes (NDM) | 20 Participants |
| Diabetes Type Type 2 Diabetes (T2DM) | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 35 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 34 |
| other Total, other adverse events | 3 / 35 | 2 / 34 |
| serious Total, serious adverse events | 0 / 35 | 0 / 34 |
Outcome results
Primary
Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade
The investigators will use the mean increment of insulin secretion rate above baseline in the 30 minutes after Arginine stimulation to integrate insulin secretion, the primary outcome measure, and 2-way ANOVA with and without Sitagliptin and Ex-9/saline at the two factors.
Time frame: 30 minutes
Population: Participants who completed infusion protocols.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin and Ex-9/Saline (Non-diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | With GLP-1 Blockade | 320.1 pmol/L | Standard Error 0.37 |
| Sitagliptin and Ex-9/Saline (Non-diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | Without GLP-1 Blockade | 318.7 pmol/L | Standard Error 0.37 |
| Sitagliptin and Ex-9/Saline (Diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | Without GLP-1 Blockade | 319.4 pmol/L | Standard Error 0.38 |
| Sitagliptin and Ex-9/Saline (Diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | With GLP-1 Blockade | 243.4 pmol/L | Standard Error 0.38 |
| Non-Sitagliptin and Ex-9/Saline (Non-diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | With GLP-1 Blockade | 280 pmol/L | Standard Error 0.37 |
| Non-Sitagliptin and Ex-9/Saline (Non-diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | Without GLP-1 Blockade | 371.4 pmol/L | Standard Error 0.37 |
| Non-Sitagliptin and Ex-9/Saline (Diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | With GLP-1 Blockade | 251.2 pmol/L | Standard Error 0.38 |
| Non-Sitagliptin and Ex-9/Saline (Diabetics) | Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade | Without GLP-1 Blockade | 249.2 pmol/L | Standard Error 0.38 |
p-value: <0.05Mixed Models Analysis