Healthy
Conditions
Brief summary
The purpose of this research is to help understand the relative importance of changes in insulin secretion (which lowers glucose) and changes in glucagon (which raises glucose) to regulate metabolism and the body's ability to make glucose.
Detailed description
Study A (Insulin 0.4mU/Kg/min): Subjects will be admitted to the CRTU at approximately 1700 on the day prior to study. They will then consume a standard 10kcal/kg meal (55% carbohydrate, 30% fat, 15% protein, caffeine free) and fast overnight. Blood will then be sampled for baseline enrichment and 2H20 (1.67g/kg of body water) will be given in 3 divided doses at 2200, 2400 and 0200. The following morning (approximately 0530), a forearm vein will be cannulated to allow infusions to be performed. In addition, a cannula will be inserted retrogradely into a vein of the contra-lateral dorsum of the hand. This will be placed in a heated Plexiglas box maintained at around 120oF to allow sampling of arterialized venous blood. At approximately 0600 (-180 min), a primed, (10microCi prime, 0.1microCi/min continuous) infusion containing trace amounts of glucose labeled with \[3-3H\] glucose will be started and continued till 0900 (0 min). At 0900 (0 min), the infusion will be varied so as to mimic the anticipated pattern of fall of EGP. In addition, glucose also labeled with \[3-3H\] glucose will be infused so as to maintain glucose concentrations at \ 95mg/dL. Peripheral venous glucose concentrations will be measured every 10 minutes to allow the infusion rate of glucose to be adjusted as necessary. Simultaneously, an infusion of somatostatin (60ng/kg/min) will be started at time 0 to inhibit endogenous islet secretion and therefore ensure identical portal insulin concentrations on the two study days. Insulin will be infused at a constant rate known to produce \ 50% suppression of EGP (0.4mU/Kg/min). From 0900 (0 min) to 1030 (90 min) no glucagon will be infused. Subsequently, a glucagon infusion will commence (91 - 180 min) at 0.35 ng/Kg/min and then increase to 0.70 ng/Kg/min (181- 270 min), a rate which will be maintained till the end of the study (1330). Study B (0.8mU/Kg/min): Approximately 1-2 weeks after the first study visit, subjects will be asked to return to the CRTU. This study visit will be similar to Study A. However, insulin will be infused at 0.8mU/Kg/min 0 to 270 minutes.
Interventions
DRUG0.4mU Insulin followed by withdrawal period followed by 0.8mU study
Clamp study with insulin infused at 0.4 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.8 mU/Kg/min
DRUG0.8mU Insulin followed by withdrawal period followed by 0.4mU study
Clamp study with insulin infused at 0.8 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.4 mU/Kg/min
Sponsors
Adrian Vella
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* We will recruit 15 otherwise healthy subjects using intramural and local extramural advertising after approval from the Mayo Clinic Institutional Review Board. Individuals who express interest in participating will be invited for a screening visit. Individuals with a BMI \< 19 or \> 28 kg/m2 will be excluded from the study to avoid potential confounding effects that may result from extreme leanness or from obesity. Subjects will have no known systemic illness, taking any medication that could affect glucose metabolism and no history of upper gastrointestinal surgery.
Exclusion criteria
* Subjects \< 18 years of age or \> 40 years of age will not be studied to minimize the potential confounding effects of age on glucagon and insulin action. The subjects will not be taking medications that affect glucose metabolism (to be determined by PI) and have no history of chronic illness or upper gastrointestinal surgery. We are seeking to recruit subjects who do not have diabetes (fasting glucose \<100mg/dL).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production (EGP) | It will be quantified at 90, 180 and 270 minutes for the study with 0.4mU insulin infusion and compared to values obtained for the study with 0.8mU insulin infusion at the same timepoints | is calculated by tracer-based measurement and expressed per kg lean body mass |
Countries
United States
Participant flow
Pre-assignment details
The study is a cross-over study - subjects participated in both arms
Participants by arm
| Arm | Count |
|---|---|
| 0.4 Then 0.8 Subjects will undergo the 0.4 clamp first during which insulin is infused at 0.4mU/Kg/Min
following a suitable washout period,
Subjects will undergo the 0.8 clamp second during which insulin is infused at 0.8mU/Kg/Min | 5 |
| 0.8 Then 0.4 Subjects will undergo the 0.8 clamp first during which insulin is infused at 0.8mU/Kg/Min
following a suitable washout period,
Subjects will undergo the 0.4 clamp second during which insulin is infused at 0.4mU/Kg/Min | 7 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | IV access lost during the study | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | 0.4 Then 0.8 | 0.8 Then 0.4 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 5 Participants | 5 Participants |
| Age, Continuous | 35 years STANDARD_DEVIATION 11 | 34 years STANDARD_DEVIATION 13 | 37 years STANDARD_DEVIATION 10 |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment United States | 12 participants | 5 participants | 7 participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 1 / 12 | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Endogenous Glucose Production (EGP)
is calculated by tracer-based measurement and expressed per kg lean body mass
Time frame: It will be quantified at 90, 180 and 270 minutes for the study with 0.4mU insulin infusion and compared to values obtained for the study with 0.8mU insulin infusion at the same timepoints
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.4mU Insulin | Endogenous Glucose Production (EGP) | At 90 minutes | 4.99 umol/kg/min | Standard Error 0.53 |
| 0.4mU Insulin | Endogenous Glucose Production (EGP) | At 180 minutes | 6.82 umol/kg/min | Standard Error 0.82 |
| 0.4mU Insulin | Endogenous Glucose Production (EGP) | At 270 minutes | 8.48 umol/kg/min | Standard Error 1.07 |
| 0.8mU Insulin | Endogenous Glucose Production (EGP) | At 90 minutes | 5.02 umol/kg/min | Standard Error 0.74 |
| 0.8mU Insulin | Endogenous Glucose Production (EGP) | At 180 minutes | 5.52 umol/kg/min | Standard Error 0.96 |
| 0.8mU Insulin | Endogenous Glucose Production (EGP) | At 270 minutes | 5.38 umol/kg/min | Standard Error 1.13 |