Type 1 Diabetes
Conditions
Brief summary
In normal physiology insulin is secreted by beta cells into the portal vein. There have been a number of purported benefits among long-term intraperitoneal insulin users. In the present study we will inject ultra-rapid acting insulin into the upper and lower peritoneum under ultrasound guidance and compare it to subcutaneous injection. We will measure glucose, insulin and glucagon following these injections, to assess for benefits in counter-regulatory hormone production and insulin pharmacokinetics.
Detailed description
The eventual goal of this line of work is an implanted insulin pump that delivers insulin automatically into the peritoneum based on continuous glucose data. All prior intraperitoneal pharmacokinetic studies used only concentrated regular insulin, which may be too slow to provide full closed-loop insulin delivery without meal announcement. A description of intraperitoneal ultra-rapid insulin kinetics, as well as counter-regulatory hormonal factors that may counter hypoglycemia is needed. Upper versus lower peritoneal delivery may also affect insulin kinetics. A possible benefit of intraperitoneal insulin is restoration of glucagon response in longstanding diabetes and clearance of insulin by the liver, both of which could provide hypoglycemic rescue in automated insulin delivery systems.
Interventions
DRUGUltra-rapid insulin
Following 0.5-3 hours of insulin suspension from insulin pump, participants will receive insulin injection in respective locations (separated by at least 1 week) and then have serial lab measurements (YSI glucose, insulin and glucagon) taken during induced hypoglycemia.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Intervention model description
Participants will each come in for 3 visits separated by at least 1 week. During the first two visits they will be randomized to either upper or lower peritoneal injection followed by the other site. During the third visit a subcutaneous injection will be performed to provide comparative data to the standard of care.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. 18-60 years of age 2. Clinical diagnosis of type 1 diabetes 3. On insulin pump therapy and continuous glucose monitor (CGM) for at least 3 months 4. Ability to safely receive intraperitoneal injection 5. For females, not currently known to be pregnant 6. Understanding and willingness to follow the protocol and sign informed consent 7. Ability to speak, read and write in the language of the investigators
Exclusion criteria
1. Diabetic ketoacidosis in the past 3 months 2. Severe hypoglycemia resulting in seizure or loss of consciousness within 3 months prior to enrollment 3. Pregnant or lactating 4. Active infection 5. A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol 6. Known cardiovascular events in the last 6 months 7. Known seizure disorder 8. Inpatient psychiatric treatment in the past 6 months 9. Lack of stability on medication 1 month prior to enrollment including antihypertensive, thyroid, anti-depressant or lipid lowering medication. 10. Suspected drug or alcohol abuse 11. Chronic kidney disease (GFR \< 60 mL/min/1.73m\^2)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucagon Response to Induced Hypoglycemia | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | For each injection site we will assess the peak concentration of glucagon at time of the first induced hypoglycemic nadir. Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal). Participants must have achieved induced hypoglycemia to be evaluable for the primary outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Maximum Concentration in Plasma | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | We will assess the maximum concentration of circulating insulin for each injection site after a median injection of 40% of each participant's total daily dose (approximately 0.25 units per kilogram of body weight). Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal). |
| Hypoglycemic Treatments Required as a Measure of Glucose Values | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | We will compare the number of rescue treatments (2.5ml/kg 10% Dextrose) required to treat hypoglycemia \<50mg/dl for each injection location of approximately 0.25u/kg ultra-rapid insulin. Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal). |
| Time Until Maximum Insulin Concentration in Plasma | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | We will assess time until the maximum concentration of circulating insulin for each injection site after a median injection of 40% of each participant's total daily dose (approximately 0.25 units per kilogram of body weight). Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Upper Peritoneal, Then Lower Peritoneal, Then Subcutaneous Ultra-fast acting insulin will be injected into the upper peritoneum then lower peritoneum then subcutaneous space. | 10 |
| Lower Peritoneal, Then Upper Peritoneal, Then Subcutaneous Ultra-fast acting insulin will be injected into the lower peritoneum then upper peritoneum then subcutaneous space. | 6 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Week 1 (First Injection) | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Upper Peritoneal, Then Lower Peritoneal, Then Subcutaneous | Total | Lower Peritoneal, Then Upper Peritoneal, Then Subcutaneous |
|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 7.1 | 38.9 years STANDARD_DEVIATION 10 | 38.8 years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 14 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 15 Participants | 5 Participants |
| Region of Enrollment United States | 10 Participants | 16 Participants | 6 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 16 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 | 0 / 15 |
Outcome results
Primary
Glucagon Response to Induced Hypoglycemia
For each injection site we will assess the peak concentration of glucagon at time of the first induced hypoglycemic nadir. Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal). Participants must have achieved induced hypoglycemia to be evaluable for the primary outcome.
Time frame: Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
Population: Participants with successfully induced hypoglycemia at the respective study visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Upper Peritoneal Injection | Glucagon Response to Induced Hypoglycemia | 4.8 pg/mL |
| Lower Peritoneal Injection | Glucagon Response to Induced Hypoglycemia | 8.8 pg/mL |
| Injection- All Peritoneal | Glucagon Response to Induced Hypoglycemia | 5.8 pg/mL |
| Subcutaneous Injection | Glucagon Response to Induced Hypoglycemia | 4.2 pg/mL |
Secondary
Hypoglycemic Treatments Required as a Measure of Glucose Values
We will compare the number of rescue treatments (2.5ml/kg 10% Dextrose) required to treat hypoglycemia \<50mg/dl for each injection location of approximately 0.25u/kg ultra-rapid insulin. Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal).
Time frame: Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
Population: Participants were excluded if they took a disallowed medication, or if the suspension of basal insulin prior to injection exceeded 2 hours.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Upper Peritoneal Injection | Hypoglycemic Treatments Required as a Measure of Glucose Values | 1 Treatments |
| Lower Peritoneal Injection | Hypoglycemic Treatments Required as a Measure of Glucose Values | 1 Treatments |
| Injection- All Peritoneal | Hypoglycemic Treatments Required as a Measure of Glucose Values | 1 Treatments |
| Subcutaneous Injection | Hypoglycemic Treatments Required as a Measure of Glucose Values | 3 Treatments |
Secondary
Insulin Maximum Concentration in Plasma
We will assess the maximum concentration of circulating insulin for each injection site after a median injection of 40% of each participant's total daily dose (approximately 0.25 units per kilogram of body weight). Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal).
Time frame: Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
Population: Participants were excluded if they took a disallowed medication, or if the suspension of basal insulin prior to injection exceeded 2 hours.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Upper Peritoneal Injection | Insulin Maximum Concentration in Plasma | 56.81 mU/L |
| Lower Peritoneal Injection | Insulin Maximum Concentration in Plasma | 63.26 mU/L |
| Injection- All Peritoneal | Insulin Maximum Concentration in Plasma | 56.95 mU/L |
| Subcutaneous Injection | Insulin Maximum Concentration in Plasma | 57.47 mU/L |
Secondary
Time Until Maximum Insulin Concentration in Plasma
We will assess time until the maximum concentration of circulating insulin for each injection site after a median injection of 40% of each participant's total daily dose (approximately 0.25 units per kilogram of body weight). Analysis includes reporting groups for each type of injection, and upper and lower peritoneal injections combined (Injection- All Peritoneal).
Time frame: Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
Population: Participants were excluded if they took a disallowed medication, or if the suspension of basal insulin prior to injection exceeded 2 hours.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Upper Peritoneal Injection | Time Until Maximum Insulin Concentration in Plasma | 35 minutes |
| Lower Peritoneal Injection | Time Until Maximum Insulin Concentration in Plasma | 25 minutes |
| Injection- All Peritoneal | Time Until Maximum Insulin Concentration in Plasma | 30 minutes |
| Subcutaneous Injection | Time Until Maximum Insulin Concentration in Plasma | 60 minutes |