Evaluating the Benefits of Physiologic Insulin Delivery

Study Overview
=================
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.

Official Title
-----------------
Evaluating the Benefits of Physiologic Insulin Delivery

Conditions
-----------------
Type 1 Diabetes

Intervention / Treatment
-----------------
* Other: Ultra-rapid insulin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18-60 years of age Clinical diagnosis of type 1 diabetes On insulin pump therapy and continuous glucose monitor (CGM) for at least 3 months Ability to safely receive intraperitoneal injection For females, not currently known to be pregnant Understanding and willingness to follow the protocol and sign informed consent Ability to speak, read and write in the language of the investigators Exclusion Criteria: Diabetic ketoacidosis in the past 3 months Severe hypoglycemia resulting in seizure or loss of consciousness within 3 months prior to enrollment Pregnant or lactating Active infection A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol Known cardiovascular events in the last 6 months Known seizure disorder Inpatient psychiatric treatment in the past 6 months Lack of stability on medication 1 month prior to enrollment including antihypertensive, thyroid, anti-depressant or lipid lowering medication. Suspected drug or alcohol abuse Chronic kidney disease (GFR < 60 mL/min/1.73m^2)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Upper Peritoneal, then Lower Peritoneal, then Subcutaneous<br>Ultra-fast acting insulin will be injected into the upper peritoneum then lower peritoneum then subcutaneous space. | Other: Ultra-rapid insulin<br>* 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.<br>|
| Experimental: Lower Peritoneal, then Upper Peritoneal, then Subcutaneous<br>Ultra-fast acting insulin will be injected into the lower peritoneum then upper peritoneum then subcutaneous space. | Other: Ultra-rapid insulin<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon response to induced hypoglycemia | For each injection site we will assess the change in glucagon from nadir to peak during induced hypoglycemia. | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin concentration in plasma |  | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max | 
| Glucose Values |  | Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max |