Evaluating the Benefits of Physiologic Insulin Delivery

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Ultra-rapid insulin

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94304
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Upper Peritoneal, then Lower Peritoneal, then Subcutaneous; Ultra-fast acting insulin will be injected into the upper peritoneum then lower peritoneum then subcutaneous space.	Drug: Ultra-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.
Experimental: Lower Peritoneal, then Upper Peritoneal, then Subcutaneous; Ultra-fast acting insulin will be injected into the lower peritoneum then upper peritoneum then subcutaneous space.	Drug: Ultra-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.

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 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.	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 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).	Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
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).	Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max
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).	Peritoneal: Every 5 minutes for 180 minutes max; Subcutaneous: Every 15 minutes for 360 minutes max

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Rayhan Lal, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Actual): June 2, 2023
• Study Completion (Actual): June 2, 2023

Study Registration Dates

• First Submitted: June 2, 2020
• First Submitted That Met QC Criteria: June 2, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 5, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: IRB-57032; 1K23DK122017 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No current plan

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes