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Physiologic Response to Glucagon at Varying Insulin Levels

Primary Purpose

Type 1 Diabetes Mellitus

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Glucagon
Insulin
Sponsored by
Legacy Health System
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Type 1 Diabetes Mellitus focused on measuring diabetes, glucagon, insulin, dideuterated glucose

Eligibility Criteria

21 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of type 1 diabetes mellitus for at least 1 year
  • Male or female subjects 21 to 65 years of age
  • Current use of an insulin pump
  • Willingness to sign informed consent and HIPAA documents and follow all study procedures

Exclusion Criteria:

  • Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study
  • Renal insufficiency (serum creatinine of 2.0 mg/dL or greater)
  • Liver abnormalities: Serum ALT or AST equal to or greater than 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as a serum albumin of less than 3.3 g/dL; or serum bilirubin of over 2
  • Adrenal insufficiency
  • Hematocrit of less than or equal to 34%
  • A history of cerebrovascular disease or coronary artery disease regardless of the time since occurrence
  • Congestive heart failure, NYHA class III or IV
  • Cardiac rhythm disturbance characterized by: 2nd or 3rd degree heart block, bradycardia of less than 50 bpm (exception of bradycardia in an aerobic athlete), tachycardia of greater than 100 bpm, or any arrhythmia judged by the investigator to be exclusionary
  • Any active infection
  • Active foot ulceration
  • Severe peripheral arterial disease characterized by ischemic rest pain or severe claudication
  • Active alcohol abuse, substance abuse, or severe mental illness (as judged by the principal investigator)
  • Active malignancy, except basal cell or squamous cell skin cancers
  • Major surgical operation within 30 days prior to screening
  • Seizure disorder
  • Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen
  • Chronic usage of any immunosuppressive medication
  • Current administration of oral or parenteral corticosteroids
  • Use of an investigational drug within 30 days prior to screening
  • Bleeding disorder, treatment with warfarin, or platelet count below 50,000
  • Allergy to glucagon
  • Past history of pheochromocytoma or a family history of MEN 2, neurofibromatosis, or von Hippel-Lindau disease
  • Insulin resistance requiring more than 200 units per day

Sites / Locations

  • Legacy Health System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Low, Medium and High insulin infusion

Low, High and Medium insulin infusion

Medium, Low and High insulin infusion

Medium, High and Low insulin infusion

High, Low and Medium insulin infusion

High, Medium and Low insulin infusion

Arm Description

All study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration.

All study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration.

All study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration.

All study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration.

All study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration.

All study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration.

Outcomes

Primary Outcome Measures

Area Under the Curve for Glucose Above Baseline
The change in the rate of glucose appearance will be assessed by measuring the stable glucose isotope (dideuterated glucose, D2) using a gas chromatography-mass spectrometry assay. The units of the area under the curve are defined as milligrams per kilogram of glucose, since the dependent variable is a rate of glucose production [mg/kg/min] measured over time [min]. The time variable therefore cancels out. Additionally, this area under the curve is being normalized per microgram of glucagon delivered.

Secondary Outcome Measures

Full Information

First Posted
November 29, 2011
Last Updated
March 1, 2016
Sponsor
Legacy Health System
Collaborators
Juvenile Diabetes Research Foundation, Oregon Health and Science University
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1. Study Identification

Unique Protocol Identification Number
NCT01483651
Brief Title
Physiologic Response to Glucagon at Varying Insulin Levels
Official Title
The Hepatic Glucose Response to Glucagon at Varying Insulin Levels: Implications for Closed Loop Glycemic Control.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2016
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Legacy Health System
Collaborators
Juvenile Diabetes Research Foundation, Oregon Health and Science University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this research study is to test how different levels of insulin block the effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood glucose. Both are natural hormones made by people without diabetes. Sensor-based blood glucose control studies have been done by our research group using glucagon in small doses to prevent hypoglycemia (low blood sugar). However, sometimes glucagon does not work to raise blood sugar. The investigators believe this is because of too much insulin in the body. This study will help determine how different levels of insulin in the body affect the ability of glucagon to raise blood sugar.
Detailed Description
We investigators have been working on the development of a closed loop (artificial endocrine pancreas) insulin and glucagon infusion system since 2005 and are part of the Juvenile Diabetes Research Foundation Artificial Pancreas Consortium. As part of our studies, we give small doses of glucagon to prevent hypoglycemia. As we assessed the success and failure of glucagon administration during these studies, we found the use of glucagon reduced the frequency of hypoglycemia by about 75%. However, the fact that approximately 25% of administrations of glucagon are ineffective remains a concern. The primary question to be addressed by this study is, in the setting of low dose subcutaneous glucagon administration, how do plasma glucagon and plasma insulin quantitatively interact? In other words, as the rate of insulin administration is increased, how much more glucagon is necessary to overcome the effect of insulin to prevent hypoglycemia? This study is designed to address this question. Subjects will be brought in to a Legacy Hospital for four 10 hour experiments on each of four separate days. On each study day, there will be a continuous infusion of a different rate of IV Regular insulin in order to achieve different steady state free insulin levels. At each insulin level, there will be four subcutaneous glucagon doses given. Octreotide will be infused by IV at a constant rate to suppress endogenous production of glucagon. A stable glucose isotope will also be infused to allow for measurement of hepatic glucose production and glucose turnover. Arterialized venous blood glucose will be measured by the HemoCue Glucose 201 Analyzer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus
Keywords
diabetes, glucagon, insulin, dideuterated glucose

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low, Medium and High insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration.
Arm Title
Low, High and Medium insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration.
Arm Title
Medium, Low and High insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration.
Arm Title
Medium, High and Low insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration.
Arm Title
High, Low and Medium insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration.
Arm Title
High, Medium and Low insulin infusion
Arm Type
Experimental
Arm Description
All study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration.
Intervention Type
Drug
Intervention Name(s)
Glucagon
Other Intervention Name(s)
GlucaGen
Intervention Description
The first dose of glucagon will be delivered approximately one hour after infusion of IV insulin has started. The subsequent three doses will be delivered every two hours. The dosage will depend on the IV insulin infusion (50 units regular insulin in 499.5 mL 0.9% saline): Study 1) insulin 0.01 units/kg/hour and glucagon doses (ug): 10,25,45,70; Study 2) insulin 0.02 units/kg/hr and glucagon doses (ug): 25,45,70,100; Study 3) insulin 0.04 units/kg/hr and glucagon doses (ug): 45,70,100,135; Study 4) insulin 0.08 units/kg/hr and glucagon doses (ug): 70,100,135,175. Insulin levels and glucagon doses will be randomized. Glucagon will be reconstituted with 10 mL of sterile water and administered subcutaneously.
Intervention Type
Drug
Intervention Name(s)
Insulin
Other Intervention Name(s)
Regular insulin
Intervention Description
Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.
Primary Outcome Measure Information:
Title
Area Under the Curve for Glucose Above Baseline
Description
The change in the rate of glucose appearance will be assessed by measuring the stable glucose isotope (dideuterated glucose, D2) using a gas chromatography-mass spectrometry assay. The units of the area under the curve are defined as milligrams per kilogram of glucose, since the dependent variable is a rate of glucose production [mg/kg/min] measured over time [min]. The time variable therefore cancels out. Additionally, this area under the curve is being normalized per microgram of glucagon delivered.
Time Frame
60 minutes after each glucagon administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of type 1 diabetes mellitus for at least 1 year Male or female subjects 21 to 65 years of age Current use of an insulin pump Willingness to sign informed consent and HIPAA documents and follow all study procedures Exclusion Criteria: Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study Renal insufficiency (serum creatinine of 2.0 mg/dL or greater) Liver abnormalities: Serum ALT or AST equal to or greater than 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as a serum albumin of less than 3.3 g/dL; or serum bilirubin of over 2 Adrenal insufficiency Hematocrit of less than or equal to 34% A history of cerebrovascular disease or coronary artery disease regardless of the time since occurrence Congestive heart failure, NYHA class III or IV Cardiac rhythm disturbance characterized by: 2nd or 3rd degree heart block, bradycardia of less than 50 bpm (exception of bradycardia in an aerobic athlete), tachycardia of greater than 100 bpm, or any arrhythmia judged by the investigator to be exclusionary Any active infection Active foot ulceration Severe peripheral arterial disease characterized by ischemic rest pain or severe claudication Active alcohol abuse, substance abuse, or severe mental illness (as judged by the principal investigator) Active malignancy, except basal cell or squamous cell skin cancers Major surgical operation within 30 days prior to screening Seizure disorder Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen Chronic usage of any immunosuppressive medication Current administration of oral or parenteral corticosteroids Use of an investigational drug within 30 days prior to screening Bleeding disorder, treatment with warfarin, or platelet count below 50,000 Allergy to glucagon Past history of pheochromocytoma or a family history of MEN 2, neurofibromatosis, or von Hippel-Lindau disease Insulin resistance requiring more than 200 units per day
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
W Kenneth Ward, MD
Organizational Affiliation
Legacy Health System
Official's Role
Principal Investigator
Facility Information:
Facility Name
Legacy Health System
City
Portland
State/Province
Oregon
ZIP/Postal Code
97210
Country
United States

12. IPD Sharing Statement

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Physiologic Response to Glucagon at Varying Insulin Levels

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