Physiologic Response to Glucagon at Varying Insulin Levels

• Sponsor: Legacy Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT01483651
• Collaborator: Juvenile Diabetes Research Foundation (Other), Oregon Health and Science University (Other)
• Enrollment: 11
• Location: 1
• Arms: 6
• Duration (Months): 16
• Patients Per Site Per Month: 0.7

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Glucagon; Drug: Insulin	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: The Hepatic Glucose Response to Glucagon at Varying Insulin Levels: Implications for Closed Loop Glycemic Control.
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low, Medium and High insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin
Experimental: Low, High and Medium insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin
Experimental: Medium, Low and High insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin
Experimental: Medium, High and Low insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin
Experimental: High, Low and Medium insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin
Experimental: High, Medium and Low insulin infusion 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.	Drug: Glucagon; 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.; Other Names: GlucaGen ; Drug: Insulin; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.; Other Names: Regular insulin

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve for Glucose Above Baseline [60 minutes after each glucagon administration]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Legacy Health System	Portland	Oregon	United States	97210

Sponsors and Collaborators

• Legacy Health System
• Juvenile Diabetes Research Foundation
• Oregon Health and Science University

Investigators

• Principal Investigator: W Kenneth Ward, MD, Legacy Health System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: W. Kenneth Ward, Senior Scientist, Legacy Health System
• ClinicalTrials.gov Identifier: NCT01483651
• Other Study ID Numbers: kw02
• First Posted: Dec 1, 2011
• Last Update Posted: Mar 29, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by W. Kenneth Ward, Senior Scientist, Legacy Health System: diabetes; glucagon; insulin; dideuterated glucose
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Glucagon

Study Results

Participant Flow

Arm/Group Title	Low, Medium and High Insulin Infusion Rate	Low, High and Medium Insulin Infusion Rate	Medium, Low and High Insulin Infusion Rate	Medium, High and Low Insulin Infusion	High, Low and Medium Insulin Infusion	High, Medium and Low Insulin Infusion
Arm/Group 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.
Period Title: Overall Study
STARTED	1	3	2	1	2	2
COMPLETED	1	2	1	1	2	1
NOT COMPLETED	0	1	1	0	0	1

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Regular insulin given at each of three study visits with a different infusion rate at each visit, either low, medium or high insulin infusion with glucagon administration.
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	5 45.5%
Male	6 54.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Insulin Infusion Rate	Medium Insulin Infusion Rate	High Insulin Infusion Rate
Arm/Group Description	Regular insulin infused at lowest level of glucagon administration.	Regular insulin infused at medium level with glucagon administration.	Regular insulin infused at highest level with glucagon administration.
Measure Participants	10	9	10
Mean (Standard Deviation) [mg/kg glucose per mcg glucagon]	0.623 (0.3)	0.59 (0.4)	0.03 (0.16)

Adverse Events

Time Frame	1 year
Arm/Group Title	Low Insulin Infusion		Medium Insulin Infusion		High Insulin Infusion
Arm/Group Description	Regular insulin infused at lowest level with glucagon administration.		Regular insulin infused at medium level with glucagon administration.		regular insulin infused at highest level with glucagon administration.
All Cause Mortality
	Low Insulin Infusion		Medium Insulin Infusion		High Insulin Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Low Insulin Infusion		Medium Insulin Infusion		High Insulin Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Low Insulin Infusion		Medium Insulin Infusion		High Insulin Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/10 (70%)		8/9 (88.9%)		5/10 (50%)
Blood and lymphatic system disorders
Hematoma	1/10 (10%)	1	0/9 (0%)	0	0/10 (0%)	0
ketosis	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
Gastrointestinal disorders
Diarrhea	3/10 (30%)	4	2/9 (22.2%)	3	3/10 (30%)	3
vomiting	1/10 (10%)	1	1/9 (11.1%)	1	1/10 (10%)	1
nausea	5/10 (50%)	5	2/9 (22.2%)	2	4/10 (40%)	4
Metabolism and nutrition disorders
hyperglycemia	1/10 (10%)	1	2/9 (22.2%)	2	0/10 (0%)	0
hypoglycemia	1/10 (10%)	1	2/9 (22.2%)	2	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
weakness	1/10 (10%)	1	1/9 (11.1%)	1	1/10 (10%)	1
Nervous system disorders
headache	2/10 (20%)	2	3/9 (33.3%)	3	2/10 (20%)	2
Renal and urinary disorders
excessive thirst	1/10 (10%)	1	0/9 (0%)	0	0/10 (0%)	0
Skin and subcutaneous tissue disorders
extravasation	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
dermititis	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.