Safety Study of Repeated Doses of Glucagon on Animal Starch in the Liver

• ClinicalTrials.gov Identifier: NCT01986231
• Recruitment Status: Completed
• First Posted: November 18, 2013
• Results First Posted: April 30, 2015
• Last Update Posted: May 4, 2015
• Sponsor: Legacy Health System
• Collaborators: Juvenile Diabetes Research Foundation; Oregon Health and Science University
• Information provided by (Responsible Party): W. Kenneth Ward, Legacy Health System

Study Description

Brief Summary:

The purpose of this study is to learn if giving multiple doses of a hormone called glucagon can cause a major decrease in liver glycogen (animal starch). Glucagon is currently approved by the Food and Drug Administration to be given as a large dose to treat severe low blood sugar. Our group is studying whether glucagon can be given in repeated small doses to prevent hypoglycemia.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Glucagon	Not Applicable

Detailed Description:

Hypoglycemia remains a barrier to optimal glucose control, which is necessary to prevent diabetes-related complications including eye, kidney, and nerve diseases. Despite treatment advances such as insulin pump therapy and continuous glucose monitoring, hypoglycemia remains a concern, even when insulin is given in a closed-loop system. A closed-loop system consists of a glucose-measuring device, from which data are collected and entered into an algorithm, which in turn controls insulin delivery. The difficulty of delivering regular or analog insulin in such a manner is related to its slow onset and prolonged effect when delivered subcutaneously. Until a more rapidly-acting insulin preparation is available, discontinuation of subcutaneous insulin during impending hypoglycemia, with any algorithm, may be insufficient to prevent hypoglycemia.

Glucagon, a hormone secreted from the alpha cells of the normal endocrine pancreas, rapidly raises circulating glucose levels within minutes via glycogenolysis, even when given subcu-taneously. Glucagon is approved for use as a parenteral injection for treatment of severe hypoglycemia. Our group has successfully completed studies in humans using a closed-loop system that delivers insulin (in a nearly continuous fashion) to prevent and treat hyperglycemia as well as glucagon (intermittently) to prevent and treat hypoglycemia.

However, it is unknown whether or not repeated doses lead to hepatic glycogen depletion, which would increase the risk of a severe hypoglycemic episode. 13C MRS (magnetic resonance spectroscopy) has been successfully used to quantify hepatic glycogen in a non-invasive fashion. We are proposing to use 13C MRS to compare glycogen stores in subjects with type 1 diabetes after a period without glucagon vs after a period of repeated glucagon dosing. The comparisons will be made when glycogen stores should be replete (after a lunch meal) and when glycogen stores should be lower (after an overnight fast). If repeated doses of glucagon do cause glycogen depletion, then we would revise our dosing strategy in the closed-loop system and/or consider alternative methods for preventing hypoglycemia.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Effect of Repeated Doses of Subcutaneous Glucagon on Hepatic Glycogen Stores in Persons With Type 1 Diabetes
• Study Start Date: January 2011
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: December 2012

Arms and Interventions

Arm

Intervention/treatment

Experimental: Open-Label Glucagon; Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg.

Drug: Glucagon; Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.; Other Name: GlucaGen

Outcome Measures

Primary Outcome Measures :

1. Assess Difference in Hepatic Glycogen Measured in the Fasting State Before vs. After Repeated Glucagon Administration [ Time Frame: Baseline and 41 hours ]
   The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fasting state.

Secondary Outcome Measures :

1. Assess Difference in Hepatic Glycogen Measured in the Fed State Before vs. After Repeated Glucagon Administration [ Time Frame: Baseline and 41 hours ]
   The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fed state.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Type 1 diabetes mellitus diagnosed for at least 6 months
• Current usage of subcutaneous insulin pump treatment
• Age 18-65 years
• HbA1c of 5.5 - 7.7% at screening visit
• BMI 18-35 kg/m2
• Willingness to follow all study procedures, including attending all clinic visits
• Willingness to sign informed consent and HIPAA documents

Exclusion Criteria:

• Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test.
• Renal insufficiency (serum creatinine of 2.0 mg/dL or greater).
• 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.
• Hematocrit of less than or equal to 34%.
• Congestive heart failure, NYHA class II, III or IV.
• Coronary artery or cerebrovascular disease.
• Active foot ulceration.
• 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 (epilepsy).
• Contraindication to an MRI scan, including having metallic splinters in the eye, a cardiac pacemaker, defibrillator, or any other ferromagnetic or electronically charged implanted device, or ferromagnetic clip(s) in the central nervous system.
• Currently 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.
• History weight loss of ≥ 5 lbs over the prior month.
• Weight ≥ 300 lbs.
• Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen.
• Any reason the principal investigator deems exclusionary.

Contacts and Locations

Locations

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Castle JR, El Youssef J, Bakhtiani PA, Cai Y, Stobbe JM, Branigan D, Ramsey K, Jacobs P, Reddy R, Woods M, Ward WK. Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System. Diabetes Care. 2015 Nov;38(11):2115-9. doi: 10.2337/dc15-0754. Epub 2015 Sep 4.

• Responsible Party: W. Kenneth Ward, Senior Scientist, Legacy Health System
• ClinicalTrials.gov Identifier: NCT01986231
• Other Study ID Numbers: IRB00006947
• First Posted: November 18, 2013
• Results First Posted: April 30, 2015
• Last Update Posted: May 4, 2015
• Last Verified: April 2015

Keywords provided by W. Kenneth Ward, Legacy Health System:

diabetes; insulin; glucagon; glycogen; MRS

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Glucagon; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs