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
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.
- 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
- 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
- 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
- Any reason the principal investigator deems exclusionary.