Effects of Glucagon Administration on Energy Expenditure

1. To compare the effect of prolonged hyperglucagonemia to that of acute hyperglucagonemia
on energy expenditure in healthy subjects using room indirect calorimetry in the setting
of octreotide-mediated prevention of plasma insulin excursions.

2. To compare the effects of prolonged hyperglucagonemia to acute hyperglucagonemia on EGP
in healthy subjects in the setting of octreotide-mediated prevention of plasma insulin
excursions.

3. To determine the effects of prolonged hyperglucagonemia to acute hyperglucagonemia on
rates of substrate oxidation, fibroblast growth factor21 and metabolites of interest.

Inclusion Criteria:

- Subject is a male between the ages of 18 and 50 years.

- Subject has a body mass index (BMI) less than or equal to 26 kg/m2. BMI = weight
(kg)/height (m) and body weight greater than or equal to 50 kg at the pre-study
(screening) visit

- Subject has been weight stable over the last 3 months (plus or minus 3 kg)

- Subject is judged to be non-diabetic and in good health on the basis of medical
history, physical examination, electrocardiogram, and routine laboratory data.

- Subject understands the procedures and agrees to participate in the study program by
giving written informed consent, and is willing to comply with the trial restrictions.

- Subject is willing to avoid alcohol consumption for 48 hours prior to each period.

- Subject is willing to avoid strenuous physical activity (i.e., strenuous or
unaccustomed weight lifting, running, bicycling, etc.) beginning 72 hours prior to
first drug administration period and for the duration of the study.

- Subject is willing to avoid consumption of caffeine and caffeinated beverages for 24
hours prior to drug administration in each period. Subject is willing to consume no
more than 2 caffeinated beverages per day during all other parts of the study.

Exclusion Criteria:

- is mentally or legally incapacitated, has significant emotional problems at the time
of pretrial (screening) visit or expected during the conduct of the trial or has a
history of clinically significant psychiatric disorder of the last 5 years. Subjects
who have had situational depression may be enrolled in the trial at the discretion of
the investigator.

- has a history of clinically significant endocrine (including type 1 or type 2, or
steroid-induced diabetes), gastrointestinal (including prior history of pancreatitis),
cardiovascular (including hypertension, angina, coronary artery disease, valvular
disease, heart rate or rhythm abnormalities), hematological, hepatic, immunological,
renal, respiratory, genitourinary or major neurological (including stroke and chronic
seizures) abnormalities or diseases. Subjects with a history of uncomplicated kidney
stones or childhood asthma may be enrolled in the trial at the discretion of the
investigator.

- has a known history of any endocrine tumors (e.g. pheochromocytoma, glucagonoma, or
insulinoma, etc.)

- has a clinically significant abnormality on screening ECG or evidence or a history of
myocardial ischemia, atrioventricular block, Wolf-Parkinson-White syndrome or other
conduction abnormality. Subjects having any clinically significant ECG abnormality at
screening may be included at the discretion of the PI.

- has a fasting blood glucose (FPG) less than or equal to 65 mg/dL or greater than or
equal to 100 mg/dL on the pre-study screening labs.

- has impaired kidney or liver function, as evidenced by screening blood work.

- has irritable bowel disease, or recurrent occurrences of nausea, vomiting, diarrhea,
constipation or abdominal pain.

- has a history of any illness that, in the opinion of the study investigator, might
confound the results of the study or poses an additional risk to the subject by their
participation in the study.

- has an estimated creatinine clearance of ≤80 mL/min based on the Cockcroft-Gault
equation

- has a history of neoplastic disease

- has a history of significant multiple and/or severe allergies (e.g. food, drug, latex
allergy), or has had an anaphylactic reaction or significant intolerability to
prescription or non-prescription drugs or food; or allergy/intolerability to insulin,
glucagon, or octreotide.

- is positive for hepatitis B surface antigen, hepatitis C antibodies, or HIV

- had major surgery within 3 months, donated or lost 1 unit of blood (approximately 500
mL) within 4 weeks prior to the pretrial (screening) visit.

- has participated in another investigational trial within 4 weeks prior to the pretrial
(screening) visit. The 4 week window will be derived from the date of the last trial
medication and / or blood collection in a previous trial and/or adverse event related
to trial drug to the pretrial/screening visit of the current trial.

- consumes greater than 2 glasses of alcoholic beverages (1 glass is approximately
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits
[29.5 mL/1 ounce]) per day. Patients that consume 4 glasses of alcoholic beverages per
day may be enrolled at the discretion of the investigator.

- consumes excessive amounts, defined as greater than 4 servings

(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola,
energy-drinks, or other caffeinated beverages per day.

- is currently a regular user (including "recreational use") of any illicit drugs or has
a history of drug (including alcohol) abuse within approximately 3 months of the
screening visit.

- is unwilling or unable to adhere to the dietary needs during the study, or to consume
the standardized meals during the study, and/or is on a carbohydrate restricted diet
(i.e., a diet <100 grams per day of carbohydrate).

- is any concern by the investigator regarding the safe participation of the subject in
the trial or for any other reason; the investigator considers the subject
inappropriate for participation in the trial.

- has a history of claustrophobia or is claustrophobic.

- has ever had an organ transplant.

- is a smoker or uses other nicotine-containing products (for at least 6 months prior to
drug administration); plans to begin smoking or using nicotine-containing products
during the conduct of the study.

- has poor intravenous access.

- has used any medications that are known to influence glucose, fat, or energy
metabolism within the last 3 months (growth hormones, steroids, etc.)

- has blood pressure at screening visit less than or equal to 100/50 mm Hg or greater
than or equal to 160/100 mm Hg.