Effects of Glucagon Administration on Energy Expenditure

Condition(s) targeted: Hyperglucagonemia; Obesity

Intervention: Glucagon (Drug); Octreotide (Drug); Placebo (Behavioral); Insulin (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Translational Research Institute for Metabolism and Diabetes, Florida

Official(s) and/or principal investigator(s):
Christian Meyer, MD, Principal Investigator, Affiliation: Translational Research Institute for Metabolism and Diabetes

Overall contact:
Celines Martinez, Phone: 407-303-7100

The purpose of this study is to collect data to help researchers better understand the effects of glucagon on the amount of calories burned.

Official title: A Prospective Randomized, Placebo (Saline)-Controlled, Balanced, 3-treatment Regimen Crossover Study Comparing the Effects of Prolonged (13 h) Hyperglucagonemia With Those of Acute (3 hr) Hyperglucagonemia on Energy Expenditure and Endogenous Glucose Protection (EGP).

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Primary outcome: Measure of energy expenditure

Secondary outcome: Measure of endogenous glucose production

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Male.

Criteria:

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.

Celines Martinez, Phone: 407-303-7100

Florida Hospital Translational Research Institute for Metabolism and Diabetes, Orlando, Florida 32804, United States; Recruiting
Celines Martinez, Phone: 407-303-7100
Christian Meyer, MD, Principal Investigator

Florida Hospital Translational Research Institute for Metabolism and Diabetes

Related publications:

Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009 Nov 7;374(9701):1606-16. doi: 10.1016/S0140-6736(09)61375-1. Epub 2009 Oct 23. Erratum in: Lancet. 2010 Mar 20;375(9719):984.

Flint A, Raben A, Rehfeld JF, Holst JJ, Astrup A. The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes Relat Metab Disord. 2000 Mar;24(3):288-98.

Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012 Mar;153(3):1039-48. doi: 10.1210/en.2011-1499. Epub 2011 Dec 13. Review.

SCHULMAN JL, CARLETON JL, WHITNEY G, WHITEHORN JC. Effect of glucagon on food intake and body weight in man. J Appl Physiol. 1957 Nov;11(3):419-21.

Nair KS. Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J Clin Endocrinol Metab. 1987 May;64(5):896-901.

Calles-Escandón J. Insulin dissociates hepatic glucose cycling and glucagon-induced thermogenesis in man. Metabolism. 1994 Aug;43(8):1000-5.

Miyoshi H, Shulman GI, Peters EJ, Wolfe MH, Elahi D, Wolfe RR. Hormonal control of substrate cycling in humans. J Clin Invest. 1988 May;81(5):1545-55.

Billington CJ, Briggs JE, Link JG, Levine AS. Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo. Am J Physiol. 1991 Aug;261(2 Pt 2):R501-7.

Gimeno RE, Moller DE. FGF21-based pharmacotherapy--potential utility for metabolic disorders. Trends Endocrinol Metab. 2014 Jun;25(6):303-11. doi: 10.1016/j.tem.2014.03.001. Epub 2014 Apr 5. Review.

Boyle PJ, Justice K, Krentz AJ, Nagy RJ, Schade DS. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab. 1993 Mar;76(3):752-6.

Krentz AJ, Boyle PJ, Macdonald LM, Schade DS. Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism. 1994 Jan;43(1):24-31.

Tan TM, Field BC, McCullough KA, Troke RC, Chambers ES, Salem V, Gonzalez Maffe J, Baynes KC, De Silva A, Viardot A, Alsafi A, Frost GS, Ghatei MA, Bloom SR. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013 Apr;62(4):1131-8. doi: 10.2337/db12-0797. Epub 2012 Dec 17.

Lam YY, Redman LM, Smith SR, Bray GA, Greenway FL, Johannsen D, Ravussin E. Determinants of sedentary 24-h energy expenditure: equations for energy prescription and adjustment in a respiratory chamber. Am J Clin Nutr. 2014 Apr;99(4):834-42. doi: 10.3945/ajcn.113.079566. Epub 2014 Feb 5.

Starting date: September 2014
Last updated: May 11, 2015