Study of Glucagon, Ghrelin and Growth Hormone as Counterregulatory Hormones

Glucagon, Ghrelin and Growth Hormone as Counterregulatory Hormones

Glucagon has been used for decades as a test of growth hormone (GH) reserve. The pathway by which GH is stimulated by glucagon is not established. Acyl ghrelin has been shown to increase GH levels and to be stimulated by an increase in adrenergic activity. The proposed study will test the concept that with the fall in blood glucose it is likely that there is a sympathetic discharge which contributes to the increase in acyl ghrelin and indirectly leads to the increase in GH and cortisol.

Glucagon given to healthy adults in doses of 1-1.5 mg i.m. has been shown to result in a peak glucagon level in the circulation after 30 min, followed by an increase in glucose and insulin levels. The subsequent decline in glucose, insulin and glucagon was followed by an increase in cortisol and GH. Ghrelin is a 28 amino acid peptide which is released from the fundus of the stomach, within the oxyntic glands and the small intestine. It circulates in two major forms, acylated and des-acylated ghrelin. Acylated ghrelin has strong GH-releasing effects which are mediated via the G-protein coupled ghrelin receptor. The proposed study will test the concept that with the fall in blood glucose during a glucagon test it is likely that there is a sympathetic discharge which contributes to the increase in acyl ghrelin and indirectly leads to the increase in GH and cortisol.

Inclusion Criteria:

1. Healthy normal men
2. Age 18-30 yrs
3. BMI 18-27 kg/m2

Exclusion Criteria:

1. Medication or previous surgery known to affect ghrelin secretion.
2. Medications known to have an impact on body weight (Seroquel, tricyclic antidepressants).
3. Medications known to have an impact on the beta adrenergic system.
4. Coronary artery disease, congestive heart failure, peripheral vascular disease, diabetes mellitus, significant hypertension (BP >180 systolic or >100 diastolic at rest); renal, hepatic, pulmonary disease; untreated hypothyroidism, untreated hyperthyroidism; history of seizure disorder; history of malignancy (other than some skin cancers), history of active chronic infections (e.g., HIV, tuberculosis).
5. Endocrine disorders, i.e., pheochromocytoma, adrenal insufficiency
6. Hematocrit < 41% men
7. History of daily tobacco use within past 3 months
8. Chronic alcohol abuse by history
9. Weight not stable (more than 10% weight change or more over past 6 months)
10. Strenuous exercise for average of more than 60 min/day
11. Investigational drug within past 6 weeks
12. Psychiatric history especially eating disorders
13. Transmeridian travel within 2 weeks prior to or during study
14. Known hypersensitivity to beta-blockers
15. Estimated Glomerular Filtration Rate below 60 mL/min/1.73m2.
16. Known cardiac dysrhythmia, especially first degree heart block. -