Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.
BACKGROUND
Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance.


OBJECTIVE
To study the metabolic effects of GH blockade during fasting in obese subjects.


METHODS
Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies.


RESULTS
GH levels increased with fasting (P < 0.01), and the fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P < 0.05). Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P < 0.01) primarily due to reduced endogenous glucose production (P = 0.003). Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA.


CONCLUSIONS
Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects.
Medical Research Laboratory, Department of Endocrinology and Internal Medicine.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Morten Høgild
MH
Pedersen
Medical Research Laboratory, Department of Endocrinology and Internal Medicine.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Mads Vandsted
MV
Svart
Department of Biomedicine and.
Janne
J
Lebeck
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität, 80336 Munich, Germany.
Martin
M
Bidlingmaier
The MR Research Center, and.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Hans
H
Stødkilde-Jørgensen
Medical Research Laboratory, Department of Endocrinology and Internal Medicine.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Steen Bønløkke
SB
Pedersen
Medical Research Laboratory, Department of Endocrinology and Internal Medicine.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Niels
N
Møller
Department of Clinical Pharmacology, Aarhus University Hospital 8000 Aarhus, Denmark.
Niels
N
Jessen
Medical Research Laboratory, Department of Endocrinology and Internal Medicine.|Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Jens O L
JOL
Jørgensen
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D009765:Obesity / Q000378:metabolism*; D010919:Placebos; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D010919:Placebos; D019382:Human Growth Hormone; D005947:Glucose; C406545:pegvisomant