Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 102, Issue 4, Pages 1340-1349Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2016-3835
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Funding
- Danish Council for Independent Research [DFF-4004-00304]
- Novo Nordisk Foundation [NNF-13OC0007869]
- Novo Nordisk Foundation
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Context: 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. Subjects and 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.
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