title: Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids.
abstract: Ghrelin produced in the gut stimulates GH and ACTH secretion from the pituitary and also stimulates appetite and gastric emptying. We have shown that ghrelin also induces insulin resistance via GH-independent mechanisms, but it is unknown if this effect depends on ambient fatty acid (FFA) levels. We investigated the impact of ghrelin and pharmacological antilipolysis (acipimox) on insulin sensitivity and substrate metabolism in 8 adult hypopituitary patients on stable replacement with GH and hydrocortisone using a 2 × 2 factorial design: Ghrelin infusion, saline infusion, ghrelin plus short-term acipimox, and acipimox alone. Peripheral and hepatic insulin sensitivity was determined with a hyperinsulinemic euglycemic clamp in combination with a glucose tracer infusion. Insulin signaling was assayed in muscle biopsies. Peripheral insulin sensitivity was reduced by ghrelin independently of ambient FFA concentrations and was increased by acipimox independently of ghrelin. Hepatic insulin sensitivity was increased by acipimox. Insulin signaling pathways in skeletal muscle were not consistently regulated by ghrelin. Our data demonstrate that ghrelin induces peripheral insulin resistance independently of GH, cortisol, and FFA. The molecular mechanisms remain elusive, but we speculate that ghrelin is a hitherto unrecognized direct regulator of substrate metabolism. We also suggest that acipimox per se improves hepatic insulin sensitivity.
authors.affiliation: Medical Research Laboratory, Aarhus University, Nørrebrogade 44 building 3B, 8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44 building 2A, 8000 Aarhus C, Denmark.|Department of Pediatrics, Randers Regional Hospital, Randers 8930 Denmark.
authors.forename: Esben T
authors.initials: ET
authors.lastname: Vestergaard
authors.affiliation: Medical Research Laboratory, Aarhus University, Nørrebrogade 44 building 3B, 8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44 building 2A, 8000 Aarhus C, Denmark.|Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Nørrebrogade 44 building 3A, 8000 Aarhus C, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Medical Research Laboratory, Aarhus University, Nørrebrogade 44 building 3B, 8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44 building 2A, 8000 Aarhus C, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
authors.affiliation: Medical Research Laboratory, Aarhus University, Nørrebrogade 44 building 3B, 8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44 building 2A, 8000 Aarhus C, Denmark.
authors.forename: Jens Otto Lunde
authors.initials: JO
authors.lastname: Jørgensen