title: Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques.
abstract: Dexamethasone has well-described effects to induce insulin resistance and increase insulin secretion. Herein, we examined potential contributors to the effect of dexamethasone to increase insulin secretion in rhesus macaques. Six male rhesus macaques received daily injections of either saline or dexamethasone (0.25 mg/kg i.m. for 7 days) in random order with 3 weeks between treatments. At the end of the treatment period, animals were fasted overnight and underwent a feeding study the next day, during which blood samples were taken before and for 60 min after a meal in order to assess islet hormone and incretin secretion. Dexamethasone induced marked increases in fasting plasma insulin, glucagon, leptin, and adiponectin concentrations (P<0.05). Surprisingly, the glycemic response after meal ingestion was decreased twofold during dexamethasone treatment (P<0.05). Dexamethasone-treated animals exhibited a significant increase in both insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion during the feeding study (P<0.05). However, glucagon-like peptide-1 secretion was significantly lower in dexamethasone-treated animals compared with controls (P<0.01). Fasting and meal-stimulated pancreatic polypeptide concentrations (an index of the parasympathetic input to the islet) did not differ between saline and dexamethasone treatments. However, the proinsulin:insulin ratio was decreased throughout the feeding study with dexamethasone treatment suggesting an improvement of β-cell function (P<0.05). In conclusion, the maintenance of euglycemia and reduction of postprandial glycemia with short-term dexamethasone treatment appears to be due to the marked elevations of fasting and meal-stimulated insulin secretion. Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA. bpcummings@ucdavis.edu
authors.forename: Bethany P
authors.initials: BP
authors.lastname: Cummings
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Bremer
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: David
authors.initials: D
authors.lastname: D'Alessio
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005215:Fasting / Q000097:blood; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D008253:Macaca mulatta; D008297:Male; D019518:Postprandial Period / Q000187:drug effects; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D003907:Dexamethasone; C041086:gastric inhibitory polypeptide receptor