Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans

Abstract

Objective: Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.

Research design and methods: A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0-28.3] years; BMI: 26.4 [24.3-28.0] kg/m(2)) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.

Results: PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).

Conclusions: The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Trial registration: ClinicalTrials.gov NCT00744224.

Figures

Figure 1

The effect of PRED with or without concomitant EXE infusion on plasma glucose (A), insulin (B), C-peptide (C), and glucagon (D) levels during the meal challenge. PRED increased AUCG, which was prevented by EXE (A), despite lower insulin and C-peptide levels (B,C). EXE infusion reduced postprandial glucagon levels compared with PRED (D). Mean ± SEM shown. Black solid line with closed squares: PLB+SAL; gray intersected line with closed circles: PRED+SAL; black dotted line with open circles: PRED+EXE.

Figure 2

The effect of PRED with or without concomitant EXE infusion on C-peptide (A) and insulin (B) concentrations during the hyperglycemic clamp. PRED+SAL decreased first-phase (min 0–10) and arginine-stimulated C-peptide secretion (min 80–110), which were completely restored and improved by concomitant EXE administration (black solid line with closed squares: PLB+SAL; gray intersected line with closed circles: PRED+SAL; black dotted line with open circles: PRED+EXE). C: PRED-induced changes in M-value during the euglycemic clamp. PRED reduced combined first- and second-phase (min 0–80) DI (D) and arginine-stimulated (min 80–110) DI (E), which was restored and improved by EXE (box-and-whisker plots [min-max] are shown).