Glucagon-Like Peptide-1 Receptor Agonist Treatment Prevents Glucocorticoid-Induced Glucose Intolerance and Islet-Cell Dysfunction in Humans

Abstract

OBJECTIVEGlucocorticoids (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 METHODSA 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/m2) 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.RESULTSPRED+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).CONCLUSIONSThe 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.

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

“…The fact that in humans the incretin effect is reduced by GCs, despite normal concentrations of (active) GLP1 (33,34), suggests that GCs may impair GLP1-mediated activation of PKA. On the other hand, exenatide infusions, resulting in pharmacological levels of GLP1, were shown to prevent the acute diabetogenic effects of prednisolone in healthy volunteers (15). An additional mechanism by which GLP1 receptor agonist treatment, in contrast to DPP-4 inhibitors (35,36), may prevent GC-induced hyperglycemia is by reducing gastric emptying rate -an effect attributed to the higher pharmacological levels of GLP1.…”

“…A cannula was inserted into the antecubital vein of the dominant arm to allow blood sampling. After completion of the fasting blood collections (TZK15 min), the standardized mixed-meal, consisting of 905 kcal (75 g carbohydrates, 36 g proteins, and 50 g fat) (15), was served. The participants were instructed to consume the meal within 10 min.…”

“…In a proof-of-principle study, i.v. administration of the GLP1 receptor agonist, exenatide, prevented postprandial hyperglycemia and islet-cell dysfunction induced by high-dose of prednisolone treatment for 2 days in healthy young men (15). In a clinical setting, however, high-dose GCs are often prescribed for a prolonged period of time, before tapering down, to middle-aged patients suffering from low-to-high grade inflammation (16).…”

Glikokortykosteroidy a zaburzenia metabolizmu glukozy

“…Duże nadzieje wiąże się ze stosowaniem analogów GLP-1 w leczeniu hiperglikemii wywołanej przez GS [67][68][69]. Bardzo interesujące wydają się próby zastosowania tej grupy leków inkretynowych w prewencji zaburzeń tolerancji glukozy u osób przyjmujących GS.…”

Medications affecting glycemic control

“…Shorter acting agents might be more appropriate, but exenatide is the only agent studied for GIH ( Table 2) [88]. Exenatide targets postprandial hyperglycemia and has been shown to prevent prednisone induced glucose intolerance [98].…”