Endocrine Abstracts

Impaired glucose tolerance and insulin sensitivity are established hallmarks of diabetes and it was speculated that also fructose tolerance could be impaired. However, investigation of fructose tolerance has been hampered by the lack of easy accessible pharmacodynamic markers. In humans, the hormone FGF21 has recently been demonstrated to be a sensitive pharmacodynamic marker responding to an oral fructose bolus and exhibiting a divergent secretion pattern in obese diabetic and healthy lean subjects. Here we investigated whether FGF21 excursion after an oral fructose challenge follows the same rules in mice.

Methods: Fasted male obese ob/ob mice received an oral fructose bolus (1 g/kg, n=10). Lean ob/- mice were gavaged with water, only (n=10/group). Another cohort of ob/ob mice was pre-treated with Sitagliptin (at t=−30 min, 40 μg/mouse, MSD Sharp and Dohme) before exposure to oral fructose (‘ob/ob-S’, n=10). Blood was collected at timepoints −30, 0, 30, 60, 120 and 180 min after fructose or vehicle treatment for analysis of glucose, plasma insulin, GLP-1 and FGF21.

Results: ob/ob mice displayed higher plasma insulin when compared to lean mice (P<0.001). Sitagliptin pre-treated ob/ob mice had significantly higher GLP-1 concentrations compared to ob/ob mice without pre-treatment (P<0.05). Similar to humans, the oral fructose bolus did not significantly change blood glucose concentrations between 0–180 min (e.g. at t=30 min; ob/-: 8.1±0.2 mmol/l; ob/ob: 9.5±1.4 mmol/l; ob/ob-S: 11.9±2.0 mmol/l). Throughout the study, ob/ob mice (independent of pre-treatment) showed significantly higher FGF21 concentrations compared to ob/- mice (e.g. at t=30 min; ob/-: 317±108 pg/ml; ob/ob: 2268±330 pg/ml; ob/ob-S: 2071±298 pg/ml). However, plasma FGF21 concentrations were not significantly affected by oral fructose ingestion in lean and obese mice at all timepoints.

Conclusion: In mice, circulating FGF21 was not responsive to an oral fructose load, at least under the conditions studied. Thus, the oral fructose tolerance test with the pharmacodynamic readout FGF21 cannot be easily translated from humans to laboratory rodents.