Background:Due to the shortage of multi-organ donors, human pancreaticislet transplantation has now been extended to islets originating from obesesubjects. In this study, our aim is to compare the respective sensitivity ofhuman islets from lean vs obese donors to chronic high glucose or highpalmitate.Methods:Human islets were isolated from pancreases harvested from brain-dead multi-organ donors. Islets were cultured during 72 hours in the presenceof moderate (16.7 mmol/L) or high (28 mmoL/L) glucose concentrations, orglucose (5.6 mmoL/L) and palmitate (0.4 mmoL/L), before measurement oftheir response to glucose.Results:We first observed a greater insulin response in islets from obesedonors under both basal and high-glucose conditions, confirming their hyper-responsiveness to glucose. When islets from obese donors were cultured in thepresence of moderate or high glucose concentrations, insulin response to glu-cose remained unchanged or was slightly reduced, as opposed to that observedin lean subjects. Moreover, culturing islets from obese donors with high palmi-tate also induced less reduction in insulin response to glucose than in lean sub-jects. This partial protection of obese islets is associated with less induction ofinducible nitric oxide synthase in islets, together with a greater expression ofthe transcription factor forkhead box O1 (FOXO1).Conclusions:Our data suggest that in addition to an increased sensitivity toglucose, islets from obese subjects can be considered as more resistant to glucose and fatty acid excursions and are thus valuable candidates fortransplantation.Highlights•Human islets from obese subjects display low sensitivity to gluco-lipotoxicity.•Partial protection is associated with less induction of inducible nitric oxidesynthase (iNOS) and greater expression of forkhead box protein O1(FOXO1)