Pro-Inflammatory Cytokines Induce Insulin and Glucagon Double Positive Human Islet Cells That Are Resistant to Apoptosis

The presence of islet cells double positive for insulin and glucagon (Ins(+)/Glu(+)) has been described in the pancreas from both type 2 (T2D) and type 1 (T1D) diabetic subjects. We studied the role of pro-inflammatory cytokines on the occurrence, trajectory, and characteristics of Ins(+)/Glu(+) cells in human pancreatic islets. Pancreas samples, isolated islets, and dispersed islet cells from 3 T1D and 11 non-diabetic (ND) multi-organ donors were studied by immunofluorescence, confocal microscopy, and/or electron microscopy. ND islet cells were exposed to interleukin-1 beta and interferon-gamma for up to 120 h. In T1D islets, we confirmed an increased prevalence of Ins(+)/Glu(+) cells. Cytokine-exposed islets showed a progressive increase of Ins(+)/Glu(+) cells that represented around 50% of endocrine cells after 120h. Concomitantly, cells expressing insulin granules only decreased significantly over time, whereas those containing only glucagon granules remained stable. Interestingly, Ins(+) /Glu(+) cells were less prone to cytokine-induced apoptosis than cells containing only insulin. Cytokine-exposed islets showed down-regulation of beta-cell identity genes. In conclusion, pro-inflammatory cytokines induce Ins(+) /Glu(+) cells in human islets, possibly due to a switch from a beta- to a beta-/alpha-cell phenotype. These Ins(+) /Glu(+) cells appear to be resistant to cytokine-induced apoptosis.