Abstract
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-1β and interferon-γ 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 β-cell identity genes. In conclusion, pro-inflammatory cytokines induce Ins+/Glu+ cells in human islets, possibly due to a switch from a β- to a β-/α-cell phenotype. These Ins+/Glu+ cells appear to be resistant to cytokine-induced apoptosis.
Highlights
Electron microscopy showed the presence of cells containing both insulin and glucagon granules, as determined by the typical ultrastructural appearance of these granules [12,19,20] and insulin or glucagon gold immunostaining (Figure 1E,F)
We show the key role of proHuman islets in type 1 diabetes (T1D) contain Ins+/Glu+ cells
We show the key role of pro-ininflammatory cytokines in the occurrence of Ins+ /Glu+ cells in human pancreatic islets
Summary
A relatively small proportion of islet cells expresses more than one single hormone, and cells containing both insulin and glucagon (Ins+ /Glu+ cells) have been identified. Ins+ /Glu+ cells have been observed during prenatal pancreas development, representing 8–9% of the islet cell population between the Biomolecules 2021, 11, 320. The prevalence of Ins+ /Glu+ cells may increase in insulin-resistant, non-diabetic (ND) individuals that have undergone pancreatoduodenectomy [5,6], in subjects with impaired glucose tolerance, and in patients with newly diagnosed or established type 2 diabetes (T2D) [7,8]. An increased number of Ins+ /Glu+ cells has been described in a small number of type 1 diabetes (T1D)
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