IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation

Aims/hypothesis IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas. Methods Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham-operated mouse pancreases. Proliferation of glucagon + cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody. Results In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained. Conclusions/interpretation In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells.