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Lrrc55 is a novel prosurvival factor in pancreatic islets.

ABSTRACT: Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ?-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ?-cell mass. Prolactin also prevents ?-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ?-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ?-cell proliferation/apoptosis (thus ?-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ?-cells had minimal effect on ?-cell proliferation and glucose-stimulated insulin secretion but protected ?-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ?-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ?-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ?-cell survival.

SUBMITTER: Makkar G

PROVIDER: S-EPMC6879869 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Lrrc55 is a novel prosurvival factor in pancreatic islets.

Makkar Guneet G Shrivastava Vipul V Hlavay Brittyne B Pretorius Marle M Kyle Barry D BD Braun Andrew P AP Lynn Francis C FC Huang Carol C

American journal of physiology. Endocrinology and metabolism 20190917 5

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating β-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower β-cell mass. Prolactin also prevents β-cell apoptosis. Many genes participate in these adaptive changes in the islet, and <i>Lrrc55</i> is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increa ...[more]

PMID: 31526288

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Project description:The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement" strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally.

Dataset Information

Lrrc55 is a novel prosurvival factor in pancreatic islets.

Publications

Lrrc55 is a novel prosurvival factor in pancreatic islets.

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