Beta-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1 beta is associated with changes in expression of beta-cell maturity genes and associated histone modifications

TY - JOUR

T1 - Beta-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1 beta is associated with changes in expression of beta-cell maturity genes and associated histone modifications

AU - Urizar, Adriana Ibarra

AU - Prause, Michala

AU - Wortham, Matthew

AU - Sui, Yinghui

AU - Thams, Peter

AU - Sander, Maike

AU - Christensen, Gitte Lund

AU - Billestrup, Nils

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1 beta induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1 beta at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome. Following removal of IL-1 beta, beta-cell function was normalized and mRNA expression of beta-cell identity genes, such as insulin and Ucn3 returned to pre-stimulation levels. Our findings indicate that prolonged exposure to low concentrations of IL-1 beta induces epigenetic changes associated with loss of beta-cell identity as observed in Type 2 diabetes

AB - Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1 beta induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1 beta at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome. Following removal of IL-1 beta, beta-cell function was normalized and mRNA expression of beta-cell identity genes, such as insulin and Ucn3 returned to pre-stimulation levels. Our findings indicate that prolonged exposure to low concentrations of IL-1 beta induces epigenetic changes associated with loss of beta-cell identity as observed in Type 2 diabetes

KW - Beta-cell dysfunction

KW - Histone modifications

KW - Beta-cell dedifferentiation

KW - Cytokines

KW - Proliferation

KW - Insulin secretion

U2 - 10.1016/j.mce.2019.110524

DO - 10.1016/j.mce.2019.110524

M3 - Review

C2 - 31362031

SN - 0303-7207

VL - 496

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

M1 - 110524

ER -