TY - JOUR

T1 - MCPIP1 is a novel link between diabetogenic conditions and impaired insulin secretory capacity

AU - Tyka, Karolina

AU - Joerns, Anne

AU - Dunst, Alessia

AU - Tang, Yadi

AU - Bryde, Tenna Holgersen

AU - Mehmeti, Ilir

AU - Walentinsson, Anna

AU - Marselli, Lorella

AU - Cnop, Miriam

AU - Tyrberg, Bjorn

AU - Marzec, Michal T.

AU - Gurgul-Convey, Ewa

PY - 2021

Y1 - 2021

N2 - During diabetes development insulin production and glucose-stimulated insulin secretion (GSIS) are defective due to inflammation-related, yet not fully understood mechanisms. MCPIP1 (monocyte chemotactic protein-induced protein-1) is a strong regulator of inflammation, and acts predominantly as a specific RNase. The impact of MCPIP1 on insulin secretory capacity is unknown.We show that the expression of the ZC3H12A gene, which encodes MCPIP1, was induced by T1DM- and by T2DM-simulating conditions, with a stronger effect of cytokines. The number of MCPIP1-positive pancreatic islet-cells, including beta-cells, was significantly higher in diabetic compared to nondiabetic individuals. In the 3' UTR regions of mRNAs coding for Pdx1 (pancreatic and duodenal homeobox 1), FoxO1 (forkhead box protein O1), and of a novel regulator of insulin handling, Grp94 (glucose-regulated protein 94), MCPIP1-target structures were detected. Overexpression of the wild type MCPIP1(wt), but not of the mutant MCPIP1(D141N) (lacking the RNase activity), decreased the expression of genes involved in insulin production and GSIS. Additionally INS1-E-MCPIP1(wt) cells exhibited a higher Ire1 (inositol-requiring enzyme 1) expression. MCPIP1(wt) overexpression blunted GSIS and glucose-mediated calcium influx with no deleterious effects on glucose uptake or glucokinase activity.We identify MCPIP1 as a new common link between diabetogenic conditions and beta-cell failure. MCPIP1 may serve as an interesting target for novel beta-cell protective approaches.

AB - During diabetes development insulin production and glucose-stimulated insulin secretion (GSIS) are defective due to inflammation-related, yet not fully understood mechanisms. MCPIP1 (monocyte chemotactic protein-induced protein-1) is a strong regulator of inflammation, and acts predominantly as a specific RNase. The impact of MCPIP1 on insulin secretory capacity is unknown.We show that the expression of the ZC3H12A gene, which encodes MCPIP1, was induced by T1DM- and by T2DM-simulating conditions, with a stronger effect of cytokines. The number of MCPIP1-positive pancreatic islet-cells, including beta-cells, was significantly higher in diabetic compared to nondiabetic individuals. In the 3' UTR regions of mRNAs coding for Pdx1 (pancreatic and duodenal homeobox 1), FoxO1 (forkhead box protein O1), and of a novel regulator of insulin handling, Grp94 (glucose-regulated protein 94), MCPIP1-target structures were detected. Overexpression of the wild type MCPIP1(wt), but not of the mutant MCPIP1(D141N) (lacking the RNase activity), decreased the expression of genes involved in insulin production and GSIS. Additionally INS1-E-MCPIP1(wt) cells exhibited a higher Ire1 (inositol-requiring enzyme 1) expression. MCPIP1(wt) overexpression blunted GSIS and glucose-mediated calcium influx with no deleterious effects on glucose uptake or glucokinase activity.We identify MCPIP1 as a new common link between diabetogenic conditions and beta-cell failure. MCPIP1 may serve as an interesting target for novel beta-cell protective approaches.

KW - MCPIP1

KW - Diabetes

KW - Beta-cells

KW - Human islets

KW - Insulin production and secretion

KW - Inflammation

KW - NF-KAPPA-B

KW - INFLAMMATION

KW - CELLS

KW - DEGRADATION

KW - PROTEIN

KW - TYPE-1

KW - GENES

KW - RNASE

U2 - 10.1016/j.bbadis.2021.166199

DO - 10.1016/j.bbadis.2021.166199

M3 - Journal article

C2 - 34144091

VL - 1867

JO - B B A - Molecular Basis of Disease

JF - B B A - Molecular Basis of Disease

SN - 0925-4439

IS - 10

M1 - 166199

ER -