Loss of ZNF148 enhances insulin secretion in human pancreatic β cells
Eleonora de Klerk, Yini Xiao, Christopher H. Emfinger, Mark P. Keller, David I. Berrios, Valentina Loconte, Axel A. Ekman, Kate L. White, Rebecca L. Cardone, Richard G. Kibbey, Alan D. Attie, Matthias Hebrok
Eleonora de Klerk, Yini Xiao, Christopher H. Emfinger, Mark P. Keller, David I. Berrios, Valentina Loconte, Axel A. Ekman, Kate L. White, Rebecca L. Cardone, Richard G. Kibbey, Alan D. Attie, Matthias Hebrok
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Research Article Metabolism Stem cells

Loss of ZNF148 enhances insulin secretion in human pancreatic β cells

Abstract

Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of ZNF148 in human islets, and its deletion in stem cell–derived β cells (SC–β cells), enhances insulin secretion. Transcriptomics of ZNF148-deficient SC–β cells identifies increased expression of annexin and S100 genes whose proteins form tetrameric complexes involved in regulation of insulin vesicle trafficking and exocytosis. ZNF148 in SC–β cells prevents translocation of annexin A2 from the nucleus to its functional place at the cell membrane via direct repression of S100A16 expression. These findings point to ZNF148 as a regulator of annexin-S100 complexes in human β cells and suggest that suppression of ZNF148 may provide a novel therapeutic strategy to enhance insulin secretion.

Authors

Eleonora de Klerk, Yini Xiao, Christopher H. Emfinger, Mark P. Keller, David I. Berrios, Valentina Loconte, Axel A. Ekman, Kate L. White, Rebecca L. Cardone, Richard G. Kibbey, Alan D. Attie, Matthias Hebrok

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Figure 8

Effects of ZNF148 downregulation on insulin secretion in human islets.

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Effects of ZNF148 downregulation on insulin secretion in human islets. (...
(A) Dynamic secretion of C-peptide in response to stimulation with 20 mM glucose and 30 mM KCl, starting with basal glucose concentration of 2.8 mM, in control cadaveric islets (80 islets) and islets treated with siRNA targeting ZNF148 (80 islets). Inset picture shows secretion during the acute first phase. n = 3. *P < 0.05 determined by 2-tailed t test. (B) Dynamic secretion of C-peptide in control cadaveric islets and islets treated with siRNA targeting ZNF148. Data are presented as mean of fold change (20 mM/2.8 mM) relative to control islets. n = 3. (C) Dynamic secretion of C-peptide during acute first phase secretion (minute 22–26) in control cadaveric islets and islets treated with siRNA targeting ZNF148. Data are presented as AUC. Dotted line indicates islets from the same biological sample. (D) C-peptide secretion of ZNF148 knockdown (n = 4) and scramble control (n = 3) human islets normalized to total C-peptide content per minute upon the ramp up glucose challenge. (E) AUC of C-peptide secretion shown in D of ZNF148 knockdown (n = 4) and scramble control (n = 3) human islets. (F) Relative ZNF148 gene expression of ZNF148-knockdown (n = 3) and scramble control (n = 2) human islets. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01 determined by 2-tailed t test.