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DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes

Bugliani, Marco; Syed, Farooq; Paula, Flavia M.M.; Omar, Bilal A. LU ; Suleiman, Mara; Mossuto, Sandra; Grano, Francesca; Cardarelli, Francesco; Boggi, Ugo and Vistoli, Fabio, et al. (2018) In Molecular and Cellular Endocrinology
Abstract

It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western... (More)

It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-βH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-βH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival.

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publication status
epub
subject
keywords
Apoptosis, Beta cells, Cytokines, DPP-4, MK-0626, Type 2 diabetes
in
Molecular and Cellular Endocrinology
publisher
Elsevier
external identifiers
  • scopus:85044729622
ISSN
0303-7207
DOI
10.1016/j.mce.2018.01.019
language
English
LU publication?
yes
id
29f386d9-ebb9-46e6-9870-57ecf5aa8998
date added to LUP
2018-04-12 15:33:43
date last changed
2018-10-16 04:08:19
@article{29f386d9-ebb9-46e6-9870-57ecf5aa8998,
  abstract     = {<p>It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-βH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-βH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival.</p>},
  author       = {Bugliani, Marco and Syed, Farooq and Paula, Flavia M.M. and Omar, Bilal A. and Suleiman, Mara and Mossuto, Sandra and Grano, Francesca and Cardarelli, Francesco and Boggi, Ugo and Vistoli, Fabio and Filipponi, Franco and De Simone, Paolo and Marselli, Lorella and De Tata, Vincenzo and Ahren, Bo and Eizirik, Decio L. and Marchetti, Piero},
  issn         = {0303-7207},
  keyword      = {Apoptosis,Beta cells,Cytokines,DPP-4,MK-0626,Type 2 diabetes},
  language     = {eng},
  month        = {02},
  publisher    = {Elsevier},
  series       = {Molecular and Cellular Endocrinology},
  title        = {DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes},
  url          = {http://dx.doi.org/10.1016/j.mce.2018.01.019},
  year         = {2018},
}