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01.09.2013 | Article

Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function

verfasst von: Chen Wang, Xiaowen Li, Kaida Mu, Ling Li, Shihong Wang, Yunxia Zhu, Mingliang Zhang, Jiyoon Ryu, Zhifang Xie, Dongyun Shi, Weiping J. Zhang, Lily Q. Dong, Weiping Jia

Erschienen in: Diabetologia | Ausgabe 9/2013

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Abstract

Aims/hypothesis

Adaptor protein, phosphotyrosine interaction, pleckstrin homology domain and leucine zipper containing 1 (APPL1) is an adapter protein that positively mediates adiponectin signalling. Deficiency of APPL1 in the target tissues of insulin induces insulin resistance. We therefore aimed, in the present study, to determine its role in regulating pancreatic beta cell function.

Methods

A hyperglycaemic clamp test was performed to determine insulin secretion in APPL1 knockout (KO) mice. Glucose- and adiponectin-induced insulin release was measured in islets from APPL1 KO mice or INS-1(832/13) cells with either APPL1 knockdown or overproduction. RT-PCR and western blotting were conducted to analyse gene expression and protein abundance. Oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential were assayed to evaluate mitochondrial function.

Results

APPL1 is highly expressed in pancreatic islets, but its levels are decreased in mice fed a high-fat diet and db/db mice compared with controls. Deletion of the Appl1 gene leads to impairment of both the first and second phases of insulin secretion during hyperglycaemic clamp tests. In addition, glucose-stimulated insulin secretion (GSIS) is significantly decreased in islets from APPL1 KO mice. Conversely, overproduction of APPL1 leads to an increase in GSIS in beta cells. In addition, expression levels of several genes involved in insulin production, mitochondrial biogenesis and mitochondrial OCR, ATP production and mitochondrial membrane potential are reduced significantly in APPL1-knockdown beta cells. Moreover, suppression or overexproduction of APPL1 inhibits or stimulates adiponectin-potentiated GSIS in beta cells, respectively.

Conclusions/interpretation

Our study demonstrates the roles of APPL1 in regulating GSIS and mitochondrial function in pancreatic beta cells, which implicates APPL1 as a therapeutic target in the treatment of type 2 diabetes.

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Titel: Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function
verfasst von: Chen Wang
Xiaowen Li
Kaida Mu
Ling Li
Shihong Wang
Yunxia Zhu
Mingliang Zhang
Jiyoon Ryu
Zhifang Xie
Dongyun Shi
Weiping J. Zhang
Lily Q. Dong
Weiping Jia
Publikationsdatum: 01.09.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 9/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-2971-4

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Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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