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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1999-2009
Number of pages11
JournalDiabetologia
Volume56
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Insulin-Secreting Cells
Insulin
Glucose
Adiponectin
Knockout Mice
Mitochondrial Membrane Potential
Oxygen Consumption
Adenosine Triphosphate
Leucine Zippers
Phosphotyrosine
Proteins
Gene Deletion
High Fat Diet
Organelle Biogenesis
Islets of Langerhans
Type 2 Diabetes Mellitus
Insulin Resistance
Western Blotting
Gene Expression
Polymerase Chain Reaction

Keywords

  • Adiponectin
  • APPL1
  • Beta cells
  • Insulin
  • Mitochondrial function

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. / Wang, Chen; Li, Xiaowen; Mu, Kaida; Li, Ling; Wang, Shihong; Zhu, Yunxia; Zhang, Mingliang; Ryu, Jiyoon; Xie, Zhifang; Shi, Dongyun; Zhang, Weiping J.; Dong, Lily Q; Jia, Weiping.

In: Diabetologia, Vol. 56, No. 9, 09.2013, p. 1999-2009.

Research output: Contribution to journalArticle

Wang, C, Li, X, Mu, K, Li, L, Wang, S, Zhu, Y, Zhang, M, Ryu, J, Xie, Z, Shi, D, Zhang, WJ, Dong, LQ & Jia, W 2013, 'Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function', Diabetologia, vol. 56, no. 9, pp. 1999-2009. https://doi.org/10.1007/s00125-013-2971-4
Wang, Chen ; Li, Xiaowen ; Mu, Kaida ; Li, Ling ; Wang, Shihong ; Zhu, Yunxia ; Zhang, Mingliang ; Ryu, Jiyoon ; Xie, Zhifang ; Shi, Dongyun ; Zhang, Weiping J. ; Dong, Lily Q ; Jia, Weiping. / Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. In: Diabetologia. 2013 ; Vol. 56, No. 9. pp. 1999-2009.
@article{184b9e38ba474873936075a5b32eea89,
title = "Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function",
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.",
keywords = "Adiponectin, APPL1, Beta cells, Insulin, Mitochondrial function",
author = "Chen Wang and Xiaowen Li and Kaida Mu and Ling Li and Shihong Wang and Yunxia Zhu and Mingliang Zhang and Jiyoon Ryu and Zhifang Xie and Dongyun Shi and Zhang, {Weiping J.} and Dong, {Lily Q} and Weiping Jia",
year = "2013",
month = "9",
doi = "10.1007/s00125-013-2971-4",
language = "English (US)",
volume = "56",
pages = "1999--2009",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "9",

}

TY - JOUR

T1 - Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function

AU - Wang, Chen

AU - Li, Xiaowen

AU - Mu, Kaida

AU - Li, Ling

AU - Wang, Shihong

AU - Zhu, Yunxia

AU - Zhang, Mingliang

AU - Ryu, Jiyoon

AU - Xie, Zhifang

AU - Shi, Dongyun

AU - Zhang, Weiping J.

AU - Dong, Lily Q

AU - Jia, Weiping

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Adiponectin

KW - APPL1

KW - Beta cells

KW - Insulin

KW - Mitochondrial function

UR - http://www.scopus.com/inward/record.url?scp=84881612123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881612123&partnerID=8YFLogxK

U2 - 10.1007/s00125-013-2971-4

DO - 10.1007/s00125-013-2971-4

M3 - Article

C2 - 23793716

AN - SCOPUS:84881612123

VL - 56

SP - 1999

EP - 2009

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -