Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells

Xiwen Xiong, Gaihong Wang, Rongya Tao, Pengfei Wu, Tatsuyoshi Kono, Kevin Li, Wen Xing Ding, Xin Tong, Sarah A. Tersey, Robert Harris, Raghu Mirmira, Carmella Evans-Molina, X. Dong

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Aims/hypothesis: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. Methods: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. Results: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. Conclusions/interpretation: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.

Original languageEnglish (US)
Pages (from-to)151-160
Number of pages10
JournalDiabetologia
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Insulin-Secreting Cells
Insulin
Glucose
Knockout Mice
Oxygen Consumption
Mitochondria
Gene Knockdown Techniques
Calcium
Potassium Chloride
Fura-2
Glycolysis
Fluorescent Dyes
Islands
DNA Repair
Electron Microscopy
Adenosine Triphosphate

Keywords

  • Beta cell
  • Calcium
  • Glucose metabolism
  • Insulin secretion
  • Mitochondria
  • SIRT6

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells. / Xiong, Xiwen; Wang, Gaihong; Tao, Rongya; Wu, Pengfei; Kono, Tatsuyoshi; Li, Kevin; Ding, Wen Xing; Tong, Xin; Tersey, Sarah A.; Harris, Robert; Mirmira, Raghu; Evans-Molina, Carmella; Dong, X.

In: Diabetologia, Vol. 59, No. 1, 01.01.2016, p. 151-160.

Research output: Contribution to journalArticle

Xiong, Xiwen ; Wang, Gaihong ; Tao, Rongya ; Wu, Pengfei ; Kono, Tatsuyoshi ; Li, Kevin ; Ding, Wen Xing ; Tong, Xin ; Tersey, Sarah A. ; Harris, Robert ; Mirmira, Raghu ; Evans-Molina, Carmella ; Dong, X. / Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells. In: Diabetologia. 2016 ; Vol. 59, No. 1. pp. 151-160.
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abstract = "Aims/hypothesis: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. Methods: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. Results: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50{\%} decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. Conclusions/interpretation: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.",
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AU - Xiong, Xiwen

AU - Wang, Gaihong

AU - Tao, Rongya

AU - Wu, Pengfei

AU - Kono, Tatsuyoshi

AU - Li, Kevin

AU - Ding, Wen Xing

AU - Tong, Xin

AU - Tersey, Sarah A.

AU - Harris, Robert

AU - Mirmira, Raghu

AU - Evans-Molina, Carmella

AU - Dong, X.

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N2 - Aims/hypothesis: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. Methods: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. Results: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. Conclusions/interpretation: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.

AB - Aims/hypothesis: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. Methods: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. Results: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. Conclusions/interpretation: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.

KW - Beta cell

KW - Calcium

KW - Glucose metabolism

KW - Insulin secretion

KW - Mitochondria

KW - SIRT6

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