Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca2+ release from the ER
Ryota Inoue,
Takahiro Tsuno,
Yu Togashi,
Tomoko Okuyama,
Aoi Sato,
Kuniyuki Nishiyama,
Mayu Kyohara,
Jinghe Li,
Setsuko Fukushima,
Tatsuya Kin,
Daisuke Miyashita,
Yusuke Shiba,
Yoshitoshi Atobe,
Hiroshi Kiyonari,
Kana Bando,
A.M. James Shapiro,
Kengo Funakoshi,
Rohit N. Kulkarni,
Yasuo Terauchi,
Jun Shirakawa
Affiliations
Ryota Inoue
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Takahiro Tsuno
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Yu Togashi
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Tomoko Okuyama
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Aoi Sato
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
Kuniyuki Nishiyama
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Mayu Kyohara
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Jinghe Li
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Setsuko Fukushima
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
Tatsuya Kin
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
Daisuke Miyashita
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Yusuke Shiba
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Yoshitoshi Atobe
Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
Hiroshi Kiyonari
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
Kana Bando
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
A.M. James Shapiro
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
Kengo Funakoshi
Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
Rohit N. Kulkarni
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
Yasuo Terauchi
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Jun Shirakawa
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; Corresponding author
Summary: Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
