1. Insulin biosynthesis and secretion

Diabetes mellitus is a chronic hyperglycemic condition in which blood sugar is not taken up by tissues due to deficiency or reduced action of insulin. Insulin biosynthesis and secretion in pancreatic β cells, which are insulin-producing cells, is a central problem of β cell biology. We are studying glucose-stimulated insulin biosynthesis and secretion, focusing on the CD38-cyclic ADP-ribose-ryanodine receptor-Ca²⁺ signaling system discovered in our laboratory.

2. Death and regeneration of insulin-producing cells

Pancreatic β cells, which are insulin-producing cells, are damaged by immune abnormalities and various radicals, leading to their death. Therefore, their regeneration would be expected to contribute to a fundamental cure for diabetes. We are studying the “Reg (regenerating gene) protein/Reg receptor signaling system” in which Reg proteins act on receptors as cell growth factors to explore the possibility of tissue regeneration.

3. Molecular biology of intermittent hypoxia

Sleep apnea syndrome (SAS), which is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for lifestyle diseases such as diabetes, obesity, hypertension, and atherosclerosis. We are attempting to elucidate the effects of IH on the complications of lifestyle diseases from a molecular biological perspective. We have found that IH causes impaired function and compensatory proliferation of pancreatic β cells, increased expression of hepatokines in hepatocytes, increased expression of adipokines in adipocytes, and increased expression of myokines in skeletal muscle cells, which may increase the susceptibility to complications of type 2 diabetes.

Publications

• Takasawa S.
  CD38-cyclic ADP-ribose signal system in physiology, biochemistry, and pathophysiology.
  Int J Mol Sci 23: 4306, 2022.
• Takeda Y, Itaya-Hironaka A, Yamauchi A, Makino M, Sakuramoto-Tsuchida S, Ota H, Kawaguchi R, Takasawa S.
  Intermittent hypoxia upregulates the Renin and CD38 mRNAs in renin-producing cells via the downregulation of miR-203.
  Int J Mol Sci 22: 10127, 2021.
• Uchiyama T, Itaya-Hironaka A, Yamauchi A, Makino M, Sakuramoto-Tsuchida S, Shobatake R. Ota H, Takeda M, Ohbayashi C, Takasawa S.
  Intermittent hypoxyia up-regulates CCL2, RETN, and TNFα mRNAs in adipocytes via down-regulation of miR-452.
  Int J Mol Sci 20: 1960, 2019.
• Shobatake R, Takasawa K, Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Uchiyama T, Makino M, Sugie K, Takasawa S, Ueno S.
  Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells.
  Int J Biochem Cell Biol 95: 100-107, 2018.
• Tsuchida C, Sakuramoto-Tsuchida S, Takeda M, Itaya-Hironaka A, Yamauchi A, Misu M, Shobatake R, Uchiyama T, Makino M, Pujol-Autonell I, Vives-Pi M, Ohbayashi C, Takasawa S.
  Expression of REG family genes in human inflammatory bowel diseases and its regulation.
  Biochem Biophys Rep 12: 198-205, 2017.
• Mikami S, Ota I, Masui T, Itaya-Hironaka A, Shobatake R, Okamoto H, Takasawa S, Kitahara T.
  Effect of resveratrol on cancer progression through the REG III expression pathway in head and neck cancer cells.
  Int J Oncol 49: 1553-1560, 2016.
• Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Ota H, Takeda M, Fujimura T, Takasawa S, Ogata N.
  Human retinal pigment epithelial cell proliferation by the combined stimulation of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene.
  Biochem Biophys Rep 2: 123-131, 2015.
• Fujimura T, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Yoshimoto K, Yamauchi A, Sakuramoto-Tsuchia S, Kondo S, Takeda M, Tsujinaka H, Azuma M, Tanaka Y, Takasawa S.
  Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren’s syndrome patients, in salivary duct epithelial cells.
  Biochem Biophys Rep 2: 69-74, 2015.
• Enami N, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Takasawa S, Takahashi Y.
  The CD38 genotype (rs1800561 (4693C>T): R140W) is associated with an increased risk of admission to the neonatal intensive care unit.
  Early Human Dev 91: 467-470, 2015.
• Yamauchi A, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Takeda M, Yoshimoto K, Miyaoka T, Fujimura T, Tsujinaka H, Tsuchida C, Ota H, Takasawa S.
  Synergistic activation of REG Iα and REG Iβ promoters by IL-6 and glucocorticoids through JAK/STAT pathway in human pancreatic beta cells.
  J Diabetes Res 2015: 173058, 2015.
• Kyotani Y, Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Zhao J, Ozawa K, Nakayama K, Ito S, Takasawa S, Kimura H, Uno M, Yoshizumi M.
  Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor.
  Exp Cell Res 319(19): 3042-3050, 2013.
• Yoshimoto K, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Sakuramoto-Tsuchida S, Yamauchi A, Takeda M, Kasai T, Nakagawara K-I, Nonomura A, Takasawa S.
  Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren’s syndrome.
  Clin Exp Immunol 174(1): 1-9, 2013.
• Ota H, Tamaki S, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Morioka T, Takasawa S, Kimura H.
  Attenuation of glucose-induced insulin secretion by intermittent hypoxia via down-regulation of CD38.
  Life Sci 90(5-6): 206-211, 2012.