Alteration in nutrient sensing and metabolic diseases

• Project/Area Number: 25282028
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Kanazawa Medical University
• Principal Investigator: KOYA Daisuke 金沢医科大学, 医学部, 教授 (70242980)
• Co-Investigator(Kenkyū-buntansha): KITADA Munehiro 金沢医科大学, 医学部, 准教授 (40434469) ; KANASAKI Keizo 金沢医科大学, 医学部, 准教授 (60589919)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
• Keywords: オートファジー / カロリー制限 / たんぱく質制限 / ケイ原性アミノ酸 / 糖尿病 / たんぱく質 / メチオニン / 代謝異常 / 腎障害 / ポドサイト / 線維化 / ケト原性アミノ酸 / 骨格筋 / 代謝 / mTOR / SIRT1

Outline of Final Research Achievements

High-calorie diet caused deregulation of the nutrient sensing signaling such as sirtuin-autophagy, thereby resulting in metabolic abnormalities and non-alcoholic fatty liver disease. Those metabolic abnormalities and pathological findings were improved through normalization of sirtuin-autophagy dysregulation by treatment with ketogenic amino acid load. Furthermore, in addition to the calorie restriction, protein-restricted diet intervened autophagy dysregulation in diabetic condition in the kidney, especially proximal tubular cells, resulting in advanced renal pathologies. In particular, improvement of metabolic abnormalities were accompanied by an improvement in insulin resistance, which might be due to the normalization of autophagy dysregulation in insulin sensitivity organs. In conclusion, autophagy regulation could be a crucial therapeutic strategy for metabolic unhealth and its related organ injury.

Research Products

• [Journal Article] A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. (2016)
  • Author(s): Kitada M, Ogura Y, Suzuki T, Sen S, Lee SM, Kanasaki K, Kume S, Koya D.
  • Journal Title: Diabetologia Volume: in press Issue: 6 Pages: 1307-17
  • DOI: 10.1007/s00125-016-3925-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen (2016)
  • Author(s): Nitta K, Shi S, Nagai T, Kanasaki M, Kitada M, Srivastava SP, Haneda M, Kanasaki K, Koya D.
  • Journal Title: Biomed Res Int Volume: 2016:9172157 Pages: 9172157-9172157
  • DOI: 10.1155/2016/9172157
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition (2016)
  • Author(s): Shi S, Kanasaki K, Koya D
  • Journal Title: Biochem Biophys Res Commun Volume: 26 Issue: 1 Pages: 184-190
  • DOI: 10.1016/j.bbrc.2016.01.154
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy. (2015)
  • Author(s): Kume S, Koya D.
  • Journal Title: Diabetes Metab J. Volume: 39 Issue: 6 Pages: 451-460
  • DOI: 10.4093/dmj.2015.39.6.451
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interactions of DPP-4 and integrin β1 influences endothelial-to mesenchymal transition. (2015)
  • Author(s): Shi S, Srivastava SP, Kanasaki M, He J, Kitada M, Nagai T, Nitta K, Takagi S, Kanasaki K, Koya D.
  • Journal Title: Kidney Int. Volume: - Issue: 3 Pages: 479-489
  • DOI: 10.1038/ki.2015.103
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma. (2015)
  • Author(s): Sasagawa Y, Tachibana O, Nakagawa A, Koya D, Iizuka H.
  • Journal Title: J Clin Neurosci Volume: 22 Issue: 3 Pages: 601-603
  • DOI: 10.1016/j.jocn.2014.08.015
  • Peer Reviewed
• [Journal Article] The biological significance of angiotensisn-converting enzyme inhibition to combat kidney fibrosis (2015)
  • Author(s): Nagai T, Nitta K, Kanasaki M, Koya D, Kanasaki K.
  • Journal Title: Clin Exp Nephrol. Volume: 19 Issue: 1 Pages: 65-74
  • DOI: 10.1007/s10157-014-1000-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical therapeutic strategies for early stage of diabetic kidney disease. (2014)
  • Author(s): Kitada M, Kanasaki K, Koya D
  • Journal Title: World J Diabetes. Volume: 5 Issue: 3 Pages: 342-356
  • DOI: 10.4239/wjd.v5.i3.342
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization and apoptosis in podocytes. (2014)
  • Author(s): Yasuda M, Tanaka Y, Kume S, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki SI, Koya D, Haneda M, Kashiwagi A, Maegawa H, Uzu T.
  • Journal Title: Biochim Biophys Acta. Volume: 1842 Issue: 7 Pages: 1097-1108
  • DOI: 10.1016/j.bbadis.2014.04.001
  • Peer Reviewed / Open Access
• [Journal Article] Linagriptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabeticmice by inhibiting endothelial-to mesenchymal transition in a therapeutic regimen. (2014)
  • Author(s): Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, Ishigaki Y, Kitada M, Srivastava SP, Koya D.
  • Journal Title: Diabetes. Volume: 63 Issue: 6 Pages: 2120-2131
  • DOI: 10.2337/db13-1029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autophagy: emerging therapeutic target for diabetic nephropathy. (2014)
  • Author(s): Kume S, Yamahara K, Yasuda M, Maegawa H, Koya D.
  • Journal Title: Semin Nephrol. Volume: 34 Issue: 1 Pages: 9-16
  • DOI: 10.1016/j.semnephrol.2013.11.003
  • Peer Reviewed
• [Journal Article] Role of sirtuins in kidney disease. (2014)
  • Author(s): Kitada M, Kume S, Koya D.
  • Journal Title: Curr Opin Nephrol Hypertens. Volume: 23 Issue: 1 Pages: 75-79
  • DOI: 10.1097/01.mnh.0000437330.85675.ac
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT1 in Type 2 Diabetes: Mechanisms and Therapeutic Potential. (2013)
  • Author(s): Kitada M, Koya D.
  • Journal Title: Diabetes Metab J. Volume: 37 Pages: 315-325
  • Peer Reviewed
• [Journal Article] Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP1c Tg mice fed high-fat and high-fructose diet (2013)
  • Author(s): Wada T, Miyashita Y, Sasaki M, Aruga Y, Nakamura Y, Ishii Y, Sasahara M, Kanasaki K, Kitada M, Koya D, Shimano H, Tsuneki H, Sasaoka
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 305 Issue: 11 Pages: E1415-E1425
  • DOI: 10.1152/ajpendo.00419.2013
  • Peer Reviewed
• [Journal Article] Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. (2013)
  • Author(s): Yamahara K, Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki S, Haneda M, Matsusaka T, Kashiwagi A, Maegawa H, Uzu T.
  • Journal Title: J Am Soc Nephrol. Volume: 24 Issue: 11 Pages: 1769-81
  • DOI: 10.1681/asn.2012111080
  • Peer Reviewed
• [Journal Article] Altered unfolded protein response is implicated in the age-related exacerbation of proteinuria-induced proximal tubular cell damage. (2013)
  • Author(s): Takeda N, Kume S, Tanaka Y, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki S, Haneda M, Koya D, Kashiwagi A, Maegawa H, Uzu T.
  • Journal Title: Am J Pathol. Volume: 183 Issue: 3 Pages: 774-85
  • DOI: 10.1016/j.ajpath.2013.05.026
  • Peer Reviewed
• [Journal Article] Cilostazol attenuates spontaneous microaggregation of platelets in type 2 diabetic patients with insufficient platelet response to aspirin. (2013)
  • Author(s): Araki S, Matsuno H, Haneda M, Koya D, Kanno Y, Kume S, Isshiki K, Araki H, Ugi S, Kawai H, Kashiwagi A, Uzu T, Maegawa H.
  • Journal Title: Diabetes Care Volume: 36(7) Issue: 7 Pages: e92-e93
  • DOI: 10.2337/dc12-2702
  • Peer Reviewed
• [Journal Article] Calorie restriction in overweight males ameliorates obesity-related metabolic alterations and cellular adaptations through anti-aging effects, possibly including AMPK and SIRT1 activation. (2013)
  • Author(s): Kitada M, Kume S, Takeda-Watanabe A, Tsuda S, Kanasaki K, Koya D.
  • Journal Title: Biochim Biophys Acta Volume: 1830(10) Issue: 10 Pages: 4820-4827
  • DOI: 10.1016/j.bbagen.2013.06.014
  • Peer Reviewed
• [Journal Article] The biological consequence of obesity on the kidney (2013)
  • Author(s): Keizo Kanasaki, Munehiro Kitada, Megumi Kanasaki, Daisuke Koya
  • Journal Title: Nephrology Dialysis and Transplantation Volume: Suppl 4 Issue: suppl 4 Pages: iv1-iv7
  • DOI: 10.1093/ndt/gft098
  • Peer Reviewed
• [Journal Article] Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways. (2013)
  • Author(s): Nishizawa M, Nakabayashi H, Uehara K, Nakagawa A, Uchida K, Koya D.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 305 Issue: 3 Pages: E376-E387
  • DOI: 10.1152/ajpendo.00565.2012
  • Peer Reviewed
• [Journal Article] Ketogenic essential amino acids replacement diet ameliorated hepatosteatosis with altering autophagy-associated molecules. (2013)
  • Author(s): Xu L, Kanasaki M, He J, Kitada M, Nagao K, Jinzu H, Noguchi Y, Maegawa H, Kanasaki K, Koya D.
  • Journal Title: Biochim Biophys Acta. Volume: 1832(10) Issue: 10 Pages: 1605-1612
  • DOI: 10.1016/j.bbadis.2013.05.003
  • Peer Reviewed
• [Journal Article] Statin use in patients with diabetes and kidney disease: the Japanese experience. (2013)
  • Author(s): Koya D, Campese VM.
  • Journal Title: J Atheroscler Thromb. Volume: 20 Pages: 407-24
  • NAID: 130004444686
• [Journal Article] Sirtuins as possible drug targets in type 2 diabetes. (2013)
  • Author(s): Kitada M, Kume S, Kanasaki K, Takeda-Watanabe A, Koya D.
  • Journal Title: Curr Drug Targets Volume: 14 Pages: 622-36
  • Peer Reviewed
• [Journal Article] Role of the Endothelial-to-mesenchymal Transition in Renal Fibrosis of Chronic Kidney Disease (2013)
  • Author(s): Jianhua He, Yong Xu, Daisuke Koya, Keizo Kanasaki
  • Journal Title: 2013 Clin Exp Nephrol Clin Exp Nephrol Volume: 17(4) Issue: 4 Pages: 488-497
  • DOI: 10.1007/s10157-013-0781-0
  • NAID: 10031195312
  • Peer Reviewed
• [Remarks] 金沢医科大学 糖尿病・内分泌内科学
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/
• [Remarks] 金沢医科大学 糖尿病・内分泌内科学
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/