Skip to main content
Log in

Pathophysiological roles of nutrient-sensing mechanisms in diabetes and its complications

  • Review Article
  • Published:
Diabetology International Aims and scope Submit manuscript

Abstract

Diabetic nephropathy, which is characterized by increased albuminuria, has been the most common cause of end-stage kidney disease for many years in Japan and many other countries. Although the renal prognosis of the disease has been improving in recent years because of the clinical implementation of strict glucose, blood pressure, and lipid controls, some diabetes patients continue to exhibit treatment-resistant macroalbuminuria leading to end-stage kidney disease. Furthermore, renal function decline without macroalbuminuria in diabetes is an emerging issue in Japan, which might be partly due to aging. Thus, a novel therapeutic strategy is needed to further improve renal outcome in diabetes patients. We have recently reported the involvement of dysregulation of intracellular nutrient-sensing signals and the related cellular process, autophagy, in the pathogenesis of diabetic nephropathy and abnormal insulin secretion pattern in type 2 diabetes. This review discusses potential roles of intracellular nutrient-sensing signals and autophagy as novel therapeutic targets for type 2 diabetes and diabetic nephropathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.

    Article  CAS  Google Scholar 

  2. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1:1430–2.

    Article  CAS  Google Scholar 

  3. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997;99:342–8.

    Article  CAS  Google Scholar 

  4. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17:2974–84.

    Article  CAS  Google Scholar 

  5. Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, de Boer IH. Clinical manifestations of kidney disease among US adults with diabetes, 1988–2014. JAMA. 2016;316:602–10.

    Article  Google Scholar 

  6. Kume S, Araki SI, Ugi S, Morino K, Koya D, Nishio Y, Haneda M, Kashiwagi A, Maegawa H. Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes from 1996 to 2014. J Diabetes Investig. 2018;10:1032–40.

    Article  Google Scholar 

  7. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273:59–63.

    Article  CAS  Google Scholar 

  8. Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011;585:1537–42.

    Article  CAS  Google Scholar 

  9. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063.

    Article  CAS  Google Scholar 

  10. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517:302–10.

    Article  CAS  Google Scholar 

  11. Kume S, Thomas MC, Koya D. Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes. 2012;61:23–9.

    Article  CAS  Google Scholar 

  12. Zhou XJ, Rakheja D, Yu X, Saxena R, Vaziri ND, Silva FG. The aging kidney. Kidney Int. 2008;74:710–20.

    Article  CAS  Google Scholar 

  13. Tanaka T, Kato H, Kojima I, Ohse T, Son D, Tawakami T, Yatagawa T, Inagi R, Fujita T, Nangaku M. Hypoxia and expression of hypoxia-inducible factor in the aging kidney. J Gerontol A Biol Sci Med Sci. 2006;61(8):795–805.

    Article  Google Scholar 

  14. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, Sugimoto T, Haneda M, Kashiwagi A, Koya D. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest. 2010;120:1043–55.

    Article  CAS  Google Scholar 

  15. Haigis MC, Guarente LP. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20(21):2913–21.

    Article  CAS  Google Scholar 

  16. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–422.

    Article  CAS  Google Scholar 

  17. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.

    Article  CAS  Google Scholar 

  18. Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002;13(12):3005–15.

    Article  Google Scholar 

  19. Hartleben B, Gödel M, Meyer-Schwesinger C, Liu S, Ulrich T, Köbler S, Wiech T, Grahammer F, Arnold SJ, Lindenmeyer MT, Cohen CD, Pavenstädt H, Kerjaschki D, Mizushima N, Shaw AS, Walz G, Huber TB. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120:1084–96.

    Article  CAS  Google Scholar 

  20. Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Asanuma K, Kim EH, Haneda M, Kajiwara N, Hayashi K, Ohashi H, Ugi S, Maegawa H, Uzu T. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes. 2016;65:755–67.

    Article  CAS  Google Scholar 

  21. Yasuda-Yamahara M, Kume S, Tagawa A, Maegawa H, Uzu T. Emerging role of podocyte autophagy in the progression of diabetic nephropathy. Autophagy. 2015;11:2385–6.

    Article  CAS  Google Scholar 

  22. 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. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol. 2013;24:1769–81.

    Article  CAS  Google Scholar 

  23. Kitada M, Ogura Y, Suzuki T, Sen S, Lee SM, Kanasaki K, Kume S, Koya D. 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. Diabetologia. 2016;59:1307–17.

    Article  CAS  Google Scholar 

  24. Takagi A, Kume S, Kondo M, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Haneda M, Chano T, Matsusaka T, Nagao K, Adachi Y, Chan L, Maegawa H, Uzu T. Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation. Sci Rep. 2016;6:18944.

    Article  CAS  Google Scholar 

  25. Takagi A, Kume S, Maegawa H, Uzu T. Emerging role of mammalian autophagy in ketogenesis to overcome starvation. Autophagy. 2016;12:709–10.

    Article  CAS  Google Scholar 

  26. Krebs HA, Bennett DA, De Gasquet P, Gasquet P, Gascoyne T, Yoshida T. Renal gluconeogenesis The effect of diet on the gluconeogenic capacity of rat-kidney-cortex slices. Biochem J. 1963;86:22–7.

    Article  CAS  Google Scholar 

  27. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–62.

    Article  CAS  Google Scholar 

  28. Seino S, Shibasaki T, Minami K. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J Clin Invest. 2011;121:2118–255.

    Article  CAS  Google Scholar 

  29. Kume S, Kondo M, Maeda S, Nishio Y, Yanagimachi T, Fujita Y, Haneda M, Kondo K, Sekine A, Araki SI, Araki H, Chin-Kanasaki M, Ugi S, Koya D, Kitahara S, Maeda K, Kashiwagi A, Uzu T, Maegawa H. Hypothalamic AMP-activated protein kinase regulates biphasic insulin secretion from pancreatic β cells during fasting and in type 2 diabetes. EBioMedicine. 2016;13:168–80.

    Article  Google Scholar 

  30. Lundbaek K. Metabolic abnormalities in starvation diabetes. Yale J Biol Med. 1948;20(6):533–44.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This review is a summary of my presentation in the Lilly Award Lecture at the 62nd annual meeting of the Japan Diabetes Society, Sendai, Japan. I would like to express sincere gratitude to Professor Hiroshi Maegawa, Professor Daisuke Koya, Professor Masakazu Haneda, Professor Atsunori Kashiwagi, Professor Ryuichi Kikkawa, and all members of department of medicine, Shiga University of Medical Science for their guidance and support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shinji Kume.

Ethics declarations

Conflict of interest

Shinji Kume declares that he has no conflict of interest.

Statement of animal and/or human participants

This article does not contain any studies with human or animal subjects.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kume, S. Pathophysiological roles of nutrient-sensing mechanisms in diabetes and its complications. Diabetol Int 10, 245–249 (2019). https://doi.org/10.1007/s13340-019-00406-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13340-019-00406-9

Keywords

Navigation