SpringerLink
Log in

Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications

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

Abstract

It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress ‘response failure’ contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by ‘imbalanced adipokines’ in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.

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

Access this article

Log in via an institution

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this review.

References

  1. The Japan Diabetes Society Group. Treatment guide for diabetes 2022–2023. Tokyo: Bunkodo; 2022.

    Google Scholar 

  2. Kubota N, Kubota T, Itoh S, et al. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab. 2008;8(1):49–64.

    Article  PubMed  CAS  Google Scholar 

  3. Kadowaki T, Ueki K, Yamauchi T, Kubota N. SnapShot: insulin signaling pathways. Cell. 2012;148(3):624,e1.

    Article  PubMed  Google Scholar 

  4. Rinella ME, Lazarus JV, Ratziu V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023. https://doi.org/10.1016/j.aohep.2023.101133. (In press).

    Article  PubMed  Google Scholar 

  5. Sasako T, Ohsugi M, Kubota N, et al. Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism. Nat Commun. 2019;10(1):947.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Park SW, Zhou Y, Lee J, et al. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med. 2010;16(4):429–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat Med. 2010;16(4):438–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Fukuda S, Sumii M, Masuda Y, et al. Murine and human SDF2L1 is an endoplasmic reticulum stress-inducible gene and encodes a new member of the Pmt/rt protein family. Biochem Biophys Res Commun. 2001;280(1):407–14.

    Article  PubMed  CAS  Google Scholar 

  9. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.

    Article  PubMed  CAS  Google Scholar 

  10. Sasako T, Ueki K. ER stress response failure and steatohepatitis comorbid with diabetes. In: Psychology and patho-physiological outcomes of eating. IntechOpen Ltd; 2021. p. 69–83.

    Google Scholar 

  11. Tateishi R, Matsumura T, Okanoue T, et al. Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan. J Gastroenterol. 2021;56(3):261–73.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Soeda K, Sasako T, Enooku K, et al. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis. Nat Commun. 2023;14(1):6584.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bhattarai KR, Chaudhary M, Kim HR, Chae HJ. Endoplasmic reticulum (ER) stress response failure in diseases. Trends Cell Biol. 2020;30(9):672–5.

    Article  PubMed  CAS  Google Scholar 

  14. Yagil C, Varadi-Levi R, Ifrach C, Yagil Y. Dysregulated UPR and ER stress related to a mutation in the Sdf2l1 gene are involved in the pathophysiology of diet-induced diabetes in the Cohen diabetic RAT. Int J Mol Sci. 2023;24(2):1355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Sazonovs A, Stevens CR, Venkataraman GR, et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nat Genet. 2022;54(9):1275–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl. 2011;120:S1-6.

    Article  CAS  Google Scholar 

  17. Butlen D, Vadrot S, Roseau S, Morel F. Insulin receptors along the rat nephron: [125I] insulin binding in microdissected glomeruli and tubules. Pflugers Arch. 1988;412(6):604–12.

    Article  PubMed  CAS  Google Scholar 

  18. Tiwari S, Singh RS, Li L, et al. Deletion of the insulin receptor in the proximal tubule promotes hyperglycemia. J Am Soc Nephrol. 2013;24(8):1209–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sasaki M, Sasako T, Kubota N, et al. Dual regulation of gluconeogenesis by insulin and glucose in the proximal tubules of the kidney. Diabetes. 2017;66(9):2339–50.

    Article  PubMed  CAS  Google Scholar 

  20. Rubera I, Poujeol C, Bertin G, et al. Specific Cre/Lox recombination in the mouse proximal tubule. J Am Soc Nephrol. 2004;15(8):2050–6.

    Article  PubMed  CAS  Google Scholar 

  21. Bingham M. In this issue of Diabetes. Diabetes. 2017;66(9):2325–6.

    Article  CAS  Google Scholar 

  22. Packer M. Role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient overabundance. Circulation. 2020;141(25):2095–105.

    Article  PubMed  CAS  Google Scholar 

  23. Liu H, Sridhar VS, Lovblom LE, et al. Markers of kidney injury, inflammation, and fibrosis associated with ertugliflozin in patients with CKD and diabetes. Kidney Int Rep. 2021;6(8):2095–104.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sasako T, Tanaka T, Yamauchi T. Adaptive response as a potential key link between SGLT2 inhibition and renoprotection. Kidney Int Rep. 2021;6(8):2022–4.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–23.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16–31.

    Article  PubMed  Google Scholar 

  27. Chen LK, Woo J, Assantachai P, et al. Asian working group for sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment. J Am Med Dir Assoc. 2020;21(3):300–7.

    Article  PubMed  Google Scholar 

  28. Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lee CG, Boyko EJ, Barrett-Connor E, et al. Insulin sensitizers may attenuate lean mass loss in older men with diabetes. Diabetes Care. 2011;34(11):2381–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011;1(1):4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Jaiswal N, Gavin M, Loro E, et al. AKT controls protein synthesis and oxidative metabolism via combined mTORC1 and FOXO1 signalling to govern muscle physiology. J Cachexia Sarcopenia Muscle. 2022;13(1):495–514.

    Article  PubMed  Google Scholar 

  32. Sasako T, Umehara T, Soeda K, et al. Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice. Nat Commun. 2022;13(1):5655.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kirk B, Al Saedi A, Duque G. Osteosarcopenia: a case of geroscience. Aging Med (Milton). 2019;2(3):147–56.

    Article  PubMed  Google Scholar 

  34. [Press Release: Elucidating impact of imparied insulin action in diabetes on aging of skeletal muscle and systemic lonevity]. https://www.h.u-tokyo.ac.jp/participants/research/saishinkenkyu/__icsFiles/afieldfile/2022/10/03/release_20221005.pdf. Accessed 31 Oct 2023.

  35. Tian J, Chung HK, Moon JS, et al. Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice. J Cachexia Sarcopenia Muscle. 2022;13(3):1785–99.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hosoi T, Yakabe M, Sasakawa H, et al. Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor. Proc Natl Acad Sci USA. 2023;120(4): e2218032120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sasako T, Ueki K. Sarcopenia: loss of mighty armor against frailty and aging. J Diabetes Investig. 2023;14(10):1145–7.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yamauchi T, Kadowaki T. Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab. 2013;17(2):185–96.

    Article  PubMed  CAS  Google Scholar 

  39. Sasako T, Kadowaki H, Fujiwara T, et al. Severe aortic stenosis during leptin replacement therapy in a patient with generalized lipodystrophy-associated progeroid syndrome due to an LMNA variant: a case report. J Diabetes Investig. 2022;13(9):1636–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hosoe J, Miya F, Kadowaki H, et al. Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance. Diabetes Res Clin Pract. 2020;169: 108461.

    Article  PubMed  CAS  Google Scholar 

  41. Hussain I, Patni N, Ueda M, et al. A novel generalized lipodystrophy-associated progeroid syndrome due to recurrent heterozygous LMNA p.T10I mutation. J Clin Endocrinol Metab. 2018;103(3):1005–14.

    Article  PubMed  Google Scholar 

  42. [Case report of severe aortic stenosis develo** during leptin replacement therapy for a rare disease of lipidystrophy]. https://www.h.u-tokyo.ac.jp/participants/research/saishinkenkyu/20220708-1.html. Accessed 31 Oct 2023.

  43. Seki Y, Yamada T, Kiyosue A, et al. Asymptomatic myocardial infarction in a patient with myotonic dystrophy type 1. J Cardiol Cases. 2022;26(4):248–51.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Nakagawa-Nagahama Y, Igarashi M, Miura M, Sasako T, Yamauchi T. A case of variant hemoglobin Hb Hoshida [β 43 Glu (GAG) → Gln (CAG) ] diagnosed at the onset of acute-onset type 1 diabetes mellitus. J Japan Diab Soc. 2022;65(9):505–11.

    Google Scholar 

  45. Sasako T, Yamauchi T. Clinical trials in participants with type 2 diabetes undertaken in Japan. J Japan Diab Soc. 2022;65(10):518–21.

    Google Scholar 

  46. Yazaki Y, Kadowaki T. Combating diabetes and obesity in Japan. Nat Med. 2006;12(1):73–4.

    Article  PubMed  CAS  Google Scholar 

  47. Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3). https://clinicaltrials.gov/ct2/show/NCT00300976. Accessed 31 Oct 2023.

  48. Ueki K, Sasako T, Kato M, et al. Design of and rationale for the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3): a multicenter, open-label, randomized, parallel-group trial. BMJ Open Diabetes Res Care. 2016;4(1): e000123.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ueki K, Sasako T, Okazaki Y, et al. Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):951–64.

    Article  PubMed  Google Scholar 

  50. Study results. http://www.jdoit3.jp/en/result.html. Accessed 31 Oct 2023.

  51. Sone H, Tanaka S, Iimuro S, et al. Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicentre randomised controlled trial (the Japan Diabetes Complications Study). Diabetologia. 2010;53(3):419–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Griffin SJ, Rutten G, Khunti K, et al. Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(12):925–37.

    Article  PubMed  Google Scholar 

  53. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.

    Article  PubMed  CAS  Google Scholar 

  54. Sasako T, Kadowaki T, Ueki K. ADDITION-Europe: the first decade and beyond. Lancet Diabetes Endocrinol. 2019;7(12):891–3.

    Article  PubMed  Google Scholar 

  55. Ueki K, Sasako T, Okazaki Y, et al. Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes. Kidney Int. 2021;99(1):256–66.

    Article  PubMed  CAS  Google Scholar 

  56. Sasako T, Yamauchi T. Addressing screams for evidence on renoprotection by GLP-1 receptor agonists. Kidney Int. 2022;101(2):222–4.

    Article  PubMed  CAS  Google Scholar 

  57. Sasako T, Ueki K, Miyake K, et al. Effect of a multifactorial intervention on fracture in patients with type 2 diabetes: subanalysis of the J-DOIT3 study. J Clin Endocrinol Metab. 2021;106(5):e2116–28.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chan JCN. How can we optimise diabetes care in real-world practice? Lancet Diabetes Endocrinol. 2017;5(12):927–9.

    Article  PubMed  Google Scholar 

  59. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.

    Article  PubMed  CAS  Google Scholar 

  60. Sasako T, Yamauchi T, Ueki K. Intensified multifactorial intervention in patients with type 2 diabetes mellitus. Diabetes Metab J. 2023;47(2):185–97.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This review is a summary of my presentation in the Lilly Award Lecture at the 66th annual meeting of the Japan Diabetes Society, Kagoshima, Japan. I would like to express sincere gratitude to Dr. Takashi Kadowaki, Dr. Kazuyuki Tobe, Dr. Kohjiro Ueki, Dr. Naoto Kubota, and Dr. Toshimasa Yamauchi for their mentoring and to my colleagues and collaborators for their support.

Author information

Authors and Affiliations

  1. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan

    Takayoshi Sasako

Authors
  1. Takayoshi Sasako
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takayoshi Sasako.

Ethics declarations

Conflict of interest

I declare that I have no conflicts of interest.

Research involves human and animal participants

This article does not contain any studies with human or animal subjects performed by any of the authors.

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

Sasako, T. Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications. Diabetol Int 15, 34–40 (2024). https://doi.org/10.1007/s13340-023-00677-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13340-023-00677-3

Keywords

Search

Navigation