Vol 69, No 6 (2018)
Review paper
Published online: 2018-10-01

open access

Page views 3596
Article views/downloads 1882
Get Citation

Connect on Social Media

Connect on Social Media

Klotho protein function among patients with type 1 diabetes

Justyna Flotyńska1, Aleksandra Uruska1, Aleksandra Araszkiewicz1, Dorota Zozulińska-Ziółkiewicz1
Pubmed: 30620382
Endokrynol Pol 2018;69(6):696-704.


The fibroblast growth factor 23 (FGF23) and Klotho system play a very important role in the regulation of the human body metabolism. On the one hand, they promote longevity, and on the other hand they promote insulin resistance. Nowadays, accelerated aging in diabetes as the main consequence of chronic complications of the disease is postulated. Signalling pathways induced by insulin, insulin-like growth factor (IGF-1), and their homologues play an important role in controlling the aging process. Because FGF23/Klotho system affects glucose metabolism and gene expression of antioxidant enzymes, changes in its concentration may be a marker of chronic complications of diabetes or a treatment option. Despite huge improvements in the treatment of diabetes, its chronic complications remain an important clinical problem. An interesting issue is the relationship between the concentration of FGF23/Klotho and management of the disease, duration, insulin resistance, and development of complications in type 1 diabetes.

Article available in PDF format

View PDF Download PDF file


  1. Buschur E, Sarma AV, Pietropaolo M, et al. DCCT/EDIC Research Group. Self-reported autoimmune disease by sex in the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study. Diabetes Care. 2014; 37(2): e28–e29.
  2. IDF Diabetes Atlas. 7th edition. International Diabetes Federation, Brussels 2015.
  3. Nielsen HB, Ovesen LL, Mortensen LH, et al. Type 1 diabetes, quality of life, occupational status and education level - A comparative population-based study. Diabetes Res Clin Pract. 2016; 121: 62–68.
  4. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. J Pediatr. 1994; 125(2): 177–188.
  5. Afshari P, Yazdizadeh S, Abedi P, et al. The Relation of Diabetes Type 2 with Sexual Function among Reproductive Age Women in Iran, a Case-Control Study. Adv Med. 2017; 2017: 4838923.
  6. Ou HT, Lee TY, Li CY, et al. Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan. BMJ Open. 2017; 7(6): e015117.
  7. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54(6): 1615–1625.
  8. Uruska A, Araszkiewicz A, Zozulinska-Ziolkiewicz D, et al. Insulin resistance is associated with microangiopathy in type 1 diabetic patients treated with intensive insulin therapy from the onset of disease. Exp Clin Endocrinol Diabetes. 2010; 118(8): 478–484.
  9. Rogowicz-Frontczak A, Majchrzak A, Zozulińska-Ziółkiewicz D. Insulin resistance in endocrine disorders - treatment options. Endokrynol Pol. 2017; 68(3): 334–351.
  10. Koivisto VA, Stevens LK, Mattock M, et al. Cardiovascular disease and its risk factors in IDDM in Europe. EURODIAB IDDM Complications Study Group. Diabetes Care. 1996; 19(7): 689–697.
  11. Schwab KO, Doerfer J, Hecker W, et al. DPV Initiative of the German Working Group for Pediatric Diabetology. Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV). Diabetes Care. 2006; 29(2): 218–225.
  12. Uruska A, Araszkiewicz A, Uruski P, et al. Higher risk of microvascular complications in smokers with type 1 diabetes despite intensive insulin therapy. Microvasc Res. 2014; 92: 79–84.
  13. Uruska A, Michalska A, Ostrowska J, et al. Is cathelicidin a novel marker of diabetic microangiopathy in patients with type 1 diabetes? Clin Biochem. 2017; 50(18): 1110–1114.
  14. Nathan DM, Genuth S, Lachin J, et al. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329(14): 977–986.
  15. Cusick M, Meleth AD, Agrón E, et al. Early Treatment Diabetc Retinopathy Study Research Group. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27. Diabetes Care. 2005; 28(3): 617–625.
  16. Balazard F, Le Fur S, Valtat S, et al. Isis-Diab collaborative group. Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study. BMC Public Health. 2016; 16(1): 1021.
  17. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes: data from the Diabetes Control and Complications Trial. Diabetes Care. 2008; 31(11): 2198–2202.
  18. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016; 20(4): 546–551.
  19. Wegner M, Piorunska-Stolzmann M, Araszkiewicz A, et al. Does oxidized LDL contribute to atherosclerotic plaque formation and microvascular complications in patients with type 1 diabetes? Clin Biochem. 2012; 45(18): 1620–1623.
  20. Shah MS, Brownlee M. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. Circ Res. 2016; 118(11): 1808–1829.
  21. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013; 17(1): 20–33.
  22. Bartke A. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol Metab. 2006; 17(2): 33–35.
  23. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev. 2012; 92(1): 131–155.
  24. Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun. 2000; 277(2): 494–498.
  25. Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res. 2012; 318(9): 1040–1048.
  26. Fukumoto S, Shimizu Y. Fibroblast growth factor 23 as a phosphotropic hormone and beyond. J Bone Miner Metab. 2011; 29(5): 507–514.
  27. Liu S, Tang W, Zhou J, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006; 17(5): 1305–1315.
  28. Haussler MR, Whitfield GK, Kaneko I, et al. The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord. 2012; 13(1): 57–69.
  29. Oliveira RB, Cancela ALE, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010; 5(2): 286–291.
  30. Hu X, Ma X, Luo Y, et al. Associations of serum fibroblast growth factor 23 levels with obesity and visceral fat accumulation. Clin Nutr. 2018; 37(1): 223–228.
  31. Tsuji K, Maeda T, Kawane T, et al. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res. 2010; 25(8): 1711–1723.
  32. Yamada S, Giachelli CM. Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone. 2017; 100: 87–93.
  33. Donate-Correa J, Martín-Núñez E, Delgado NP, et al. Implications of Fibroblast growth factor/Klotho system in glucose metabolism and diabetes. Cytokine Growth Factor Rev. 2016; 28: 71–77.
  34. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006; 281(10): 6120–6123.
  35. Słomiński B, Ryba-Stanisławowska M, Skrzypkowska M, et al. The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes. Biochim Biophys Acta Mol Basis Dis. 2018; 1864(3): 758–763.
  36. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390(6655): 45–51.
  37. Tohyama O, Imura A, Iwano A, et al. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem. 2004; 279(11): 9777–9784.
  38. Unger RH. Klotho-induced insulin resistance: a blessing in disguise? Nat Med. 2006; 12(1): 56–57.
  39. Kuro-o M. Klotho and aging. Biochim Biophys Acta. 2009; 1790(10): 1049–1058.
  40. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science. 2005; 309(5742): 1829–1833.
  41. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem. 2005; 280(45): 38029–38034.
  42. Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta. 2011; 1813(11): 1938–1945.
  43. Razzaque MS. The role of Klotho in energy metabolism. Nat Rev Endocrinol. 2012; 8(10): 579–587.
  44. Ichikawa S, Imel EA, Kreiter ML, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007; 117(9): 2684–2691.
  45. Donate-Correa J, Martín-Núñez E, Martínez-Sanz R, et al. Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease. J Cell Mol Med. 2016; 20(1): 128–133.
  46. Śnit M, Nabrdalik K, Długaszek M, et al. Association of rs 3807337 polymorphism of CALD1 gene with diabetic nephropathy occurrence in type 1 diabetes — preliminary results of a family-based study. Endokrynol Pol. 2017; 68(1): 13–17.
  47. Wolf M. Fibroblast growth factor 23 and the future of phosphorus management. Curr Opin Nephrol Hypertens. 2009; 18(6): 463–468.
  48. Drüeke TB. Klotho, FGF23, and FGF receptors in chronic kidney disease: a yin-yang situation? Kidney Int. 2010; 78(11): 1057–1060.
  49. Haruna Y, Kashihara N, Satoh M, et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci U S A. 2007; 104(7): 2331–2336.
  50. Kim SS, Song SH, Kim InJ, et al. Decreased plasma α-Klotho predict progression of nephropathy with type 2 diabetic patients. J Diabetes Complications. 2016; 30(5): 887–892.
  51. Nie F, Wu D, Du H, et al. Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. J Diabetes Complications. 2017; 31(3): 594–598.
  52. Keles N, Dogan B, Kalcik M, et al. Is serum Klotho protective against atherosclerosis in patients with type 1 diabetes mellitus? J Diabetes Complications. 2016; 30(1): 126–132.
  53. Guo Y, Zhuang X, Huang Z, et al. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochim Biophys Acta Mol Basis Dis. 2018; 1864(1): 238–251.
  54. Izaguirre M, Gil MJ, Monreal I, et al. The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes. Curr Diab Rep. 2017; 17(6): 43.
  55. Ors D, Eroglu Altinova A, Yalçın MM, et al. Fıbroblast growth factor 21 and ıts relatıonshıp wıth ınsulın sensıtıvıty ın fırst-degree relatıves of patıents wıth type 2 dıabetes mellıtus. Endokrynol Pol. 2016; 67(3): 260–264.
  56. Silva AP, Mendes F, Pereira L, et al. Klotho levels: association with insulin resistance and albumin-to-creatinine ratio in type 2 diabetic patients. Int Urol Nephrol. 2017; 49(10): 1809–1814.
  57. Lin Yi, Sun Z. Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes. Diabetes. 2015; 64(12): 4298–4311.