Association of α-klotho with subclinical carotid atherosclerosis in subjects with type 1 diabetes mellitus

Cardiovasc Diabetol. 2022 Oct 11;21(1):207. doi: 10.1186/s12933-022-01640-3.

Abstract

Background: Compelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects.

Methods: This cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, and vitamin D levels were also determined. Negative binomial regression models were used to examine relationship between parameters studied and subclinical carotid atherosclerosis.

Results: Only FGF23 was increased in T1D compared with non-diabetic subjects (> 2-fold; p < 0.05). α-klotho was higher in subjects with subclinical carotid atherosclerosis (1.4-fold, p < 0.05). Regression analysis revealed that the log α-klotho concentration was positively associated with the presence of subclinical carotid atherosclerosis both in T1D subjects (incidence rate ratio [IRR]: 1.41; 95% confidence interval [CI], 1.06-1.89; p < 0.05) and in non-T1D subjects (IRR: 1.65; 95% CI, 1.02-2.75; p < 0.05). The models also showed that age, smoking and albuminuria-to-creatinine ratio were positively associated with subclinical carotid atherosclerosis in T1D subjects. Interestingly, sex-related protection against plaque was also revealed in T1D women.

Conclusion: Higher α-klotho was associated with subclinical carotid atherosclerotic in the absence of kidney dysfunction. This finding also points to a new pathophysiological pathway involved in the development and progression of this complication.

Keywords: Fibroblast growth factor 23; Mineral metabolism; Type 1 diabetes mellitus; α-klotho.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium
  • Carotid Artery Diseases* / diagnostic imaging
  • Carotid Artery Diseases* / epidemiology
  • Carotid Artery Diseases* / etiology
  • Creatinine
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 1* / complications
  • Diabetes Mellitus, Type 1* / diagnosis
  • Female
  • Fibroblast Growth Factors
  • Glucuronidase
  • Humans
  • Parathyroid Hormone
  • Phosphates
  • Plaque, Atherosclerotic*
  • Vitamin D

Substances

  • Parathyroid Hormone
  • Phosphates
  • Vitamin D
  • Fibroblast Growth Factors
  • Creatinine
  • Glucuronidase
  • Calcium