Glucose variability aggravates cardiac fibrosis by altering AKT signalling path

Diab Vasc Dis Res. 2017 Jul;14(4):327-335. doi: 10.1177/1479164117698917. Epub 2017 Mar 17.


Objective: To study the effect of blood glucose variability on cardiac fibrosis and its mechanism in a model of diabetic cardiomyopathy.

Methods: A total of 45 Sprague Dawley rats were randomly divided into three groups: control, control diabetes mellitus and fluctuated blood glucose groups. Fluctuated blood glucose was induced by daily subcutaneous insulin and intraperitoneal glucose injections at different time points. Blood lipids and glycosylated haemoglobin A1c were assessed. Super oxide dismutase activity and malondialdehyde level in rat heart homogenates were determined by assay kit. Structural cardiac tissue changes were observed by haematoxylin and eosin staining and Masson's trichrome staining. Collagen type 3, fibronectin, phosphorylated Ser/Thr protein kinase, phosphorylated glycogen synthase kinase-3 beta, glycogen synthase kinase-3 beta, nuclear factor kappa-light-chain-enhancer of activated B cells, cleaved-cysteinyl aspartate-specific proteinase-3 (caspase-3) and tumour necrosis factor-α levels were determined by western blot.

Results: Compared with the control group, cardiac fibrosis and oxidative stress in heart tissue were aggravated in diabetic rats, which were more pronounced in glucose variability rats. However, the expression levels of AKT and glycogen synthase kinase-3 beta were not significantly different in three groups, but the expression levels of phosphorylated Ser/Thr protein kinase and phosphorylated glycogen synthase kinase-3 beta were significantly decreased in the control diabetes mellitus and fluctuated blood glucose groups compared to control group, and levels in the fluctuated blood glucose group were significantly less than in the control diabetes mellitus group. In addition, the expression levels of nuclear factor kappa B and caspase-3 in both the control diabetes mellitus and fluctuated blood glucose groups were higher than in the control group, with the highest levels measured in the fluctuated blood glucose group.

Conclusion: Blood glucose variability can aggravate heart tissue fibrosis, possibly involving oxidative stress by inhibiting AKT signalling path.

Keywords: AKT; Blood glucose variability; diabetic cardiomyopathy; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Blood Glucose / metabolism*
  • Caspase 3 / metabolism
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetic Cardiomyopathies / blood
  • Diabetic Cardiomyopathies / enzymology
  • Diabetic Cardiomyopathies / etiology*
  • Diabetic Cardiomyopathies / pathology
  • Fibrosis
  • Glycated Hemoglobin A / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Lipids / blood
  • Male
  • Myocardium / enzymology*
  • Myocardium / pathology
  • NF-kappa B / metabolism
  • Oxidative Stress
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism


  • Biomarkers
  • Blood Glucose
  • Glycated Hemoglobin A
  • Lipids
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Casp3 protein, rat
  • Caspase 3