3-nitrotyrosine and Glycosuria

The Goto-Kakizaki (GK) rat, a non-obese model of type 2 diabetes mellitus (T2DM), was generated by the selective inbreeding of glucose-intolerant Wistar rats. This is a convenient model for studying diabetes-induced cardiomyopathy independently from the effects of the metabolic syndrome. We investigated the myocardial functional and structural changes and underlying molecular pathomechanisms of short-term and mild T2DM. The presence of DM was confirmed by an impaired oral glucose tolerance in the GK rats compared with the age-matched nondiabetic Wistar rats. Data from cardiac catheterization showed that in GK rats, although the systolic indexes were not altered, the diastolic stiffness was increased compared with nondiabetics (end-diastolic-pressure-volume-relationship: 0.12 ± 0.04 vs. 0.05 ± 0.01 mmHg/μl, P < 0.05). Additionally, DM was associated with left-ventricular hypertrophy and histological evidence of increased myocardial fibrosis. The plasma pro-B-type natriuretic peptide, the cardiac troponin-T, glucose, and the urinary glucose concentrations were significantly higher in GK rats. Among the 125 genes surveyed using PCR arrays, DM significantly altered the expression of five genes [upregulation of natriuretic peptide precursor-A and connective tissue growth factor, downregulation of c-reactive protein, interleukin-1β, and tumor necrosis factor (TNF)-α mRNA-level]. Of the altered genes, which were evaluated by Western blot, only TNF-α protein expression was significantly decreased. The ECG recordings revealed no significant differences. In conclusion, while systolic dysfunction, myocardial inflammation, and abnormal electrical conduction remain absent, short-term and mild T2DM induce the alteration of cardiac TNF-α at both the mRNA and protein levels. Further assessments are required to reveal if TNF-α plays a role in the early stage of diabetic cardiomyopathy development.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Glucose; C-Reactive Protein; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Down-Regulation; Echocardiography; Electrocardiography; Fibrosis; Glucose Tolerance Test; Glycosuria; Hypertrophy, Left Ventricular; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Interleukin-1beta; Male; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Troponin T; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure