Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-alpha or -gamma agonists in a type 2 diabetic animal model

Diabetes Metab Res Rev. Nov-Dec 2003;19(6):487-93. doi: 10.1002/dmrr.410.

Abstract

Objectives: The aim of this study was to determine whether the peroxisome proliferator-activated receptor (PPAR) ligands could prevent left-ventricular diastolic dysfunction (LVDD) in rats with advanced diabetes. In addition, this study examined whether the activity of malonyl-CoA decarboxylase (MCD), which is an enzyme related to the degradation of malonyl-CoA that is known to regulate the fatty acid metabolism, is changed by the diabetic state itself or by treatment with the PPAR ligands.

Methods: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes, aged 28 weeks, were divided into 3 groups: the untreated, pioglitazone-treated (10 mg/kg/d), and fenofibrate-treated (150 mg/kg/d) groups. The rats were treated for 10 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic control. Doppler echocardiography and measurements of the MCD activity at the myocardium were performed.

Results: At the age of 38 weeks, the OLETF rats treated with either pioglitazone or fenofibrate showed an improvement in the plasma glucose levels after glucose loading as well as an improvement in the fasting plasma insulin, triglyceride, and FFA levels compared to the untreated OLETF rats. The untreated OLETF rats showed a prolonged deceleration time of the E-wave (DTE) (74.3 +/- 3.7 vs LETO, 56.3 +/- 3.8 ms, P < 0.05) and a reduced ratio of the peak early diastolic velocity wave to the late diastolic wave (E/A ratio) (1.25 +/- 0.06 vs LETO 1.54 +/- 0.08, P < 0.05). Pioglitazone treatment in the OLETF rats improved the DTE (51.6 +/- 1.7 ms, P < 0.05), and the fenofibrate treatment also improved the DTE (61.4 +/- 4.3 ms, P < 0.05) and E/A ratio (1.57 +/- 0.05, P < 0.05) compared to the untreated OLETF rats. The parameters related to the systolic function did not change among the groups at both pre- and post-treatments. The MCD activity of the myocardium was remarkably lower in the OLETF rats compared to the LETO rats (3.26 +/- 0.38 vs 7.76 +/- 0.84 nmol/min/mg protein, P < 0.05). The pioglitazone and fenofibrate treatments resulted in an increase in the MCD activity compared to that in the untreated rats (7.20 +/- 0.74 and 8.33 +/- 0.83 nmol/min/mg protein, P < 0.05, respectively).

Conclusions: The PPAR-alpha or -gamma agonists prevented LVDD in the advanced diabetic rat hearts, possibly through an improvement in the fatty acid metabolism in the myocardium or a correction of the hyperglycemia and/or hyperlipidemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Body Weight
  • Carboxy-Lyases / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Diabetic Angiopathies / physiopathology
  • Diabetic Angiopathies / prevention & control
  • Diastole / drug effects*
  • Disease Models, Animal
  • Echocardiography
  • Energy Intake
  • Fenofibrate / therapeutic use
  • Glucose Tolerance Test
  • Heart / drug effects
  • Heart / physiology
  • Heart / physiopathology
  • Hypoglycemic Agents / therapeutic use
  • Hypolipidemic Agents / therapeutic use*
  • Male
  • Organ Size
  • Pioglitazone
  • Rats
  • Rats, Inbred OLETF
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Reference Values
  • Thiazolidinediones / therapeutic use
  • Transcription Factors / agonists*
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Receptors, Cytoplasmic and Nuclear
  • Thiazolidinediones
  • Transcription Factors
  • Carboxy-Lyases
  • malonyl-CoA decarboxylase
  • Fenofibrate
  • Pioglitazone