Chronic effects of type 2 diabetes mellitus on cardiac muscle contraction in the Goto‐Kakizaki rat

Howarth, Frank Christopher; Shafiullah, Mohamed; Qureshi, M. A.

doi:10.1113/expphysiol.2007.038703

Cited by 34 publications

(41 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The time course of myocyte shortening and relaxation was reduced in GK-HFD compared with GK-LFD rats. Previous studies, in older rats eating normal rat chow, have demonstrated unaltered amplitude of shortening and reduced time course of relaxation in myocytes from GK rats compared with age-matched control animals (Howarth et al 2007). Interestingly, some previous experiments performed in healthy rats have shown that HFDs resulted in depressed peak myocyte shortening and prolonged time course of shortening and relengthening (Relling et al 2006;Ren et al 2008), and sucrose-enriched diet resulted in prolonged time course of myocyte shortening (Howarth et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Magnetic resonance imaging has demonstrated reduced myocardial blood flow and reduced ejection fraction, mainly as a result of a reduction in left ventricular longitudinal contraction (Iltis et al 2005). In ventricular myocytes, some studies have shown that the amplitude of shortening and corresponding amplitude of the Ca 2+ transient were unaltered (El Omar et al 2004), whilst in others the amplitude of the intracellular Ca 2+ transient was increased in ventricular myocytes from 18-monthold GK rats (Howarth et al 2007). Feeding normal healthy animals a fat-enriched diet may result in impairments of myocyte function, including depressed peak shortening, prolonged time-to-peak (t peak ) shortening and time to relengthening, and reduced intracellular Ca 2+ release and Ca 2+ clearing rate (Howarth et al 2005;Relling et al 2006;Dong et al 2007).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet

Howarth¹,

Qureshi²,

Sobhy³

et al. 2011

Experimental Physiology

View full text Add to dashboard Cite

Given the clinical prevalence of type 2 diabetes and obesity and their association with high mortality linked to cardiovascular disease, the aim of the study was to investigate the effects of feeding type 2 diabetic Goto-Kakizaki (GK) rats either high-or low-fat diets on cardiomyocyte structure and function. The GK rats were fed either a high-fat diet (HFD) or a low-fat diet (LFD) from the age of 2 months for a period of 7 months. The GK-HFD rats gained more weight, ate less food and drank less water compared with GK-LFD rats. At 7 months, non-fasting blood glucose was higher in GK-LFD (334 ± 35 mg dl −1 ) compared with GK-HFD rats (235 ± 26 mg dl −1 ). Feeding GK rats with a HFD had no significant effect on glucose clearance following a glucose challenge. Time-to-peak (t peak ) shortening was reduced in myocytes from GK-HFD (131.8 ± 2.1 ms) compared with GK-LFD rats (144.5 ± 3.0 ms), and time-to-half (t 1 /2 ) relaxation of shortening was also reduced in myocytes from GK-HFD (71.7 ± 6.9 ms) compared with GK-LFD rats (86.1 ± 3.6 ms). The HFD had no significant effect on the amplitude of shortening. The HFD had no significant effect on t peak , t 1 /2 decay, amplitude of the Ca 2+ transient, myofilament sensitivity to Ca 2+ , sarcoplasmic reticulum Ca 2+ content, fractional release of Ca 2+ and the rate of Ca 2+ uptake. Structurally, ventricular myocytes from GK-HFD rats showed extensive mitochondrial lesions, including swelling, loss of cristae, and loss of inner and outer membranes, resulting in gross vacuolarization and deformation of ventricular mitochondria with a subsequent reduction in mitochondrial density. Expression of genes encoding various L-type Ca 2+ channel proteins (Cacnb2) and cardiac muscle proteins (Myl2 and Atp2a1) were downregulated in GK-HFD compared with GK-LFD rats. Structural lesions and changed expression of genes encoding various cardiac muscle proteins might partly underlie the altered time course of myocyte shortening and relaxation in myocytes from GK-HFD compared with GK-LFD rats. A variety of diastolic and systolic dysfunctions have been widely reported in type 2 diabetic patients, and the severity of abnormalities depends on the patients' age and the duration of diabetes. Haemodynamic abnormalities include reduced left ventricular ejection fraction, impaired myocardial velocity at early diastole, abnormal relaxation during the early filling phase, prolonged isovolumetric relaxation, lower peak systolic and early diastolic velocity, impaired diastolic relaxation and filling and reduced peak filling rate (von Bibra et al. 2005;Dounis et al. 2006;Markuszewski et al. 2006;Sharman et al. 2007). The GotoKakizaki (GK) rat is a genetic animal model of type 2 diabetes, which was created by selective breeding of an outbred colony of Wistar rats with selection for high

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet

Howarth¹,

Qureshi²,

Sobhy³

et al. 2011

Experimental Physiology

View full text Add to dashboard Cite

show abstract

“…In the streptrozotocin treated rats there is a cardiomyopathy, which is characterized by reduced contractility force, relaxation time, and cardiac work [3]. Diabetic cardiomyopathy is a common complication leading to heightened risk of heart failure and death [4].…”

Section: Introductionmentioning

confidence: 99%

Effect of Exercise Training on the Expression of p53 and iNOS in the Cardiac Muscle of Type I Diabetic Rats

Al-Jarrah

2012

J Endocrinol Metab

View full text Add to dashboard Cite

Background: Diabetes is associated with a marked increase in the risk of cardiac diseases, including atherosclerosis, cardiomyopathy, and impaired ventricular function. The ability of exercise to reduce the risk of cardiac troubles has been established, but no studies have examined this link in type 1 diabetes. A randomized, controlled animal study was designed using a standard rat model of type 1 diabetes. The goal of this study was to investigate the expression of P53 and iNOS in cardiac muscle of rat with Alloxan-induced diabetes.

show abstract

“…Experiments were performed on 10 spontaneously hyperglycaemic adult male GK rats and 10 age-matched Wistar control rats at 8 weeks of age. Fasting blood glucose and glucose tolerance measurements were made following a 7 h fast by previously described methods (Howarth et al 2007). …”

Section: Experimental Modelmentioning

confidence: 99%

Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat

D’Souza

Howarth

Yanni

et al. 2011

Experimental Physiology

View full text Add to dashboard Cite

This study tested the hypothesis that experimental prediabetes can elicit structural remodelling in the left ventricle (LV). Left ventricles isolated from 8-week-old male Goto-Kakizaki (GK) rats and age-matched male Wistar control rats were used to assess remodelling changes and underlying transforming growth factor β1 (TGFβ1) activity, prohypertrophic Akt-p70S6K1 signalling and gene expression profile of the extracellular matrix (ECM) using histological, immunohistochemical, immunoblotting and quantitative gene expression analyses. Prediabetes in GK rats was confirmed by impaired glucose tolerance and modestly elevated fasting blood glucose. Left ventricle remodelling in the GK rat presented with marked hypertrophy of cardiomyocytes and increased ECM deposition that together translated into increased heart size in the absence of ultrastructural changes or fibre disarray. Molecular derangements underlying this phenotype included recapitulation of the fetal gene phenotype markers B-type natriuretic peptide and α-skeletal muscle actin, activation of the Akt-p70S6K1 pathway and altered gene expression profile of key components (collagen 1α and fibronectin) and modulators of the ECM (matrix metalloproteinases 2 and 9 and connective tissue growth factor). These changes were correlated with parallel findings of increased TGFβ1 transcription and activation in the LV and elevated active TGFβ1 in plasma of GK rats compared with control animals (Student's t test, P < 0.05 versus age-matched Wistar control animals for all parameters). This is the first report to describe LV structural remodelling in experimental prediabetes. The results suggest that ventricular decompensation pathognomonic of advanced diabetic cardiomyopathy may have possible origins in profibrotic and prohypertrophic mechanisms triggered before the onset of type 2 diabetes mellitus.

show abstract

Chronic effects of type 2 diabetes mellitus on cardiac muscle contraction in the Goto‐Kakizaki rat

Cited by 34 publications

References 38 publications

Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet

Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet

Effect of Exercise Training on the Expression of p53 and iNOS in the Cardiac Muscle of Type I Diabetic Rats

Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat

Contact Info

Product

Resources

About