Long‐term severe diabetes only leads to mild cardiac diastolic dysfunction in Zucker diabetic fatty rats

Daniels, A. U.; Linz, Dominik; Bilsen, Marc van; Rütten, Hartmut; Sadowski, Thorsten; Ruf, Sven; Juretschke, Hans-Paul; Neumann-Haefelin, Claudia; Munts, Chantal; Vusse, Ger J.; Nieuwenhoven, Frans A. van

doi:10.1093/eurjhf/hfr166

Cited by 53 publications

(67 citation statements)

References 36 publications

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“…With age, the complications of diabetes worsen and ZDF rats may become more reliant on the use of lipid reserves to meet metabolic and energy requirements. A recent study in ZDF rats [10] suggests that diabetes per se is not a critical factor in the induction of clinically significant complications and hence some other factors related to obesity might have greater impact on cardiovascular abnormalities. Studies have also suggested that prolonged exposure to insulin suppresses mitochondrial biogenesis and function and this may lead to impairment of insulin sensitivity [11,12].…”

Section: Introductionmentioning

confidence: 99%

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

Raza

John²,

Howarth³

2015

Cell Physiol Biochem

110

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Background/Aims: The Zucker diabetic fatty (ZDF, FA/FA) rat is a genetic model of type 2 diabetes, characterized by insulin resistance with progressive metabolic syndrome. We have previously demonstrated mitochondrial dysfunction and oxidative stress in the heart, kidneys and pancreas of ZDF rats. However, the precise molecular mechanism of disease progression is not clear. Our aim in the present study was to investigate oxidative stress and mitochondrial dysfunction in the liver and brain of ZDF rats. Methods: In this study, we have measured mitochondrial oxidative stress, bioenergetics and redox homeostasis in the liver and brain of ZDF rats. Results: Our results showed increased reactive oxygen species (ROS) production in the ZDF rat brain compared to the liver, while nitric oxide (NO) production was markedly increased both in the brain and liver. High levels of lipid and protein peroxidation were also observed in these tissues. Glutathione metabolism and mitochondrial respiratory functions were adversely affected in ZDF rats when compared to Zucker lean (ZL, +/FA) control rats. Reduced ATP synthesis was also observed in the liver and brain of ZDF rats. Western blot analysis confirmed altered expression of cytochrome P450 2E1, iNOS, p-JNK, and IκB-a confirming an increase in oxidative and metabolic stress in ZDF rat tissues. Conclusions: Our data shows that, like other tissues, ZDF rat liver and brain develop complications associated with redox homeostasis and mitochondrial dysfunction. These results, thus, might have implications in understanding the etiology and pathophysiology of diabesity which in turn, would help in managing the disease associated complications.

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Section: Introductionmentioning

confidence: 99%

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

Raza

John²,

Howarth³

2015

Cell Physiol Biochem

110

View full text Add to dashboard Cite

show abstract

“…This may partly account for the reduced weight in aged ZDF rats. A recent study by Daniels et al [11] suggests that diabetes per se is not a critical factor in the induction of clinically significant cardiovascular complications and some other factors related to obesity might have greater impact in ZDF rats. Studies have also suggested that prolonged exposure to insulin suppresses the mitochondrial biogenesis and function and this may lead to impairment of insulin sensitivity [12,13].…”

Section: Introductionmentioning

confidence: 99%

Increased Metabolic Stress in Zucker Diabetic Fatty Rat Kidney and Pancreas

Raza

John

Howarth

2013

Cell Physiol Biochem

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Background/Aims: Obesity and diabetes (hereafter termed diabesity) are among the most challenging global health problems. Since the main pathophysiological complications in diabesity are hyperglycemia, hyperlipidemia, insulin resistance, cardiomyopathy, nephropathy, and urinary infections, the kidney and pancreas are the potential target organs affected in the above conditions. However, the precise molecular mechanisms of disease progression and complications are still unclear. The Zucker homozygous (FA/FA) diabetic fatty (ZDF) rat is a genetic model for obesity and type 2 diabetes. Our previous studies, using cardiac muscles have demonstrated metabolic and oxidative stress in ZDF rats. In the present study, our aim was to investigate oxidative stress associated metabolic complications in ZDF rat kidney and pancreas. Methods: Here we have measured oxidative stress, glutathione (GSH)-dependent metabolism and mitochondrial respiratory functions in the kidney and pancreas of ZDF and Zucker lean (ZL, +/FA) control rats. Results: Our results showed an increase in reactive oxygen species, NO production, lipid and protein peroxidation in ZDF rat kidney and pancreas accompanied by alterations in GSH-dependent metabolism and mitochondrial function. Western blot analysis has also confirmed increased expression of oxidative stress marker proteins in ZDF rats. Conclusion: We have demonstrated that ZDF rats develop metabolic complications associated with oxidative stress and mitochondrial dysfunction. Thus, these results might have implications in understanding the etiology and pathology of diabesity.

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“…It is worth noting that the Zucker diabetic rat and db/db mouse models, both of which result from a mutation in the leptin receptor, are unlikely to reflect all the changes observed in human T2DM. Indeed, several differences have been noted between the cardiac phenotype of these models compared with that observed in diabetic patients [32].…”

Section: Discussionmentioning

confidence: 95%

Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

Sedgwick

Riches

Bageghni

et al. 2014

Cardiovascular Pathology

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Introduction: Type 2 diabetes mellitus (T2DM) promotes adverse myocardial remodelling and increased risk of heart failure; effects that can occur independently of hypertension or coronary artery disease. As cardiac fibroblasts (CF) are key effectors of myocardial remodelling, we investigated whether inherent phenotypic differences exist in CF derived from T2DM donors compared with cells from non-diabetic (ND) donors. Methods:Cell morphology (cell area), proliferation (cell counting over 7-day period), insulin signalling (phospho-Akt and phospho-ERK Western blotting) and mRNA expression of key remodelling genes (real-time RT-PCR) were compared in CF cultured from atrial tissue from 14 ND and 12 T2DM donors undergoing elective coronary artery bypass surgery. Results:The major finding was that type I collagen (COL1A1) mRNA levels were significantly elevated by 2-fold in cells derived from T2DM donors compared with those from ND donors; changes reflected at the protein level. T2DM cells had similar proliferation rates but a greater variation in cell size and a trend towards increased cell area compared with ND cells. Insulininduced Akt and ERK phosphorylation were similar in the two cohorts of cells. Conclusion:CF from T2DM individuals possess an inherent pro-fibrotic phenotype that may help to explain the augmented cardiac fibrosis observed in diabetic patients. Mini SummaryWe investigated whether inherent phenotypic differences exist between cardiac fibroblasts cultured from donors with or without Type 2 diabetes. Cell morphology, proliferation, insulin signalling and gene expression were compared between multiple cell populations. The major finding was that type I collagen levels were elevated in fibroblasts from diabetic donors, which may help explain the augmented cardiac fibrosis observed with diabetes.

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Long‐term severe diabetes only leads to mild cardiac diastolic dysfunction in Zucker diabetic fatty rats

Cited by 53 publications

References 36 publications

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

Increased Metabolic Stress in Zucker Diabetic Fatty Rat Kidney and Pancreas

Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

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