Hepatic Mitochondrial Alterations and Increased Oxidative Stress in Nutritional Diabetes-Prone Psammomys obesus Model

Mitochondrial dysfunction is considered to be a pivotal component of insulin resistance and associated metabolic diseases. Psammomys obesus is a relevant model of nutritional diabetes since these adult animals exhibit a state of insulin resistance when fed a standard laboratory chow, hypercaloric for them as compared to their natural food. In this context, alterations in bioenergetics were studied. Using liver mitochondria isolated from these rats fed such a diet for 18 weeks, oxygen consumption rates, activities of respiratory complexes, and content in cytochromes were examined. Levels of malondialdehyde (MDA) and gluthatione (GSH) were measured in tissue homogenates. Diabetic Psammomys showed a serious liver deterioration (hepatic mass accretion, lipids accumulation), accompanied by an enhanced oxidative stress (MDA increased, GSH depleted). On the other hand, both ADP-dependent and uncoupled respirations greatly diminished below control values, and the respiratory flux to cytochrome oxydase was mildly lowered. Furthermore, an inhibition of complexes I and III together with an activation of complex II were found. With emergence of oxidative stress, possibly related to a defect in oxidative phosphorylation, some molecular adjustments could contribute to alleviate, at least in part, the deleterious outcomes of insulin resistance in this gerbil species

Beneficial effects of silibinin against the progression of metabolic syndrome, increased oxidative stress, and liver steatosis in Psammomys obesus, a relevant animal model of human obesity and diabetes

Background: Insulin resistance and oxidative stress are major pathogenic mechanisms leading to chronic liver diseases in diabetic subjects. The gerbil Psammomys obesus is a unique model of nutritional diabetes resembling the disease in humans. This study investigated whether the natural ingredient silibinin, known as hepatoprotective, could decrease oxidative stress and reduce liver damage in obese gerbils. Methods: Control animals were fed their vegetable-based low caloric diet while two other rat groups ingested a high calorie diet for 14 weeks. Silibinin, or its vehicle, was administrated by gastric intubation (100mg/kg per day) from the 7th week of treatment, which corresponds to an established insulin resistance state. At the end of the experiments, the hepatic biochemical profile, markers of oxidative stress in either plasma or liver tissue, and histological alterations were examined. Results: Diabetic P.obesus displayed many metabolic disturbances (hyperinsulinemia, hyperglycemia, dyslipidemia), which were aggravated for the last 8 weeks. These events were coupled with greater oxidative stress (decline in glutathione, rise in lipoperoxidation). In addition, glutathione peroxidase activity was reduced while the level of superoxide dismutase was elevated. Interestingly, treatment with silibinin alleviated most of the metabolic defects, especially high triglyceride levels, reduced insulin resistance and largely restored antioxidant status. Also, Masson's trichrome staining revealed distinct steatosis, yet silibinin partially reversed this manifestation. Conclusion: Silibinin affords substantial protection against the progression of insulin resistance in Type 2 diabetes mellitus for P.obesus by hampering the oxidative process and improving hepatic metabolism. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

Hepatic mitochondrial alterations and increased oxidative stress in nutritional diabetes-prone Psammomys obesus model. Experimental Diabetes Research 2012:430176

Mitochondrial dysfunction is considered to be a pivotal component of insulin resistance and associated metabolic diseases. Psammomys obesus is a relevant model of nutritional diabetes since these adult animals exhibit a state of insulin resistance when fed a standard laboratory chow, hypercaloric for them as compared to their natural food. In this context, alterations in bioenergetics were studied. Using liver mitochondria isolated from these rats fed such a diet for 18 weeks, oxygen consumption rates, activities of respiratory complexes, and content in cytochromes were examined. Levels of malondialdehyde (MDA) and gluthatione (GSH) were measured in tissue homogenates. Diabetic Psammomys showed a serious liver deterioration (hepatic mass accretion, lipids accumulation), accompanied by an enhanced oxidative stress (MDA increased, GSH depleted). On the other hand, both ADPdependent and uncoupled respirations greatly diminished below control values, and the respiratory flux to cytochrome oxydase was mildly lowered. Furthermore, an inhibition of complexes I and III together with an activation of complex II were found. With emergence of oxidative stress, possibly related to a defect in oxidative phosphorylation, some molecular adjustments could contribute to alleviate, at least in part, the deleterious outcomes of insulin resistance in this gerbil species

Investigating the role of mitochondria in type 2 diabetes lessons from lipidomics and proteomics studies of skeletal muscle and liver.

Mitochondrial dysfunction is discussed as a key player in the pathogenesis of type 2 diabetes mellitus (T2Dm), a highly prevalent disease rapidly developing as one of the greatest global health challenges of this century. Data however about the involvement of mitochondria, central hubs in bioenergetic processes, in the disease development are still controversial. Lipid and protein homeostasis are under intense discussion to be crucial for proper mitochondrial function. Consequently proteomics and lipidomics analyses might help to understand how molecular changes in mitochondria translate to alterations in energy transduction as observed in the healthy and metabolic diseases such as T2Dm and other related disorders. Mitochondrial lipids integrated in a tool covering proteomic and functional analyses were up to now rarely investigated, although mitochondria]. lipids might provide a possible lynchpin in the understanding of type 2 diabetes development and thereby prevention. In this chapter state-of-the-art analytical strategies, pre -analytical aspects, potential pitfalls as well as current proteomics and lipidomics-based knowledge about the pathophysiological role of mitochondria in the pathogenesis of type 2 diabetes will be discussed