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Impaired β-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving β-cell function, it is essential to understand the cause and mechanisms about the progression of β-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of β-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic β-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic β-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.
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Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy.
We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control- or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes.
OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity.
We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.
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Obesity resulting from the delivery of an excess amount of energy to adipose tissue from glucose or free fatty acids is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) have been implicated as contributors to both the onset and the progression of insulin resistance. ROS can be generated by overloading the mitochondrial oxidative phosphorylation system, and also by nicotinamide adenine dinucleotide phosphate oxidases (NOX) produced by either adipocytes, which only produce NOX4, or by macrophages, which produce mainly NOX2. The source of the ROS might differ in the early, intermediate and late stages of obesity, switching from NOX4-dependence in the early phases to NOX2-dependence, in the intermediate phase, and transiting to mitochondria-dependence later in the time course of obesity. Thus, depending on the stage of obesity, ROS can be generated by three distinct mechanisms: i.e., NOX4, NOX2, and mitochondria. In this review, we will discuss whether NOX4-, NOX2-, and/or mitochondria-derived ROS is/are causal in the onset of adipocyte insulin resistance as obesity progresses. Moreover, we will review the pathophysiological roles of NOX4, NOX2, and mitochondria-derived ROS on adipose tissue inflammation.
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A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in diabetic complications, especially β-cell dysfunction and failure. Under physiological conditions, reactive oxygen species serve as second messengers that facilitate signal transduction and gene expression in pancreatic β-cells. However, under pathological conditions, an imbalance in redox homeostasis leads to aberrant tissue damage and β-cell death due to a lack of antioxidant defense systems. Taking into account the vulnerability of islets to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed as a way to protect β-cells against diabetic insults. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions, as well as the therapeutic benefits of antioxidants, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with β-cell failure.
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Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in subjects with diabetes. Disorders of the physiological signaling functions of reactive oxygen species (superoxide and hydrogen peroxide) and reactive nitrogen species (nitric oxide and peroxynitrite) are important features of diabetes. In the absence of an appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the vascular complications of diabetes. It has recently been suggested that diabetic subjects with vascular complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia. This raises the concept that antioxidant therapy may be of great benefit to these subjects. Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, effective therapeutic strategies to prevent or delay the development of this damage remain limited. Thus, further investigation of therapeutic interventions to prevent or delay the progression of diabetic vascular complications is needed.
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