Mitochondrial Dysfunction in Diabetic Neuropathy: a Series of Unfortunate Metabolic Events

Fernyhough, Paul

doi:10.1007/s11892-015-0671-9

Cited by 122 publications

(81 citation statements)

References 148 publications

(155 reference statements)

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“…These studies do not support the contention that a primary stimulation of mitochondrial superoxide is necessary for subsequent reduction of mitochondrial ETC activity (52). Similar data and conclusions were provided in studies with diabetic neuropathy by Fernyhough's group (5,6,16).…”

Section: Ros Production In Diabetes-and Obesity-related Kidney Diseasementioning

confidence: 56%

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

Sharma

2016

Antioxidants & Redox Signaling

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Significance: Reactive oxygen species (ROS) reactive nitrogen species (RNS) and redox processes are of key importance in obesity-and diabetes-related kidney disease; however, there remains significant controversy in the field. Recent Advances: New data from imaging and in vivo models of obesity and diabetic kidney disease have shed new insights into this field. In the setting of obesity-and diabetes-related kidney injury, there is a growing recognition that the major moieties of ROS and RNS are hydrogen peroxide and peroxynitrite with the enzymatic sources being NADPH oxidases and nitric oxide synthase, respectively. However, the role of mitochondrial superoxide as a driver of renal complications remains unclear. Critical Issues: Several key issues that are often not discussed are the specific ROS and RNS molecules, the source of generation, the location of production, and downstream targets. Future Directions: Further understanding of the role of ROS/RNS/redox and their relationship with key signaling and metabolic pathways such as AMP-activated protein kinase (AMPK) and hypoxia-inducible factor 1-a (HIF1a) will be critical to a new understanding of kidney complications of caloric challenges and new therapeutic approaches. Antioxid. Redox Signal. 25,[208][209][210][211][212][213][214][215][216]

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Section: Ros Production In Diabetes-and Obesity-related Kidney Diseasementioning

confidence: 56%

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

Sharma

2016

Antioxidants & Redox Signaling

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“…Evidence indicates that in neurons, diabetes decreases the expression of mitochondrial proteins 174 , the inner membrane potential 175 and the spare respiratory capacity 77 of otherwise functional mitochondria as a result of disruption to the AMPK-PGC1 pathway, which serves as a nutrient sensor and mitochondrial regulator 176 . These effects leave the neuron energetically viable but restricted in its capacity to respond to the increased energy demand of regrowth after physical injury, and to survive diseasemediated stress.…”

Section: Towards a New Understandingmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…The high energy consumption of neurons requires fine control of mitochondrial function (Chowdhury et al, 2013; Fernyhough, 2015) and the growth cone motility required to maintain fields of innervation consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling (Bernstein and Bamburg, 2003). Unmyelinated axons are more energetically demanding than myelinated axons, consuming 2.5–10-fold more energy per action potential (Wang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

Aghanoori

Smith

Chowdhury

et al. 2017

Experimental Neurology

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Diabetic neuropathy affects approximately 50% of diabetic patients. Down-regulation of mitochondrial gene expression and function has been reported in both human tissues and in dorsal root ganglia (DRG) from animal models of type 1 and type 2 diabetes. We hypothesized that loss of direct insulin signaling in diabetes contributes to loss of mitochondrial function in DRG neurons and to development of neuropathy. Sensory neurons obtained from age-matched adult control or streptozotocin (STZ)-induced type 1 diabetic rats were cultured with or without insulin before determining mitochondrial respiration and expression of mitochondrial respiratory chain and insulin signaling-linked proteins. For in vivo studies age-matched control rats and diabetic rats with or without trace insulin supplementation were maintained for 5 months before DRG were analyzed for respiratory chain gene expression and cytochrome c oxidase activity. Insulin (10nM) significantly (P<0.5) increased phosphorylation of Akt and P70S6K by 4-fold and neurite outgrowth by 2-fold in DRG cultures derived from adult control rats. Insulin also augmented the levels of selective mitochondrial respiratory chain proteins and mitochondrial bioenergetics parameters in DRG cultures from control and diabetic rats, with spare respiratory capacity increased by up to 3-fold (P<0.05). Insulin-treated diabetic animals exhibited improved thermal sensitivity in the hind paw and had increased dermal nerve density compared to untreated diabetic rats, despite no effect on blood glucose levels. In DRG of diabetic rats there was suppressed expression of mitochondrial respiratory chain proteins and cytochrome c oxidase activity that was corrected by insulin therapy. Insulin elevates mitochondrial respiratory chain protein expression and function in sensory neurons and this is associated with enhanced neurite outgrowth and protection against indices of neuropathy.

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Mitochondrial Dysfunction in Diabetic Neuropathy: a Series of Unfortunate Metabolic Events

Cited by 122 publications

References 148 publications

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

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