Schwann cell interactions with axons and microvessels in diabetic neuropathy

Abstract

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...

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Diabetic conditions can affect both GLUT localization (Bakirtzi et al, 2009) and activity (for example, GLUT4 activity in the periphery is impaired under type 2 diabetes) (Pearson-Leary and McNay, 2016); however, expression levels of GLUTs in glial or neuronal cells does not appear to be altered by diabetic conditions (de Preux Charles et al,2010; Hur et al, 2011; Pande et al, 2011). Schwann cells, which metabolically support axons in the PNS, are crucial cell types in the pathogenesis of diabetic neuropathy (Zenker et al, 2013; Mizisin, 2014; Feldman et al, 2017; Goncalves et al, 2017). Schwann cells need to maintain GLUT1 levels to metabolically support axons and potentially maintain their own function and survival.…”

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

“…An array of factors, such as dysfunction of mitochondria and endoplasmic reticulum, hypercholesterolemia, endothelial dysfunction, and ischemia/hypoxia, are considered to play an important role in the development of diabetic neuropathy Cashman & Höke, 2015;Feldman, Nave, Jensen, & Bennett, 2017;Gonçalves et al, 2017). Pathological studies of sural nerve biopsies from patients with diabetic neuropathy typically demonstrate axonal atrophy, demyelination, axonal degeneration with regeneration, and microangiopathy (Biessels et al, 2014;Malik et al, 1989Malik et al, , 2005Thomas et al, 1996).…”

Altered peripheral nerve structure and function in latent autoimmune diabetes in adults

“…[36][37][38] Schwann cell dysfunction has recently been recognized as an integral factor in the development of diabetic neuropathy as these cells envelope the internode and export metabolites necessary for energy production within the axon. 39 Interestingly, the degree of insulin resistance in people with LADA has been found to be similar to that of individuals with type 2 diabetes and long-term type 1 diabetes. 40,41 Earlier development of insulin resistance in the periph-…”

“…Insulin is a potent neurotrophic factor that supports axonal growth as well as Schwann cell physiology and receptors for insulin are abundantly expressed on peripheral nerves, at the node of Ranvier, and on Schwann cell membranes . Schwann cell dysfunction has recently been recognized as an integral factor in the development of diabetic neuropathy as these cells envelope the internode and export metabolites necessary for energy production within the axon . Interestingly, the degree of insulin resistance in people with LADA has been found to be similar to that of individuals with type 2 diabetes and long‐term type 1 diabetes .…”