Chapter Eight - Glucotoxic Mechanisms and Related Therapeutic Approaches

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Abstract

Neuropathy is the earliest and commonest complication of diabetes. With increasing duration of diabetes, frequency and severity of neuropathy are worsened. Long-term hyperglycemia is therefore implicated in the development of this disorder. Nerve tissues require glucose energy to function and survive. Upon excessive glucose entry into the peripheral nerve, the glycolytic pathway and collateral glucose-utilizing pathways are overactivated and initiate adverse effects on nerve tissues. During hyperglycemia, flux through the polyol pathway, formation of advanced glycation end-products, production of free radicals, flux into the glucosamine pathway, and protein kinase C activity are all enhanced to negatively influence nerve function and structure. Suppression of these aberrant metabolic pathways has succeeded in prevention and inhibition of the development of neuropathy in animal models with diabetes. Satisfactory results were not attained, however, in patients with diabetes and further clinical trials are required. In this review, the author summarizes the hitherto proposed theories on the pathogenesis of diabetic neuropathy related to glucose metabolism and future prospects for the effective treatment of neuropathy.

Introduction

There is a long history of research to clarify the pathogenetic mechanism of diabetic polyneuropathy (DPN), but it remains unsettled. Since the prevalence of DPN is primarily dependent on the duration of diabetes and the degree of blood glucose control, long-term metabolic aberration is considered to be a major cause of DPN (Pirart, 1978). A large prospective study disclosed that hyperglycemia, duration of diabetes, hypertension, hyperlipidemia, and smoking are significant risk factors for the development of DPN in patients with type 1 diabetes (Tesfaye et al., 2005). Indeed, the 10-year follow-up of patients with type 1 diabetes by the Diabetic Complication and Control Trial (DCCT) demonstrated that meticulous blood glucose control by intensive insulin therapy suppressed the incidence of DPN (DCCT Research Group, 1993). The effects of tight glycemic control persisted for a further 8 years after the termination of the trial as legacy effects termed glucose or metabolic memory (Martin et al., 2006). Although the role of hyperglycemia in driving the progression of DPN in type 2 diabetes is less clear (UKPDS Group, 1998), continuous lowering of glycated hemoglobin below 7% for 6 years was found to suppress the deterioration of DPN in patients with type 2 diabetes (Ohkubo et al., 1995). Despite the ample epidemiological data, there remains no clear-cut explanation why long-term hyperglycemia leads to DPN.

It is known that the most distal portions of somatic nerves are preferentially affected in diabetes. Both anatomical and biochemical characteristics of the peripheral nervous system seem to contribute to the distal and sensory predominant nerve lesions in diabetes (Dyck et al., 1984, Dyck et al., 1986). Structurally, the sensory neurons extend extremely long axons from their cell bodies in the dorsal root ganglia (DRG). The relative imbalance in this architecture between the soma and axon can result in insufficient supply of nerve nutrients and energy from the cell body to the distal processes. The anatomic organization of the vascular supply to the peripheral nerve may also impose negative impacts on the peripheral nerve because of the relative paucity of endoneurial blood vessels and their lack of autoregulation (Kihara, Schmelzer, et al., 1991; Smith, Kobrine, & Rizzoli, 1977). Such a vascular system likely renders the peripheral nerve ischemic, resulting in severe pathology when ischemia is further exaggerated by vascular occlusion (Nukada, McMorran, Baba, Ogasawara, & Yagihashi, 2011), though ischemic diabetic nerve is temporarily resistant to nerve conduction failure (Low, Schmelzer, & Ward, 1986). Endoneurial microangiopathic changes characteristic of diabetes may further augment nerve damage due to increased permeability and ischemia (Dyck & Giannini, 1996; Malik et al., 2005, Thrainsdottir et al., 2003). Features such as the strong expression of aldose reductase (AR) in peripheral nerve and the abundance of interstitial collagen implicate the polyol pathway and glycation as etiological factors in DPN.

Glucose metabolism in the peripheral nerve is not completely understood. Peripheral nerves express the GLUT-1 glucose transporter at the perineurial and endothelial blood:nerve barriers (Stark, Carlstedt, Cullheim, & Risling, 2000), and glucose uptake into nerve is therefore insulin independent so that endoneurial glucose concentrations will follow plasma glucose concentrations. Under normoglycemic conditions, the majority of glucose entering the cytoplasm is used by mitochondria to produce adenosine triphosphate (ATP) through the tricarboxylic acid (TCA) cycle, downstream from the glycolytic pathway. In neurons, synthesized proteins, cytoplasmic organelles, cargoes of microtubules and neurofilaments, as well as neurotransmitters, are all transported in an energy-requiring process to the distal nerve endings. It has been proposed that if the energy production in the axon is deficient then the distal portion is first affected by the insufficient supply of these materials (Scott et al., 1999, Yagihashi, Kamijo, et al., 1990b). Additionally, hyperglycemia makes glucose available for other uses and perturbed glycolytic pathways may lead to impaired nerve function and disruption of nerve structure. In this review, I will list the collateral glycolytic pathways operating downstream of hyperglycemia and discuss their possible implication in the onset and development of DPN.

Section snippets

Glucose-Metabolizing Pathways Relevant to DPN

There are a number of metabolic pathways that operate collaterally to glycolysis that may contribute to development of DPN as a downstream consequence of hyperglycemia (Fig. 1).

  • (1)

    The polyol pathway uses AR to produce sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH) (Gabbay, 1975, Kinoshita, 1990). AR has a relatively low affinity for d-glucose so this metabolic process is enhanced only when glucose concentrations are high in the cytoplasm.

  • (2)

    Hyperglycemia leads to

Metabolic Sequelae After Increased Flux Through the Polyol Pathway

A complete mechanism of how the polyol pathway is involved in development of diabetic neuropathy remains elusive. Sorbitol is an important osmoregulator and does not readily permeate the cell membrane. Accumulation of sorbitol therefore causes increased osmotic pressure within the cell (Fig. 2). The original osmotic theory proposed that increased polyol pathway flux during hyperglycemia caused intracellular hyperosmolarity by accumulation of sorbitol, resulting in the expansion of cells and

Glycation of Proteins in Diabetes

Increased nonenzymatic glycation of proteins is considered to be a major contributor to a variety of diabetic complications including micro- and macroangiopathy (Brownlee, 1992, Yamagishi et al., 2005). In a hyperglycemic environment, glucose is attached nonenzymatically to amino residues of proteins forming glucose adducts as initial glycation metabolites that progress from Schiff base to Amadori products (Thornalley, 2002). These products are unstable and likely to transform to MG or

Production of Oxidative Stress by Hyperglycemia

The generation of free radicals due to increased flux of glucose through glycolysis has been proposed as a major contributor to diabetic complications, including DPN. This hypothesis was originally raised by the short-term experiments mostly on in vitro endothelial cells and is still not confirmed in neural tissues. During hyperglycemia, increased mitochondrial oxidation of NADH and FADH2 leads to excessive formation of superoxide ions, a form of ROS (Brownlee, 2005) (Fig. 5). Reduced

PKC Activity

PKC plays a role in maintaining normal nerve function, and its aberrant regulation may contribute to the pathogenesis of DPN (Way, Katai, & King, 2001). PKC has several isoforms from α, β, γ, δ, and so on. Under ambient hyperglycemia, glucose is converted to glyceraldehydes-3-phosphate and phosphatidic acid, which in turn changes into diacylglycerol that serves as a substrate of PKC-β. Vascular tissues in diabetes thus show increased PKC activity, leading to increased permeability and

The Hexosamine Pathway

Under conditions of elevated intracellular glucose and flux into glycolysis, excess fructose 6-phosphate is converted to glucosamine 6-phosphate (GlcN-6-phosphate) by glutamine-fructose-6-phosphate amidotransferase (GFAT). GlcN-6-phosphate is then modified to UDP-N-acetylglucosamine (UDP-GlcNAc) (Du et al., 2000, Issad et al., 2010) (Fig. 6). UDP-GlcNAc has an affinity for cell membrane or nucleic acid or transcription factors and excessive modification of these substrates by posttranslational

Conclusion

It is well established that long-term hyperglycemia contributes to the genesis and development of DPN. However, the process is complicated and the precise mechanisms of how high glucose affects the assorted cell types within a nerve are still mysterious. Epidemiological studies suggest that many factors are responsible for DPN, and the targeting of a single collateral pathway may not be sufficient for the protection and suppression of DPN. Experimental studies have identified multiple pathways

Acknowledgments

The author appreciates the previous collaborators who contributed to the published works from the author's laboratory. The author also is grateful for the research funding from the Japanese government of the Ministry of Science, Culture, Education, and Sports, the Ministry of Health and Welfare, and the Juvenile Diabetes Foundation International, New York.

Duality of Interest: There is no conflict of interest for the author regarding the content of this review.

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    1

    Present address: The Nukada Institute of Medical and Biological Research, 4-16 Inage-machi, Inage-ku, Chiba, Japan. E-mail: [email protected].

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