Diabetic neuropathy: mechanisms to management

Abstract

Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.

Figure 1. Stocking Glove Configuration of DPN

Diabetic neuropathy is dependent on axon length, initiating in the toes and progressing upward until reaching the calf. Neuropathy presents at the fingertips at this point.

Figure 2. Effect of Disease Duration and Age on Prevalence of Diabetic Neuropathy

For both T1DM and T2DM, duration of diabetes (left) as well as age of patient (right) is correlated to the incidence of diabetic neuropathy. Adapted from (Young, 1993)

Figure 3. Effect of Glycemic Control on Diabetic Neuropathy in DCCT

Intensive therapy cohort which showed better glycemic control, results in lower incidences of all forms of diabetic neuropathy compared to conventional therapy. Adapted from (The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group, 1995)

Figure 4. MNSI Patient Questionnaire

Adapted with permission

Figure 5. 8 Point Clinical Examination for Diabetic Neuropathy

Adapted with permission

Figure 6. Schematic of Hyperglycemic Effects on Biochemical Pathways in Diabetic Neuropathy

Excessive glucose metabolism generates excess NADH and leads to overload of the electron transport chain causing oxidative stress, damage to Mt, activation of PARP. PARP activation by ROS acts in conjunction with the hexosamine and PKC pathway to induce inflammation and neuronal dysfunction. A combination of oxidative stress and hyperglycemia activate the detrimental pathways of AGE, polyol, hexosamine and PKC pathways which lead to redox imbalance, gene expression disturbances, and further oxidative stress. These pathways also induce inflammation and neuronal dysfunction. NF-κB :Nuclear factor kappa B; PARP: Poly(ADP-ribose) polymerase; PKC: Protein kinase C; AGE: Advanced glycation endproducts; RNS: Reactive nitrogen species; ROS: Reactive oxygen species, GSH: glutathione; GSSG: oxidized glutathione; UDPGlcNAc: UDP-N-Acetylglucosamine; VEGF: Vascular endothelial growth factor.

Figure 7. Oxidative stress and mitochondrial dysfunction(Leinninger, 2006b)

Hyperglycemia increases production of reactive oxygen species (ROS) in mitochondria. NADH and FADH₂ produced from the tricarboxylic acid cycle transfer to the mitochondria, where they serve as electron donors to the mitochondrial membrane-associated redox enzyme complexes. The electrons (e⁻) are shuttled through oxidoreductase complexes I, II, III and IV (cytochrome c), until they are donated to molecular oxygen, forming water. The electron transfer into complexes I, III and IV by NADH (and FADH₂ via complex II to complex III) produces a proton gradient at the outer mitochondrial membrane, generating a potential between the inner mitochondrial membrane and outer mitochondrial membrane. This potential drives ATP synthesis, and is crucial for mitochondrial viability, function, and normal metabolism. As electrons are passed from complex II to complex III, however, ROS are produced as by-products. The levels of ROS produced during normal oxidative phosphorylation are minimal, and they are detoxified by cellular antioxidants such as glutathione, catalase and superoxide dismutase. The hyperglycemic cell, on the other hand, shuttles more glucose through the glycolytic and tricarboxylic acid cycles, providing the cell with an over-abundance of NADH and FADH₂ electron donors. This produces a high proton gradient across the inner mitochondrial membrane, which increases the turnover of the initial complexes, and thereby produces increased levels of radicals. Accumulation of these radicals, or ROS, is severely detrimental to mitochondrial DNA, mitochondrial membranes and the whole cell. Abbreviations: Cyto-c, cytochrome c; CoQ10, coenzyme Q10; e⁻, electrons; GSH, glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; O2^•−, superoxide; P_i, phosphate; SOD, superoxide dismutase.

Figure 8. Risk of Diabetic Complications (Retinopathy) in Control vs. Intensive Therapy as related to Hb_A1C

Absolute risk of sustained retinopathy progression as a function of updated mean A1C (percentage) during the DCCT and the time of follow-up during the study (years), estimated from absolute (Poisson) regression models. (A) Conventional treatment group. (B) Intensive treatment group. Results suggest that average glucose levels may be less important to prognosis of complications than fluctuations in glucose levels. Reprinted with permission from DCCT Research Group (1995) (Hirsch & Brownlee, 2005)

Figure 9. Management of Neuropathic Pain

Stepwise instructions for treatment of the symptoms for painful diabetic neuropathy based on multiple levels of medications, pain scores and evaluations. Adapted from (Dworkin, 2007b)

Figure 10. Diagram of Benfotiamine Effect on Biochemical Pathways in Diabetic Complications

Excess glucose activates flux through hexosamine pathway creating UDPGlcNAc from F-6-P. UDPGlcNAc modifies transcription factors which lead to inflammation. Addition of benfotiamine, a thiamine analog activates transketolase (TK) which diverts substrate away from the hexosamine pathway and into the pentose phosphate pathway. Adapted from (Hammes, 2003).

Figure 11. Therapeutic targets on the AGE-RAGE pathway to DN

The process of AGE damage and RAGE activation offer multiple approaches for preventing neuronal damage, from preventing AGE formation to blocking downstream signaling cascades.

Figure 12

Activities (in blue) are hypothesis driven and attempt to identify biomarkers based on the disequilibrium of identified targets in diabetic neuropathy, leading to an abnormal accumulation of products, such as modified proteins or small molecules. Activities in red are discovery oriented and seek to identify features of the data set that are predictive of diabetic neuropathy without necessarily corresponding to a single target.

Figure 13

Discovery Approach for Novel Targets in Diabetic Neuropathy (DN). Genome wide expression profiling of neural tissues from animal models with diabetic neuropathy (DN) will yield differentially regulated transcripts. Analyses of these data using Gene Ontology (GO) will provide the data needed to define categories of genes that are functionally related providing a molecular signature for diabetic neuropathy. Further analyses of these data can define relevant pathways related to functional gene categories and shared promoter modules among members of different gene categories, providing one or more specific targets for disease regulation. These targets can be verified at the mRNA level, confirming the identification of a novel disease target.