Diabetic Neuropathy: An Intensive Review

Jeremiah John Duby; R. Keith Campbell; Stephen M. Setter; John Raymond White; Kristin A. Rasmussen

Disclosures

Am J Health Syst Pharm. 2004;61(2) 

In This Article

Pathology

Decades of research elucidating the pathophysiology of diabetic neuropathy have failed, thus far, to produce a treatment that prevents or reverses its development and progression. Recently, however, numerous competing or parallel pathological pathways have begun to intersect and complement each other, illuminating potential pharmacologic targets. The current foci of diabetic neuropathy research are oxidative stress, advanced glycation end products (AGEs), protein kinase C (PKC), and the polyol pathway. Figure 1 provides an overview of how these pathways may contribute to the pathophysiology.

General overview of the pathophysiology of diabetic neuropathy. AGE = advanced glycation end product, RAGE = receptors for AGEs, ROSs = reactive oxygen species, TCA = tricarboxylic acid.

The diabetic pathologies of the peripheral nervous and microvascular systems are inseparably intertwined by their physiological codependence. In the simplest terms, blood vessels depend on neural regulation for normal function, and neurons depend on capillaries for nutrients. The self-perpetuating potential of microvascular and neural dysfunction in the development of diabetic neuropathy is supported by a number of persuasive studies. In fact, much of the literature refers to diabetic neuropathy as a microvascular complication or neurovascular disease. Diabetic neurovascular disease is a metabolic disorder, and the key to pathogenesis is that neither vascular nor nervous tissue requires insulin for the uptake of glucose. Therefore, hyperglycemia results in elevated intracellular glucose levels that drive secondary pathologies -- oxidative stress, protein glycation -- that are likely similar in both vascular and nervous tissue. Nevertheless, although the systems are codependent and may have analogous diabetic pathologies, they are unique, especially with respect to the challenges of treatment.

Perhaps the first pathological change in the microvasculature is a physiological shift favoring vasoconstriction, evidenced by blunted vasodilation and elevated vasoconstrictor activity.[25] As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia.[26,27,28] Indeed, hemodynamic abnormalities, hypoperfusion, and neuronal ischemia are well-established characteristics of diabetic neuropathy.[25,29] Finally, diabetic animal models have demonstrated that vasodilator agents (e.g., angiotensin-converting-enzyme [ACE] inhibitors, α1-antagonists) and experimental drugs (e.g., aldose reductase inhibitors, PKC inhibitors) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in NCV.[25] Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.

Diabetes is, foremost, a hypermetabolic state that promotes elevated intracellular concentrations of glucose that can participate in a number of different pathological processes. Sugars can react with reactive oxygen species to form carbonyls that can further react with proteins or lipids to produce glycoxidation or lipoxidation compounds, respectively.[30] Glucose and its metabolites can also create carbonyl complexes with proteins directly, producing AGEs that contribute to oxidative stress as well. Alternatively, glucose metabolism itself creates free-radical byproducts in the normal production of ATP. The presence of excessive glucose may lead to increased production of reducing agents (i.e., NADH and FADH2) through glycolysis and the tricarboxylic acid cycle.[31] This surplus of electron donors may result in a dangerous imbalance in the mitochondrial electron transport chain that could accelerate the production of superoxide, a highly reactive free radical.[31,32,33] In summary, oxidative stress describes an increase in substrate for AGEs, an increase in precursors for glycoxidation and lipoxidation products, and an acceleration in free-radical formation that may be accompanied or caused by a deficiency of antioxidant and detoxification pathways.[30]

Glycoxidation and lipoxidation products represent an extensive and diverse group of potentially deleterious compounds. Superoxide anion is capable of profound tissue damage and may contribute to the activation of PKC by inducing de novo synthesis of diacylglycerol.[32] In fact, the existing evidence of oxidative stress supports a number of expert hypotheses, ranging from a unifying pathology to a universal consequence of disease itself.[30,31] However, a principal role for oxidative stress in the pathology of diabetic neuropathy currently hinges on gaps in basic research and disappointing clinical trials. Tissue concentrations of known carbonyl compounds are nearly negligible, and antioxidants have been shown to be of little benefit for the treatment of diabetic neuropathy or microvascular disease.[29,30]

Glucose and other sugars can nonenzymatically form covalent bonds with proteins through the Maillard reaction to produce Schiff bases and Amodori products, which can further degrade or react to produce AGEs. This process occurs in euglycemic individuals and normally affects only longer-lived proteins, but hyperglycemia provides an excess of substrate (i.e., glucose) that may accelerate the reaction, with pathological consequences. The glycation of essential proteins could alter their structure and impair their function.[34] There is scattered evidence linking AGEs to abnormalities in vascular tissue, lipid metabolism, and platelets that may be germane to the pathology of diabetic neuropathy.[34,35] Receptors for AGEs have also been identified that can contribute to oxidative stress and activate signal-transduction pathways, such as PKC and mitogen-activated protein.[31,34,35,36] Potent AGE cross-link inhibitors, such as aminoguanidine, have demonstrated efficacy in preventing diabetic vascular complications in animal models, but their lack of efficacy and dose-limiting toxicity have proven prohibitive in humans.[29,31,34,35]

The polyol pathway provides persuasive indications that the unifying feature of diabetes -- chronic hyperglycemia -- can induce and drive subordinate metabolic processes that promote intracellular instability and decay. It is essentially an alternative catabolic pathway that is activated and supplied by elevated intracellular glucose levels.[31,37] The first redox reaction of the polyol pathway couples the reduction of glucose by the enzyme al-dose reductase with the oxidation of NADPH to NADP+, producing sorbitol. Sorbitol is further oxidized to fructose by sorbitol dehydrogenase, which is coupled with the reduction of NAD+ to NADH. It was once believed that the accumulation of sorbitol resulted in osmotic stress that caused neuron damage, but it is generally accepted that sorbitol concentrations are relatively insignificant in the nerves and vascular tissue of patients with diabetes.[29,31,37] The current hypothesis holds that a high rate of "flux" of glucose through the polyol pathway is pathogenic, primarily by increasing the turnover of cofactors -- NADPH and NAD+. The reduction and regeneration of glutathione require NADPH, and depletion of glutathione could contribute to oxidative stress and the accumulation of toxic species.[37] Also, an imbalance in the NADH:NAD+ ratio could ultimately result in increased production of AGEs and the activation of diacylglycerol and PKC. Aldose reductase inhibitors are effective in preventing the development of diabetic neuropathy in animal models. However, human trials have demonstrated disappointing results and dose-limiting toxicity. Investigators continue to search for a potent inhibitor with adequate tissue penetration and a tolerable adverse-effect profile.[37]

There is mounting evidence that PKC may be a critical conductor in the metabolic pathologies associated with diabetic neuropathy. The term "PKC" actually describes a superfamily of 12 isoenzymes that act in the transduction of intracellular signaling and are activated by phosphorylation and subsequent binding to the second messenger diacylglycerol.[29,38] Elevated intracellular glucose has been linked to increased diacylglycerol and PKC levels in retinal, aortic, and renal tissues, but, surprisingly, neuronal concentrations of diacylglycerol and PKC appear to be largely unchanged or even decreased under diabetic conditions.[29,38] However, studies have demonstrated that PKC inhibitors can improve Na+ -K+ --ATPase activity, which is suppressed and could contribute to diminished NCV in diabetes.[38] More important, β1- and β2-specific PKC inhibitors have been shown to be capable of preventing diminished neuronal blood flow and NCV in diabetic animal models.

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