Abstract
The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.
Highlights
The prevalence of diabetes and prediabetes has continued to increase worldwide in recent years [1,2,3,4,5]
Based on these observations and that of Nukada et al [19], we suggest that inflammation may be an important factor in a multimodal pathway in the pathogenesis of diabetic neuropathy in addition to axonal degeneration of peripheral nerve fibers (Figure 2)
Since diabetic rats developed sensory neuropathy on a low iron diet but did not show lowered systemic levels of iron, we concluded that dorsal root ganglion (DRG) and peripheral nerve fibers might be more vulnerable to dietary iron deprivation than other tissues (Figure 3)
Summary
The prevalence of diabetes and prediabetes has continued to increase worldwide in recent years [1,2,3,4,5]. Despite intensive research in recent years, there is still no unifying concept of the pathophysiology of DN nor efficacious and safe specific treatments available. In this short review, we summarized the more recent aspects of two pathomechanisms based on our own experimental studies in diabetic disease models, namely inflammatory mechanisms and the modulation by manipulating systemic iron levels. We summarized the more recent aspects of two pathomechanisms based on our own experimental studies in diabetic disease models, namely inflammatory mechanisms and the modulation by manipulating systemic iron levels These has been discussed against other recent findings and hypotheses. We conclude that re-examining these inflammatory mechanisms in human DN seems warranted
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