Diabetic Neuropathy: Cytokines, Inflammation, and Treatment Targets

Half of diabetic patients experience diabetic neuropathies—primarily distal symmetrical polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN)—and the total number of cases will increase annually alongside the ever-increasing diabetes incidence rate. Diabetic neuropathy is more deadly than alcohol consumption, proteinuria, race, retinopathy, sex, smoking, type of diabetes, body mass index, duration of diabetes, or hemoglobin A1c individually.

All diabetic neuropathies increase risk of all-cause death, and adversely affect quality of life. Risk for amputation is very high; compared to diabetics without diabetic neuropathies, DSPN patients have a 25% cumulative risk of lower limb amputation and diabetic neuropathies decrease 3-year survival by 20%. CAN independently increases risk of cardiac arrhythmias, silent myocardial ischemia, and myocardial dysfunction. The Diabetes Control and Complications Trial showed that intensive glucose control is insufficient to control the risk of diabetic neuropathy.

The journal Current Diabetes Reports has published a study surveying existing research on mechanisms of low-grade inflammation as diabetic neuropathy targets in its March 2016 issue. The researchers' hypothesis is that targeting inflammation may alleviate diabetic neuropathy.

Diabetic neuropathies are driven by a number of cellular and systemic processes that manifest as markers of endothelial and inflammatory dysfunction. These include oxidative/nitrosative stress, endothelial dysfunction, altered Na+/K + −ATPase pump function, impaired C-peptide-related signaling pathways, endoplasmic reticulum stress, low-grade inflammation. Activation of polyol and protein kinase C pathways, polyADP ribosylation, neuronal damage-associated genes, and cyclooxygenase-2 (COX-2) also contribute.

The researchers call out the NF-κB pathway, a stress-induced transcription process that reacts to hyperglycemia, oxidative stress, and proinflammatory cytokines. The NF-κB axis activates or releases COX-2, nitric oxide synthase, lipoxygenase, TNF-α, and endothelin-1.

Oxidative stress (glucotoxicity, insulinopenia, and lipotoxicity) also activates several pathways that in turn lead to the release of pro-inflammatory IL-1β, IL-2, IL-6, IL-8, TNF-α, and the chemokines CCL2 and CXCL1.

Cytokine levels correlate directly with diabetic neuropathy severity.

Diabetes attenuates macrophages' anti-inflammatory function while simultaneously driving pro-inflammatory macrophage activity. Inflammation may cause maladaptive epigenetic changes to early immune cell progenitors in the bone marrow.

The researchers report that salicylate therapy lowers circulating glucose, triglycerides, free fatty acids, CRP levels, and the inhibitory effects of the IKKβ/NF-κB pathway. It also inhibits production of chemokines, interleukins, and complement. They propose that since diabetes is associated with early systemic inflammations, targeting the IKKβ/NF-κB pathway might delay development of diabetic neuropathies.