Translating diabetic peripheral neuropathy

In 2019, the PNS society Alan J Gebhart prize was awarded in Genoa to Drs. Doug Zochodne and Eva Feldman for their contributions to the field of diabetic neuropathy. Much like that famous son of Genoa, Christopher Columbus, they are optimistic of discoveries—not of new lands, but of new treatments for diabetic neuropathy. However, unlike Columbus who famously said “for the execution of the voyage to the Indies, I did not make use of intelligence, mathematics or maps” and who ended up discovering the Americas, our colleagues provide a road map for the future of disease modification in diabetic peripheral neuropathy (DPN). Zochodne and Kobayashi provide a clear, well-organized and refreshing review that places the peripheral nerve “under the microscope” by focusing on axonal, perikaryal and Schwann cell abnormalities in the context of the known nerve pathology. They question basic concepts on the pathophysiology of DPN, highlight novel mechanistic pathways, which could be exploited and then provide direction as to how these findings may be translated into meaningful treatments for DPN. They also highlight the “translational void” between preclinical studies and clinical trials in relation to the 100% attrition rate and complete lack of drugs which have been approved for DPN by the food and drug administration (FDA). To at least partially mitigate this problem, they further refine a set of conditions, which should be fulfilled for preclinical studies before embarking on costly clinical trials. Perhaps a worldlier view is that the number and diversity of preclinical studies and good science may increasingly be a bridge too far for “Big Pharma” to commit huge financial resources to translate a therapeutic concept into a viable treatment for DPN. Feldman and colleagues take us on a voyage not towards the Americas with Columbus on the Santa Maria, but away from the glucocentric view of the pathogenesis and treatment of DPN. Their review rightly acknowledges that the vast majority of patients with diabetic peripheral neuropathy suffer from type 2 diabetes and associated metabolic abnormalities, such as obesity, hypertension and hyperlipidemia. Not only do they suggest novel therapeutic targets based on modifying lipid pathways but they also emphasize the potential role of weight loss through diet and exercise or bariatric surgery as potential treatments for neuropathy. This is an encouragingly practical approach that aligns with established clinical recommendations for the general health of the majority of those with type 2 diabetes and does not require the huge development costs which inevitably themselves translate into high drug costs that must be borne by health care systems or individual patients for the rest of their lives. The challenge, as already faced by clinicians interacting with such patients, will be how to encourage the uptake and maintenance of these lifestyle modifications. It is worth recalling that despite impressive improvements in weight, HbA1c and lipids over 12 to 14 years, the look AHEAD study was only able to show an improvement in symptoms but not signs of DPN. There may be a need to develop simple biomarkers of neuropathy that are seen as meaningful by patients and can be used iteratively as positive reinforcement to encourage persistence with lifetime therapeutic regimes—much as HbA1c became a mantra for many people with type 1 diabetes. A common theme highlighted in both reviews is the potential importance of mitochondrial dysfunction that increasingly appears at the crux of multiple pathogenic mechanisms. However, the clinical paradox of myopathy not sensory neuropathy being a primary feature of the mitochondrial disease remains the pachyderm in the parlor. There is no doubt that clinical trials offer many opportunities for failure and central to the lack of an FDAapproved disease-modifying therapy for diabetic neuropathy is the inability to demonstrate efficacy using archaic protocols. Feldman and colleagues allude to the importance of assessing unmyelinated C fibers as a primary outcome measure in clinical trials as opposed to the current dogma which relies on symptoms/disability and electrophysiology. This argues for the potential utility of thermal perception thresholds and pathological end points, such as intraepidermal nerve fibre density in skin biopsies and corneal nerve measures using corneal confocal microscopy as primary end points in clinical trials of diabetic peripheral neuropathy. Indeed, recent data showing early nerve regeneration in patients after simultaneous pancreas and kidney transplantation, improvement in Received: 6 May 2020 Accepted: 7 May 2020