Diabetic neuropathy and neuropathic pain: A (CoN) fusion of pathogenic mechanisms?

Abstract

A PubMed search at 7 PM Pacific Standard TIme on February 14, 2020, using the search phrase “diabetic neuropathy treatment” returned 17,238 hits-a lot of words for a condition with no approved therapy. It is challenging to reconcile the plethora of biochemical and molecular changes in the nervous system of diabetic rodents described previously with their mildly dysfunctional neuropathy phenotype and limited nerve pathology. It is also remarkable that so many highly selective interventions against specific pathways are completely effective in preventing or reversing indices of neuropathy and pain, despite presumably continued operation of multiple other documented pathways. The sheer volume of effective interventions must raise concerns about the relevance of preclinical models and assays to the clinical condition. Experimental models of diabetic neuropathy are perhaps best viewed as hypothesis-generating tools that offer a veritable cornucopia of potential pathogenic events and plausible targets for therapeutic intervention against neurodegeneration and pain (Fig. 4). Relatively few of the biochemical and molecular changes described previously have been confirmed in humans and, when they are, it is not easy to determine whether altered protein expression and/or activity has physiological and pathological consequences or is itself a consequence of neuropathy. The challenge before us remains the same as it was over half a century ago following the advent of ARIs189-namely, translating mechanisms and interventions identified in preclinical models of diabetes into viable therapies to prevent and reverse diabetic neuropathy and neuropathic pain. Agents that appear promising in preclinical studies have consistently failed in clinical trials against degenerative diabetic neuropathy, and there has been plenty of subsequent finger pointing, from allegations of poor drug design and unrepresentative animal models to flawed clinical trial designs and outcome measures.106,221 Encouragingly, recognition and analysis of prior failings221 has prompted the development of focused in vitro models to aid mechanistic and drug screening studies,117 animal models that more closely resemble the human diabetic condition,402 refinement of clinical protocols,32 and introduction of outcome measures such as nerve fiber density in the skin and cornea that highlight small fiber neuropathy.221,274 In contrast to degenerative neuropathy, there are a number of therapies approved by regulatory agencies to alleviate pain in diabetes and others that are used off-label.9,18 However, it is notable that none were developed to target diabetes-specific mechanisms, although efficacy is both unpredictable and restricted to small subsets of patients (NNT. 5-10).112 Refinement of models of neuropathic pain and of assays towards those that incorporate more complex cognitive functions may improve the predictive value of preclinical studies87 and have begun to be used in models of diabetes.376 There is also a growing appreciation that pain in diabetic patients falls into distinct subtypes,20 potentially reflecting different dominant pathogenic mechanisms and thus responsiveness to targeted therapeutic interventions. Drugs not statistically effective against pain in an unrefined cohort have been shown to be effective in a subgroup defined by pain mechanism,85 and clinical trial designs are beginning to incorporate patient stratification based on the likely mechanism of both pain generation and the agent under investigation.315 Together, these advances may allow the identification and development of translatable therapies that are tested against the mechanistically appropriate population and open an encouraging gateway into the world of personalized medicine.