Lost in Translation? Measuring Diabetic Neuropathy in Humans and Animals

Abstract

The worldwide diabetes epidemic is estimated to currently afflict almost 500 million persons. Long-term diabetes damages multiple organ systems with the blood vessels, eyes, kidneys and nervous systems being particularly vulnerable. These complications of diabetes reduce lifespan, impede quality of life and impose a huge social and economic burden on both the individual and society. Peripheral neuropathy is a debilitating complication that will impact over half of all persons with diabetes. There is no treatment for diabetic neuropathy and a disturbingly long history of therapeutic approaches showing promise in preclinical studies but failing to translate to the clinic. These failures have prompted re-examination of both the animal models and clinical trial design. This review focuses on the functional and structural parameters used as indices of peripheral neuropathy in preclinical and clinical studies and the extent to which they share a common pathogenesis and presentation. Nerve conduction studies in large myelinated fibers have long been the mainstay of preclinical efficacy screening programs and clinical trials, supplemented by quantitative sensory tests. However, a more refined approach is emerging that incorporates measures of small fiber density in the skin and cornea alongside these traditional assays at both preclinical and clinical phases.

Keywords: Diabetic neuropathies; Electrophysiology; Microscopy, confocal; Models, animal; Neuralgia; Peripheral nervous system.

Fig. 1

Dermal and epidermal nerves identified using anti-protein gene product 9.5 antibody in human (A, B), rat (C), and mouse (D) skin. Tissue was prepared as either 50 μm frozen sections (A, B) or 6 μm sections cut from paraffin blocks (C, D) with visualization using birghtfield (A, B, D) or immunofluorescence (C) microscopy. (A, B) Image-Pro Plus software (Media Cybernetics Inc.) was used to generate a composite of serial images, alllowing tracking of nerves across multiple planes of section in the dermis and epidermis (A) and around a dermal sweat gland (B). White arrows indicate dermal nerves and yellow arrows indicate epidermal nerves (IENF). Yellow circles surround Langerhans cells and their processes. Images courtesy of Katie Frizzi and Lucie Guernsey.

Fig. 2

Images of the corneal sub-basal nerve plexus in a human (A) and a BALB/c mouse (B) taken using a corneal confocal microscope (HRT 3 with Rostock Corneal Module; Heidelberg Engineering). The relatively broad and well-defined nerves of the human allow automated image analysis of total nerve length, nerve density and branch points whereas the finer mouse nerves are not accurately detected by current imaging systems and require image enhancement and tracing by hand. Images courtesy of Katie Frizzi and Morgan Cundiff.

Fig. 3

Therapeutic development funnel designed to identify neuroprotective and regenerative agents for use against diabetic neuropathy. Progression of guaifenesin and M₁ receptor (M₁R) antagonists through the funnel is indicated by arrows.