Rethinking Neuropathy in Type 1 Diabetes: Had We Lost Sight of What Matters Most?

Abstract

Although animal and human physiological studies have informed potential mechanisms of diabetic neuropathy (1), the real‐world variability in clinical presentation and complexities in measurement have severely hindered a clear understanding of its epidemiology, its impact on the population with type 1 diabetes, and the development of therapies. The most common form—and therefore the one usually referred to simply as “diabetic neuropathy”—is the diffuse, symmetrical, slowly progressive, length‐dependent damage to the peripheral and autonomic nervous system classified technically by the term “diabetic distal symmetrical polyneuropathy” (1). It remains asymptomatic for years, may first present with abnormal sensation symmetrically at the tips of the toes, and may over time spread to the stocking‐and‐glove distribution. It involves injury to different anatomical nerve types that show variable clinical manifestations between individuals. Nerves can be classified as small, thinly myelinated or unmyelinated fibers that make up the autonomic as well as the pain and temperature sensory fibers, while large, myelinated fibers are responsible for other sensory and skeletal muscle functions. Some people have a large fiber–predominant pattern and experience numbness, tingling, or imbalance, while others have small fiber–predominance with burning and stabbing pain, impairment in sensing heat and cold, or a propensity toward clinical autonomic abnormalities like lightheadedness or gastroparesis (1). Some people experience a combination, and regardless of the pattern, people can be asymptomatic for extended periods even though their physical examination or specialized testing reveals marked impairments in nerve structure and function. With progression to foot muscle weakness or clinical autonomic manifestations like dry feet from limited sweat production, the subsequent risk of ulcer, infection, and amputation intensify. Complications like these are feared by people with diabetes more than death itself (2), and of great concern is the recent evidence of a resurgence in amputations (3–5). To study the outcomes …