Robert Schmidt, MD, PhD

Professor, WashU Pathology & Immunology

Pathogenetic mechanisms of diabetic and age-related autonomic neuropathy

Disease of the peripheral autonomic nervous system is a significant complication of diabetes and aging with clinical presentations ranging from minor pupillary and sweating problems to significant disturbances in cardiovascular, alimentary and genitourinary function, resulting in significantly increased patient morbidity and mortality. My laboratory is interested in the neuropathology and pathogenesis of diabetic and age-associated sympathetic autonomic neuropathy. In order to develop insight into the early phases of these conditions, which presumably would be most amenable to therapy and would be most tightly coupled to pathogenetic mechanisms, we have developed and validated several rodent models which show close correspondence to human disease.

We have focused on the examination of alterations in synapses in sympathetic ganglia. Diabetes and aging result in the development of degenerating, regenerating, and pathologically distinctive dystrophic nerve terminals and post-synaptic dendritic elements in prevertebral sympathetic ganglia of streptozotocin (STZ)-induced diabetic and genetically diabetic rats and mice. Identical neuropathology characterizes aged humans, rats and mice which suggests shared mechanisms between diabetes and aging. Our long term goal of understanding the pathogenesis and treatment of diabetic and age-related autonomic neuropathy has resulted in the investigation of novel therapeutic agents and neurotrophic substances. IGF-I (insulin-like growth factor-I) treatment of diabetic rats with established ganglionic neuritic dystrophy results in nearly complete normalization of dystrophic pathology without altering the metabolic severity of diabetes. Since this result occurred without normalization of blood glucose levels, we have proposed that IGF-I acts directly as a neurotrophic substance to correct ganglionic deficiency of IGF-I and normalize deficits in its neuronal signaling cascade.

Thus, using relevant animal models which are faithful replicas of the human disease, characterized by dramatic and unambiguous neuropathology and reproducible over strain and species boundaries, our long term goal is to understand the pathogenesis and treatment of diabetic and age-related autonomic neuropathy.

More about Robert Schmidt