Pancreatic islet cell adenoma, oral squamous cell carcinoma, peripheral polyneuropathy, and multiple age-associated degenerative lesions were diagnosed in an aged Sprague-Dawley rat presenting with polyuria, polydypsia, dehydration, anorexia, weight loss, and posterior weakness. Microscopically, the islet cell adenoma was encapsulated by fibrous tissue and composed of packets of oval-to-polygonal monomorphic cells in a fibrovascular stroma. Immunohistochemically, the majority of cells within the mass expressed insulin. In light of the histologic and immunohistochemical findings, a diagnosis of insulinoma was made. The oral squamous cell carcinoma, grossly presenting as gingival ulceration, was composed of nests and cords of squamous epithelial cells that focally eroded and infiltrated the hard palate and resulted in degeneration of the maxillary nerve. The peripheral polyneuropathic lesions were characterized by extensive axonal degeneration and microangiopathic changes that were highly suggestive of a hypoglycemic etiopathogenesis secondary to insulinoma.