Douglas N. Ishii, Predrag Serbedzija, James E. Madl and Shana E. Nelson
Scientific Tracks Abstracts: J Diabetes Metab
Brain atrophy and cognitive disturbances are associated with decreased brain insulin and insulin-like growth factor (IGF) levels in T1D and T2D patients. An increased risk for dementia is observed even in patients without cerebrovascular disease. We tested the hypothesis that brain atrophy, the cause of progressive dementia, is primarily due to the diminished brain insulin and IGF levels observed in T1D and T2D patients. Infusion of IGF-I s.c. prevented impaired learning and memory (Morris water maze), but neither s.c. nor i.c.v. administration prevented loss of the major bulk of brain mass, total protein or DNA content in diabetic rats. On the other hand, i.c.v. infusion of both insulin and IGF-I prevented the loss of brain wet, water and dry weights, as well as of total brain protein and DNA amounts. Th e decrease in levels of proteins abundantly expressed in all cells, such as actin and tubulins, was prevented. Further, the decline in levels of those proteins selectively expressed in neurons (neurofi laments L & M, β-tubulin class III), astrocytes (glial fi brillary acidic protein) and oligodendrocytes (myelin basic protein, proteolipid protein) was also prevented. Th e administration of replacement doses of insulin and IGF-I prevented brain atrophy independently of unabated hyperglycemia and reduced body weight. Th ese data show that insulin and IGF-I normally maintain the preponderance of adult brain mass. We propose that insulin and IGF are master switches that regulate the levels of a large set of brain proteins. (Supported in part by CDCP grant R49/CCR811509 and NINDS grant T32NS43115).
Douglas N. Ishii (B.A. Biochem., Univ. Calif. Berkeley; Ph.D. Pharmacol., and Postdoctoral Neurobiol., Stanford Univ. School of Medicine). He was Assoc. Prof. Pharmacol. at Columbia Univ. School of Medicine, is now Professor at Colorado State Univ., has published more than 60 scientifi c papers, served on various NIH study sections, and is Founder of Aurogen Inc.
