Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?

TLDR

Alzheimer’s disease is marked by neurodegeneration, amyloid‑β plaques, tau tangles, oxidative stress, and early impaired glucose utilization, yet the causal links among these abnormalities remain unclear. The authors aim to define a new pathogenic mechanism for AD by proposing the term “Type 3 Diabetes” to reflect impaired insulin and IGF signaling. They identify disrupted insulin and IGF‑I/II signaling pathways—including reduced receptor expression, IRS, PI3K, Akt, and increased GSK‑3β activity—as the underlying mechanism of neurodegeneration. The study demonstrates extensive reductions in insulin/IGF signaling components and associated gene expression changes, supporting the view that AD is a distinct neuro‑endocrine disorder resembling but differing from diabetes mellitus.

Abstract

The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-β deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factorm typer I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3β activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.