title: The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins.
abstract: A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.
authors.affiliation: School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, WA, Australia.|Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, WA, Australia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bharadwaj
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Nadeeja
authors.initials: N
authors.lastname: Wijesekara
authors.affiliation: School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, WA, Australia.
authors.forename: Milindu
authors.initials: M
authors.lastname: Liyanapathirana
authors.affiliation: School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, WA, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.affiliation: School of Medical Sciences, University of NSW, Kensington, NSW, Australia.
authors.forename: Lars
authors.initials: L
authors.lastname: Ittner
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Fraser
authors.affiliation: School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, WA, Australia.|Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, WA, Australia.|School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Australia.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Verdile
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D016875:tau Proteins
keywords: Alzheimer’s disease; amylin; amyloid-β protein; insulin; tau; type 2 diabetes