title: Increased Aβ production prompts the onset of glucose intolerance and insulin resistance.
abstract: Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.
authors.affiliation: Hospital Universitario Puerta del Mar, Planta 9°, Unidad de Investigación, Avda. Ana de Viya 21, Cádiz, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Jiménez-Palomares
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ramos-Rodríguez
authors.forename: José Francisco
authors.initials: JF
authors.lastname: López-Acosta
authors.forename: Mar
authors.initials: M
authors.lastname: Pacheco-Herrero
authors.forename: Alfonso M
authors.initials: AM
authors.lastname: Lechuga-Sancho
authors.forename: Germán
authors.initials: G
authors.lastname: Perdomo
authors.forename: Mónica
authors.initials: M
authors.lastname: García-Alloza
authors.forename: Irene
authors.initials: I
authors.lastname: Cózar-Castellano
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics* / Q000473:pathology; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D054411:Receptors, Leptin