Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Administration of Monomeric Amyloid β42 Alters Energy Metabolism And Induces Cardiac Dysfunction in Mice (#83)

Juliane K Czeczor 1 , Tim Connor 1 , Amanda J Genders 1 , Ken Walder 1 , Sean L McGee 1
  1. Deakin University, Geelong, Vic, Australia

Amyloid β42 (Aβ42) is associated with the onset of Alzheimer’s Disease (AD). Circulating Aβ42 is increased in obese/diabetic patients and contributes to altered peripheral metabolism and diabetic complications including cardiovascular disease (CVD). The aim of this study was to determine whether Aβ42 alters insulin action in vitro and whole body metabolism in vivo.
Basal and insulin stimulated glucose uptake (GU) and glucose production (GP) were measured in 3T3-L1 adipocytes and FAO hepatocytes respectively after treatment with either monomeric (m)Aβ42 or aggregated (a)Aβ42 at various concentrations (0, 100, 200, 300nM) for 48h; scrambled (scr)Aβ42 was used as control. mAβ42 increased basal (p<0.001) and insulin (p<0.01) suppressed GP at higher doses (200; 300nM) in FAO hepatocytes, while aAβ42 had no effect. In 3T3-L1 adipocytes, mAβ42 as well as aAβ42 impaired basal (p<0.001) and insulin stimulated (p<0.01) GU at higher doses (200; 300nM).
To examine the role of mAβ42in vivo, 7 week old, male C57Bl/6J mice (n=10/group) were injected i.p. with mAβ42 or control scrAβ42 for five weeks (1µg/day). Administration of mAβ42 increased total mAβ42 exposure over 24 hours (p<0.05) as well as basal circulating mAβ42 compared with control mice (basal: 3.4ng/µl vs 0.8ng/µl; p<0.05). mAβ42 treatment had no effect on bodyweight, body composition or food intake and did not induce glucose or insulin intolerance. However, mAβ42 treated mice displayed increased fasting glucose (p<0.01) and decreased whole body glucose oxidation (p<0.01). Echocardiography showed that mAβ42 treated mice had cardiac dysfunction relative to control mice.
Unlike recently published studies, we show that physiological mAβ42 administration had no impact on glucose or insulin tolerance, but altered substrate utilisation.
These data suggest not only a role for Aβ42 in AD, but Aβ42 could also dysregulate metabolism in obesity and T2D via insulin dependent and/or independent mechanisms as well as contribute to diabetic complications such as CVD.