RT info:eu-repo/semantics/doctoralThesis
T1 Role of insulin-degrading enzyme (IDE) in diabetes mellitus and insulin resistance
A1 Villa Pérez, Pablo
A2 Universidad de Valladolid. Instituto de Biología y Genética Molecular (IBGM)
K1 Hígado-Enfermedades
K1 Diabetes Mellitus
K1 Insulina - Uso terapeútico
K1 2302.21 Biología Molecular
AB Insulin degrading enzyme (IDE) is a ubiquitously expressed zinc-metalloprotease that is one of the principal enzymes involved in the degradation and clearance of insulin, in addition to glucagon, amylin and the amyloid-β protein (Aβ). Several polymorphisms of the gen IDE are associated with risk for type 2 diabetes mellitus (T2DM) in humans, whereas hepatic insulin clearance is reduced in T2DM patients. Although strongly contributing to insulin clearance in vivo, the specific role of IDE in the liver -the primary site of plasma insulin clearance- remain unclear. The aim of our study is to decipher the role of IDE in hepatic insulin signaling and its impact on whole-body glucose metabolism and insulin clearance.To ablate IDE selectively in hepatocytes, mice homozygous for a floxed IDE allele were intercrossed with albumin-Cre mice (hereafter L-IDE-KO). Metabolic studies were performed in 1 and 3-months old mice to analyze plasma levels of fasting and non-fasting glucose, insulin, glucagon, triglycerides, cholesterol, amylin, Aβ-40 and their body weight. Likewise, intraperitoneal glucose, insulin and pyruvate tolerance test and hepatic plasma insulin clearance were assessed. To analyze hepatic insulin signaling, fasted mice were injected intraperitoneally with Insulin (0,75U/Kg) 10 minutes before were sacrificed. Afterwards, liver samples were examined by western blot for levels of total and phosphorilated insulin receptor (IR), protein kinase B (AKT1 and AKT2), glycogen synthase kinase 3 (GSK3), glycogen synthase (GS), forkhead box protein O1 (FoXO1) and IDE. L-IDE-KO male mice showed hyperglycaemia, glucose intolerance and insulin resistance. These changes were not associated with augmented food intake, body weight or plasma insulin levels. Surprisingly, hepatic plasma insulin clearance was similar between L-IDE-KO and WT mice. Hepatic insulin resistance in L-IDE-KO mice was associated with reduced plasma membrane IR levels (≈30%), as well as reduced phosphorylation levels (≈55%), which induced reduced phosphorylation levels of AKT1 and AKT2 by ≈45%. In summary, we have revealed a new role for IDE in the regulation of hepatic insulin signaling. We hypothesize that IDE regulates IR recycling to the plasma membrane. Finally, our data demonstrate that IDE is not essential for hepatic plasma insulin clearance.
YR 2018
FD 2018
LK http://uvadoc.uva.es/handle/10324/39214
UL http://uvadoc.uva.es/handle/10324/39214
LA eng
NO Departamento de Bioquímica y Biología Molecular y Fisiología
DS UVaDOC
RD 24-abr-2024