RT info:eu-repo/semantics/doctoralThesis
T1 Papel de la enzima degradadora de insulina (IDE) en el metabolismo hepático
A1 Cámara Torres, Patricia
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Metabolismo hepático
K1 Insulin-degrading enzyme
K1 Enzima degradadora de insulina
K1 Insulin resistance
K1 Resistencia a la insulina
K1 Mitochondria
K1 Mitocondria
K1 Liver
K1 Hígado
K1 32 Ciencias Médicas
AB Insulin-degrading enzyme (IDE) is a zinc-dependent metalloprotease that is highly conserved across species and ubiquitously expressed. Research conducted on humans HAS demonstrated an association between genetic polymorphisms at the Ide gene locus and the susceptibility to develop type 2 diabetes mellitus (T2DM). Although it has historically been thought of as an insulin protease, new research points to IDE's non-proteolytic roles.The aim of the research in this thesis is to deepen our understanding of the physiological function of the cytoplasmic (IDE-Met42) and mitochondrial (IDE-Met1) IDE isoforms in the liver. In order to achieve this, research has been done in vitro on IDE-deficient cell models (HepG2-IDE-KO and AML12-shRNA-IDE) and ex vivo on IDE-KO and L-IDE-KO mouse models. Furthermore, specific tools have been developed to differentiate these isoforms, along with mutants lacking catalytic activity to facilitate the study of their non-proteolytic functions.The conducted studies reveal that the loss of IDE induces insulin resistance and activates glucagon signaling in hepatic cells. This implies that certain genes linked to these biological processes, mitochondrial activity, and cytoskeletal stability are dysregulated. Furthermore, IDE-Met42 is essential for regulating glucose production, while IDE-Met1 is in charge of regulation of insulin signaling, oxygen consumption, ATP production, and mitochondrial dynamics.These findings expand the boundaries of existing knowledge regarding the functions of IDE isoforms, demonstrating that both can act in coordination to regulate cellular glucose homeostasis. However, it is crucial to continue research on IDE as a potential therapeutic target, as it could generate new insights for the development of more specific and effective therapies aimed at individuals suffering from T2DM.
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/75088
UL https://uvadoc.uva.es/handle/10324/75088
LA spa
NO Escuela de Doctorado
DS UVaDOC
RD 05-abr-2025