RT info:eu-repo/semantics/doctoralThesis
T1 Insulin-Degrading Enzyme is a modulator of pancreatic beta-cell function via primary cilium and cytoskeletal dynamics
A1 Sanz González, Alba
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Medicina interna
K1 Diabetes
K1 Primary cilia
K1 Cilio primario
K1 Cytoskeleton
K1 Citoesqueleto
K1 Insulin-degrading enzime
K1 Enzima que degrada insulina
K1 2302 Bioquímica
AB Primary cilia are microtubule-based organelles essential for cellular signaling and the integration of extracellular cues. These structures are present in pancreatic beta cells, where they play a key role in regulating cell function, particularly in the integration of paracrine signals from neighboring cells. Recent studies have implicated primary cilia dysfunction in the pathogenesis of diabetes. The microtubule cytoskeleton is also central to orchestrating the dynamic changes required for efficient insulin vesicle trafficking and secretion. These microtubules extend from the Golgi apparatus to the plasma membrane and are highly dynamic, responding to metabolic changes such as glucose levels. Insulin-degrading enzyme (IDE) is expressed in pancreatic β-cells, where it plays a major role in the regulation of insulin secretion. While our group has previously reported that IDE is decreased in β-cells of type 2 diabetes (T2D) patients, the therapeutic potential of targeting IDE remains unclear.The aim of this study was to elucidate the physiological role of IDE in pancreatic β-cell function, particularly through its regulation of the tubulin cytoskeleton and primary cilium. We also investigated how IDE influences β-cell behavior under both stimulatory and inhibitory glucose conditions. To this end, we partially inhibited IDE expression both in vitro using shRNA silencing in two β-cell models (Min6-shIDE, Ins1E-shIDE), and in vivo by generating a mouse line with β-cell-specific Ide ablation (B-IDE-HT). In these models, we evaluated β-cell function and metabolic responses to glucose. Additionally, we analyzed the primary cilium and the microtubule network under these conditions. To better understand the role of the primary cilium in paracrine signaling, we used a Min6-IFT88-KD model, which lacks primary cilia.Our results demonstrated that physiological levels of IDE are essential for proper β-cell function. IDE knockdown impaired glucose-stimulated insulin secretion and calcium dynamics, altered the tubulin cytoskeleton, and reduced the number and size of primary cilia. Moreover, insulin and glucagon receptors were dysregulated in IDE-deficient cells. Interestingly, IDE is not located in the primary cilium but partially colocalizes with the Golgi apparatus (~45%). In cells lacking primary cilia (IFT88-KD), we observed reduced levels of insulin and glucagon receptors, while IDE expression and glucagon signaling remained unchanged. These findings indicate that IDE regulates β-cell function by modulating cytoskeletal dynamics and ciliogenesis, which in turn affect paracrine receptor expression.We propose that IDE plays a critical role in regulating insulin secretion and the integration of paracrine signals in pancreatic β-cells through the control of tubulin cytoskeleton dynamics and primary cilium structure. Dysregulation of these processes in the absence of IDE leads to β-cell dysfunction. These findings highlight IDE as a potential therapeutic target for preserving β-cell function and preventing the development of diabetes.
YR 2025
FD 2025
LK https://uvadoc.uva.es/handle/10324/80769
UL https://uvadoc.uva.es/handle/10324/80769
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 12-ene-2026