RT info:eu-repo/semantics/doctoralThesis
T1 Role of insulin-degrading enzyme in pancreatic alpha-cell function.
A1 Casanueva Álvarez, Elena
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Diabetes
K1 Diabetes
K1 Diabetes
K1 Glucagon
K1 Glucagón
K1 Pancreatic alpha cell
K1 Célula alfa
K1 3205.02 Endocrinología
AB Hyperglucagonemia, caused by dysregulated glucagon secretion, is a hallmark of diabetes mellitus. Understanding the molecular mechanisms underlying hyperglucagonemia will unravel new targets for diabetes treatment. Insulin- degrading enzyme (IDE) gene is in one of the genetic locus related to diabetes susceptibility. This study investigates the role of IDE in the regulation of glucagon secretion by pancreatic α-cells. In this study, we have observed a decrease in IDE protein levels under inhibitory conditions of glucagon secretion, by high glucose levels. Additionally, we have found that genetic inhibition of Ide levels in α-cells resulted in impaired glucagon secretion. We have proposed several potential mechanisms to explain the inhibitory effect of reduced IDE on glucagon secretion. First, we observed reduced levels of SNARE proteins involved in glucagon exocytosis by α-cells. Second, we found increased levels of α-synuclein in α-cells, which has been related to disruption of SNARE protein function and impaired exocytosis. Third, IDE was also found to be involved in the regulation of tubulin cytoskeleton in α-cells. Disruption of microtubule dynamics can hinder the intracellular transport of secretory granules and fusion with the plasma membrane during exocytosis, thereby affecting glucagon secretion. Fourth, IDE was found to be involved in primary cilia formation, its absence led to impaired ciliogenesis with decreased cilia length and number. Impaired ciliogenesis led to poor cell differentiation and increased α-cell proliferation. In conclusion, this study provides evidence for the involvement of IDE in the regulation of glucagon secretion in pancreatic α-cells. IDE appears to play a key role in the function of SNARE proteins, α-synuclein regulation, cytoskeleton dynamics, and ciliogenesis, all these factors could contribute to proper glucagon secretion in physiological conditions. On the other hand, sustained loss of IDE expression leads to increased α-cell number and dysregulated glucagon secretion that could lead to hyperglucagonemia.
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/66862
UL https://uvadoc.uva.es/handle/10324/66862
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 07-ago-2024