The transcription factor nuclear factor-kappa B (NF-kappa B) has a key role in the pathogenesis of diabetes and its complications. Although activation of the canonical NF-kappa B pathway in beta-cells is generally deleterious, little is known about the role of the non-canonical NF-kappa B signalling and its main regulator, the NF-kappa B-inducing kinase (NIK), on pancreatic beta-cell survival and function. Previous studies based on models of NIK overexpression in pancreatic islet cells showed that NIK induced either spontaneous beta-cell death due to islet inflammation or glucose intolerance during diet-induced obesity (DIO) in mice. Therefore, NIK has been proposed as a potential target for diabetes therapy. However, no clear studies showed whether inhibition of NIK improves diabetes development. Here we show that genetic silencing of NIK in pancreatic beta-cells neither modifies diabetes incidence nor inflammatory responses in a mouse model of immune-mediated diabetes. Moreover, NIK silencing in DIO mice did not influence body weight gain, nor glucose metabolism. In vitro studies corroborated the in vivo findings in terms of beta-cell survival, function, and downstream gene regulation. Taken together, our data suggest that NIK activation is dispensable for the development of diabetes.

NF-κB-inducing kinase (NIK) is activated in pancreatic β-cells but does not contribute to the development of diabetes

Marselli, Lorella;
2022-01-01

Abstract

The transcription factor nuclear factor-kappa B (NF-kappa B) has a key role in the pathogenesis of diabetes and its complications. Although activation of the canonical NF-kappa B pathway in beta-cells is generally deleterious, little is known about the role of the non-canonical NF-kappa B signalling and its main regulator, the NF-kappa B-inducing kinase (NIK), on pancreatic beta-cell survival and function. Previous studies based on models of NIK overexpression in pancreatic islet cells showed that NIK induced either spontaneous beta-cell death due to islet inflammation or glucose intolerance during diet-induced obesity (DIO) in mice. Therefore, NIK has been proposed as a potential target for diabetes therapy. However, no clear studies showed whether inhibition of NIK improves diabetes development. Here we show that genetic silencing of NIK in pancreatic beta-cells neither modifies diabetes incidence nor inflammatory responses in a mouse model of immune-mediated diabetes. Moreover, NIK silencing in DIO mice did not influence body weight gain, nor glucose metabolism. In vitro studies corroborated the in vivo findings in terms of beta-cell survival, function, and downstream gene regulation. Taken together, our data suggest that NIK activation is dispensable for the development of diabetes.
2022
Xiao, Peng; Takiishi, Tatiana; Violato, Natalia Moretti; Licata, Giada; Dotta, Francesco; Sebastiani, Guido; Marselli, Lorella; Singh, Sumeet Pal; Sze...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1159287
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