Type 2 diabetes is a disease of insulin resistance, and β cell function is important for maintaining normal levels of insulin production. The canonical NF-κB signaling pathway has been well studied, but little is known about the noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. In this issue, Malle et al. demonstrate that the noncanonical NF-κB–inducing kinase (NIK) is a negative regulator of β cell function in diet-induced obesity.
In the canonical NF-κB pathway, IKK activation leads to IκBα degradation and nuclear translocation of p50. In contrast, in the noncanonical NF-κB pathway, p100 is processed into p52 that complexes with RelB for nuclear localization and transcription regulation. NIK activates p100 processing and is a central regulator of this noncanonical NF-κB pathway. The link between NIK and β cell function was shown by Malle et al. using a wide variety of systems; drug-induced NIK activation resulted in impaired β cell function in zebrafish, and elevated NIK levels in ex vivo cultures of rodent and human islets from diet-induced obese mice were associated with impaired glucose-stimulated insulin secretory capacity. In addition, three complementary genetic approaches in mice showed that increased NIK activity (achieved via β cell–specific knockout of components of the NIK degradation machinery) resulted in β cell dysfunction.
The association of elevated NIK signaling and defective glucose-stimulated insulin secretion in the presence of high-fat diet is an important finding. Considering that elevated NIK also damages insulin-sensitive tissues such as muscle and liver, this study is consistent with NIK signaling as a key mechanism to propagate β cell dysfunction and insulin resistance. TNF activates NIK and has been implicated as a driver of obesity-associated systemic inflammation that can lead to insulin resistance, primarily through an increase of inflammatory macrophages in the fat tissue. This study provides evidence that inflammation, and TNF specifically, may also be driving NIK activation in β cells and that this could inhibit their ability to deal with the increased demand for insulin that occurs with insulin resistance.
The mechanistic details that underlie NIK-induced β cell dysfunction are unclear, and the relationship of this noncanonical loop of NF-κB signaling with the canonical arm that has been already implicated in β cell dysfunction and diabetes remains to be determined. Future studies should also address whether inhibition of NIK activity might be a promising therapeutic strategy for metabolic disease, by increasing β cell function and attenuating hyperglycemia. Hyperglycemia causes complications of type 2 diabetes, and blocking inflammation-induced suppression of β cell insulin production should improve glucose control and outcomes for patients with type 2 diabetes.
K. Tarbell and S. Rane are supported by the Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health.