The impact of interferons in islet antiviral responses

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Medical College of Wisconsin, Inc. $100,228 on December 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to fund research examining interferons' role in islet antiviral responses and type 1 diabetes pathogenesis.

The research investigates physiological mechanisms by which pancreatic beta cells protect themselves from interferon-mediated damage during viral infection. The project addresses the hypothesis that viral infections—particularly by picornaviruses—trigger autoimmune beta-cell destruction in type 1 diabetes through cytokine-induced pathology, and seeks to understand how beta cells respond to interferons despite their terminally differentiated state and limited proliferative capacity.

The award supports research at The Medical College of Wisconsin in Wauwatosa, Wisconsin, with performance through June 30, 2030. The assistance type is a Project Grant.

Abstract

Type 1 diabetes mellitus (T1D) is characterized as the autoimmune destruction of the insulin producing β-cells found in pancreatic islets of langerhans. IT is well known that t-lymphocytes are the primary mediators of this β-cell destruction, but the pathways initiating this autoimmune attack remain unknown. While genetic predisposition contributes to the development of T1D, the low concordance rate of monozygotic twins developing T1D suggests that an environmental trigger may be required to initiate disease pathogenesis. One environmental factor that has been proposed to initiate β-cell damage during diabetes development is viral infection, particularly by picornaviruses, which have been correlated with T1D. During a viral infection, the levels of serum cytokines such as the interferons (IFN) increase 10-1000-fold. In vitro studies have shown that β-cell function is inhibited and there is a loss of viability when β-cells are exposed to cytokines for prolonged periods of time. Consistent with the role of β-cells in maintaining whole-body glucose homeostasis through the release of insulin, islets receive a disproportionately large share of pancreatic blood flow, and are therefore directly exposed to toxins, infectious agents, and inflammatory mediators found in the blood stream. However, IT is surprising that β-cells are responsive to cytokines that are thought to be toxic (IFN), knowing that they are terminally differentiated and have a limited capacity for proliferation, and yet are frequently exposed to high concentrations of these cytokines during infection. This observation has led US to hypothesize that there must be a physiological role for cytokine signaling in β-cells; therefore, the broad goals of this research program are to understand the physiological mechanisms β-cells use to protect themselves from the damage and destruction that leads to diabetes development. Studies proposed in this application will test the hypothesis that there are physiological roles for IFN signaling in islets that are designed to protect endocrine cells from impending danger and disease pathogenesis. We hypothesize that IT is the absence of these protective mechanisms that may contribute to T1D development, and identifying pathways that protect β-cells from damage will provide novel targets for the development of therapeutic strategies designed to attenuate the loss of β-cell mass during the development of autoimmune diabetes.