Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory CD8 T-Cell Dysfunction Inga Kavazovi  c, 1 Mia Krapi  c, 1 Ammarina Beumer-Chuwonpad, 2 Bojan Poli  c, 1 Tamara Turk Wensveen, 3,4 Niels A. Lemmermann, 5 Klaas P.J.M. van Gisbergen, 2 and Felix M. Wensveen 1 Diabetes 2022;71:706–721 | https://doi.org/10.2337/db21-0209 Type 2 diabetes (T2D) causes an increased risk of morbidity and mortality in response to viral infection. T2D is characterized by hyperglycemia and is typi- cally associated with insulin resistance and compen- satory hyperinsulinemia. CD8 T cells express the insulin receptor, and previously, we have shown that insulin is able to directly modulate effector CD8 T-cell function. We therefore hypothesized that memory CD8 T-cell responsiveness in the context of T2D is negatively impacted by hyperinsulinemia or hypergly- cemia. Using a mouse model for T2D, we could show that memory CD8 T-cell function was significantly reduced in response to rechallenge by viral infection or with melanoma cells. Basal insulin injection of mice increased GLUT-1 expression and glucose uptake in memory CD8 T-cell precursors early after infection, which was prevented when these cells were deficient for the insulin receptor. However, nei- ther insulin injection nor insulin receptor deficiency resulted in a difference in metabolism, memory for- mation, cytokine production, or recall responses of memory CD8 T cells compared with controls. Impor- tantly, in context of obesity, insulin receptor defi- ciency on CD8 T cells did not affect the functional capacity of memory CD8 T cells. In contrast, we could show in vitro and in vivo that hyperglycemia signifi- cantly impairs the antiviral capacity of memory CD8 T cells. Our findings indicate that obesity impairs the memory CD8 T-cell response against viral infection and cancer through the detrimental effects of hyper- glycemia rather than hyperinsulinemia. With an increasingly obese population, type 2 diabetes (T2D) and its comorbidities are a progressively large health problem. Modern antidiabetes drugs, therefore, aim not only to lower blood glucose levels but also to diminish risks of key complications of T2D, such as cardiovascular disease and chronic kidney disease. An understudied comorbidity of T2D is reduced immune function. People with T2D are well known to have more frequent infections, such as urinary tract infection, surgical site infection, and skin infections. Moreover, patients with T2D also have a longer disease dura- tion and typically have more severe disease upon infection (1–3). Reduced immune function was never prioritized as a target of therapeutic intervention, even though this compli- cation may lead to life-threatening disease, such as gangrene of diabetic foot, pneumonia, and severe influenza infection (1,3). Notably, in infection with severe acute respiratory syn- drome coronavirus 2, T2D gives a strongly increased risk of developing severe disease, which is particularly true for peo- ple with poor glycemic control (4,5). As such, it is of acute interest to uncover exactly how T2D weakens immune func- tion and how this is affected by antidiabetes therapy. Blood glucose levels have a direct impact on immune cells, as hyperglycemia was shown to negatively regulate immune functionality (1,6). Nevertheless, glycemia does 1 Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia 2 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands 3 Center for Diabetes, Endocrinology and Cardiometabolism, Thalassotherapia, Opatija, Croatia 4 Department of Internal Medicine, Faculty of Medicine, University of Rijeka, Rijeka, Croatia 5 Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany Corresponding author: Felix M. Wensveen, felix.wensveen@medri.uniri.hr Received 12 March 2021 and accepted 6 January 2022. This article contains supplementary material online at https://doi.org/10.2337/ figshare.18019943 I.K. and M.K. contributed equally. © 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https:// www.diabetesjournals.org/journals/pages/license. IMMUNOLOGY AND TRANSPLANTATION 706 Diabetes Volume 71, April 2022 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/71/4/706/671798/db210209.pdf by guest on 09 July 2023