Glycemic Variability in Diabetes Increases the Severity of Influenza

Abstract

People with diabetes are two times more likely to die from influenza than people with no underlying medical condition. The mechanisms underlying this susceptibility are poorly understood. In healthy individuals, small and short-lived postprandial peaks in blood glucose levels occur. In diabetes mellitus, these fluctuations become greater and more frequent. This glycemic variability is associated with oxidative stress and hyperinflammation. However, the contribution of glycemic variability to the pathogenesis of influenza A virus (IAV) has not been explored. Here, we used an in vitro model of the pulmonary epithelial-endothelial barrier and novel murine models to investigate the role of glycemic variability in influenza severity. In vitro, a history of glycemic variability significantly increased influenza-driven cell death and destruction of the epithelial-endothelial barrier. In vivo, influenza virus-infected mice with a history of glycemic variability lost significantly more body weight than mice with constant blood glucose levels. This increased disease severity was associated with markers of oxidative stress and hyperinflammation both in vitro and in vivo. Together, these results provide the first indication that glycemic variability may help drive the increased risk of severe influenza in people with diabetes mellitus. IMPORTANCE Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.

Metabolic Syndrome and Viral Pathogenesis: Lessons from Influenza and Coronaviruses

“…This was recapitulated in vivo, where glucose variability in DIO mice also increased the severity of primary and secondary IAV infections (18). At 1 week postinfection, IAV-infected obese prediabetic mice exhibited reduced blood oxygen saturation, significant upregulation of gamma interferon (IFN-␥), and increased levels of oxidative stress, all of which impaired their lung function (18). Indeed, T2DM confers an increased risk of acute influenza virus infection and severe disease pathogenesis.…”

“…1) (17). A recent study demonstrated that variable glycemic conditions in the T2DM milieu also upregulated viral replication ex vivo (18). Cocultures of primary human epithelial and endothelial cells were treated with glucose and infected with IAV.…”

“…Upregulated cytokine production in the T2DM pulmonary microenvironment leads to endothelial dysfunction and pulmonary damage (18). ACE2 is expressed primarily in the heart and kidneys and regulates heart function and blood pressure (21).…”

“…More recently, cocultures of human primary epithelial and endothelial cells have been used to model cell-to-cell and immune cell interactions that occur in vivo (Table 1). This approach is commonly used to model how viral infection disrupts the epithelial-endothelial barrier in humans to increase the severity of viral disease (18). Mice are also invaluable models for studying metabolic disease and viral pathogenesis because of their genetic tractability and the ease with which experiments can be performed.…”

Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

“…[3][4][5][6][7][8] Second, patients with diabetes (both type 1 and type 2) also appear to be particularly vulnerable 5,9-12 ; hallmarks of diabetes include hyperglycemia, glycemic variability, and/or insulin dysregulation, all shown to worsen outcomes from infection. [13][14][15][16][17][18][19] Respiratory viruses, including influenza and SARS-CoV-2, can lead to acute respiratory distress syndrome (ARDS) 20,21 and death from respiratory failure. ARDS is a complex syndrome that is characterized by lung vascular endothelial injury and alveolar epithelial injury and is associated histologically with alveolar filling with protein-rich fluid.…”