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.

During strenuous exercise, markers of oxidation increase and antioxidant capacity decreases. Antioxidants such as vitamin C may combat this oxidation stress. The benefits of vitamin C to greyhounds undertaking intense sprint exercise has not been investigated. The objective of this experiment was to determine whether a large dose (1 g or 57 mmol) of ascorbic acid influences performance and oxidative stress in greyhounds. Five adult female, trained racing greyhounds were assigned to receive each of three treatments for 4 wk per treatment: 1) no supplemental ascorbate; 2) 1 g oral ascorbate daily, administered after racing; 3) 1 g oral ascorbate daily, administered 1 h before racing. Dogs raced 500 m twice weekly. At the end of each treatment period, blood was collected before and 5 min, 60 min and 24 h after racing. Plasma ascorbate, alpha-tocopherol, thiobarbituric acid-reducing substances (TBARS) and Trolox equivalent antioxidant capacity (TEAC) concentrations were measured and adjusted to compensate for hemoconcentration after racing. TBARS, TEAC and alpha-tocopherol concentrations were unaffected by supplemental vitamin C. Plasma ascorbic acid concentrations 60 min after racing were higher in dogs that received vitamin C before racing than in dogs that either received no vitamin C or received vitamin C after racing. The dogs ran, on average, 0.2 s slower when supplemented with 1 g of vitamin C, equivalent to a lead of 3 m at the finish of a 500-m race. Supplementation with vitamin C, therefore, appeared to slow racing greyhounds.

Background Influenza A virus (IAV) causes a wide range of extrarespiratory complications. However, the role of host factors in these complications of influenza virus infection remains to be defined. Methods Here, we sought to use transcriptional profiling, virology, histology, and echocardiograms to investigate the role of a high-fat diet in IAV-associated cardiac damage. Results Transcriptional profiling showed that, compared to their low-fat counterparts (LF mice), mice fed a high-fat diet (HF mice) had impairments in inflammatory signaling in the lung and heart after IAV infection. This was associated with increased viral titers in the heart, increased left ventricular mass, and thickening of the left ventricular wall in IAV-infected HF mice compared to both IAV-infected LF mice and uninfected HF mice. Retrospective analysis of clinical data revealed that cardiac complications were more common in patients with excess weight, an association which was significant in 2 out of 4 studies. Conclusions Together, these data provide the first evidence that a high-fat diet may be a risk factor for the development of IAV-associated cardiovascular damage and emphasizes the need for further clinical research in this area.

Diabetes mellitus is a known susceptibility factor for severe influenza virus infections. However, the mechanisms that underlie this susceptibility remain incompletely understood. Here, the effects of high glucose levels on influenza severity were investigated using an in vitro model of the pulmonary epithelial-endothelial barrier as well as an in vivo murine model of type II diabetes. In vitro we show that high glucose conditions prior to IAV infection increased virus-induced barrier damage. This was associated with an increased pro-inflammatory response in endothelial cells and the subsequent damage of the epithelial junctional complex. These results were subsequently validated in vivo. This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in individuals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections.

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