Takeaway: This 2017 review argues diabetes affects the immune system, vascular function, and endothelial function in ways that increase susceptibility to harm from infectious diseases affecting pulmonary function. These mechanisms are related both to chronically elevated blood glucose levels and blood glucose variability. It is not completely understood if one of these mechanisms is specifically responsible for the increased rate of flu morbidity and mortality seen in diabetics or if they work in concert to increase risk.
Each year, 5-15% of the world’s population is infected with the flu. In the majority of patients, the flu resolves without significant medical treatment, but in those with underlying conditions, the flu can be a severe, even fatal disease (1). Thus, as rates of diabetes, heart disease, and other conditions continue to increase — as they have for much of the late 20th and 21st centuries — the flu will have an increasingly burdensome effect on patient health and our health-care system (2). This review explores some of the mechanisms by which diabetes, specifically, may increase susceptibility to and severity of the flu.
Diabetes’ effect on flu severity has been known since at least the 1980s (3). The link between diabetes and the flu became particularly prominent during the 2009 H1N1 pandemic, during which surveys of Canadian and German populations found diabetes doubled or tripled rates of hospitalization and quadrupled ICU admissions (4).
Chronically elevated blood glucose levels, i.e., hyperglycemia, may directly contribute to flu vulnerability. Hyperglycemia, especially as measured via HbA1c, is generally the target of diabetic treatment, as elevated blood glucose levels have been linked to many of the complications associated with diabetes — complications such as blindness, limb amputation, kidney failure, and increased risk of heart disease (5). Hyperglycemia has specifically been linked to increased incidence and severity of bacterial infections. For instance, compared to those with more effective blood glucose control, diabetics with higher HbA1c levels have been demonstrated to experience increased rates and severity of tuberculosis (6), liver abscesses (7), complications following kidney allograft (8), bird flu (9), and respiratory tract infections (10). This may be due to the direct immunosuppressive effects of increased blood glucose levels, which impair the recruitment and effectiveness of immune cells through multiple mechanisms (11). Simultaneously, elevated blood glucose levels increase glucose concentrations in airway secretions, and thereby increase rates of viral and bacterial infection and replication (12). The stakes of this last point are particularly high given that a significant share of flu mortality is due to secondary bacterial infections (13).
In addition to chronically elevated blood glucose levels, diabetics have more extreme and frequent blood glucose oscillations, which may be independent of HbA1c (14). These glycemic oscillations may lead to endothelial dysfunction (15). Endothelial cells play a role in the cytokine and inflammatory response to influenza infection (16). An increased endothelial cytokine response, which can be directly caused by glucose oscillations, can directly impair pulmonary function and damage the lungs during the immune response (17).
Taken together, these mechanisms indicate diabetes increases one’s susceptibility to flu infection and severe disease. The authors note that as the prevalence of diabetes increases throughout the population, flu (and potentially other infectious pulmonary diseases) will become increasingly significant public health issues. They argue, “It is therefore imperative that we understand how diabetes increases influenza severity in order to mitigate the burden of future influenza epidemics and pandemics.”