Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination

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.”

---

Notes

1. One health, multiple challenges: The interspecies transmission of influenza A virus
2. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013
3. Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus; Impact of diabetes mellitus on mortality associated with pneumonia and influenza among non-Hispanic Black and White US adults
4. Diabetes and the severity of pandemic influenza A (H1N1) infection; Mortality of 2009 pandemic influenza A (H1N1) in Germany
5. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences
6. Diabetic control and risk of tuberculosis: A cohort study
7. Klebsiella pneumoniae liver abscess in diabetic patients: Association of glycemic control with the clinical characteristics
8. Infection-related mortality is higher for kidney allograft recipients with pretransplant diabetes mellitus
9. Hyperglycemia in the recent reported cases of bird flu infection in Thailand and Vietnam
10. Infection and diabetes: The case for glucose control
11. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia; High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus; Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: Abnormalities in metabolism and function; Pathogenesis of the influenza virus in diabetes model mice
12. Factors determining the appearance of glucose in upper and lower respiratory tract secretions; Glycolytic control of vacuolar-type ATPase activity: a mechanism to regulate influenza viral infection; Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose
13. Interactions between Streptococcus pneumoniae and influenza virus: a mutually beneficial relationship?
14. Impact of visit-to-visit glycemic variability on the risk of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: The ADVANCE trial; Glycemic variability and oxidative stress: A link between diabetes and cardiovascular disease?; Postprandial blood glucose as a risk factor for cardiovascular disease in type II diabetes: The epidemiological evidence
15. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture; Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells the role of protein kinase C and NAD (P) H-oxidase activation; Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta; Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients
16. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection; Pathogenesis of influenza-induced acute respiratory distress syndrome; Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions; Influenza virus and endothelial cells: A species specific relationship
17. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice; Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells the role of protein kinase C and NAD (P) H-oxidase activation; The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose