by Gertrud U. Rey
Flu season is in full swing, and hospitalizations related to influenza virus infection are on the rise. During the 2009 “swine flu” pandemic it became evident that diabetes and obesity increase one’s risk for severe influenza disease, a correlation that was also later observed in the context of COVID-19. A series of recent studies led by Kirsty Short at the University of Queensland have shed some light on the mechanisms that implicate diabetes and obesity as causal risk factors in severe influenza.
Diabetes is a metabolic disorder that is characterized by the reduced ability to produce and/or respond to insulin, a hormone that helps move glucose from the bloodstream into cells for later use as energy. Type 1 diabetes is an autoimmune disease that develops when the immune system attacks the pancreatic cells that make insulin, leading to decreased insulin production and increased levels of glucose in the blood (i.e., hyperglycemia). Type 2 diabetes is caused by advanced age and obesity and occurs when the body’s cells become resistant to the effects of insulin. The pancreas then works harder to compensate for the resistance but becomes damaged and unable to produce enough insulin over time. This series of events also gives rise to hyperglycemia.
An initial publication by Short’s group showed that hyperglycemia in mice with type 2 diabetes induces a pro-inflammatory condition that leads to the destruction of the epithelial-endothelial barrier, a series of cell layers that protect the blood and surrounding tissues from the passage of pathogens and toxins. Infection with influenza A virus (IAV) led to increased damage to the barrier in diabetic mice compared to mice with normal glucose levels, suggesting that high glucose levels prior to IAV infection caused increased virus-associated damage to the epithelial-endothelial barrier in the lungs. This type of damage ultimately increased the risk of pulmonary edema, a life-threatening condition that results from too much fluid build-up in the lungs.
In a subsequent study, Short and colleagues isolated cells from the blood samples of healthy donors and donors with type 1 or type 2 diabetes, transferred the cells to a cell culture and infected them with IAV for a period of 18 hours. The authors then analyzed the cultures for cells that expressed markers that are characteristic of T cells and proteins produced by cytotoxic T cells. Cytotoxic T cells are essential to the adaptive immune response because they identify and eliminate cancer cells and cells infected with viruses or bacteria. The authors found that IAV infection of cells from diabetic donors led to production of fewer cytotoxic T cells that secreted tumor necrosis factor alpha (TNF alpha), a protein that has strong antiviral activity against influenza virus. In contrast, IAV infection of cells from healthy donors led to increased levels of TNF alpha-producing T cells. These results suggest that hyperglycemia impedes the function of cytotoxic T cells in response to influenza virus infection in diabetic mice, and that non-diabetic mice generate more effective T cell-induced antiviral responses. This finding is consistent with the results of earlier work investigating the effects of obesity on influenza outcomes in mice, which revealed that the functional capacity of influenza-specific cytotoxic T cells is reduced in obese mice compared to lean mice. Collectively, these observations make sense, considering that obesity often leads to type 2 diabetes.
Follow-up inquiries by Short’s lab have revealed that although average blood glucose levels are an important indicator for determining the risk of adverse influenza outcomes, wide-ranging fluctuations in blood glucose levels are an even more indicative risk factor. Diabetic individuals who experience recurrent high peaks and low dips in blood glucose throughout the day have even more impaired T cell responses to influenza virus infection compared to diabetics who maintain relatively steady blood glucose levels. These results suggest that monitoring glycemic variability using constant glucose monitoring devices can provide a better predictive measure for assessing one’s antiviral immunity and risk for severe influenza.
The global prevalence of diabetes has been increasing steadily for decades, and many people who have diabetes are unaware of their status, particularly individuals with type 2 diabetes, which often goes undiagnosed because it carries a behavioral stigma. Long periods of uncontrolled hyperglycemia or high glycemic variability due to delayed diagnoses can lead to a phenomenon known as metabolic memory, where the body “remembers” the hyperglycemia and continues to be at increased risk of diabetes-associated complications even once glucose levels return to normal. Conversely, gaining early control of blood glucose levels through a combination regimen of diet, exercise, and medication, leads to profoundly reduced risks of complications associated with diabetes, including those caused by influenza virus. Finally, vaccination against influenza virus is particularly important for people living with diabetes and/or obesity because it provides an additive protective measure against severe disease.
[Kirsty Short was a guest on TWiV 1177.]