Influenza is usually described as a respiratory virus, but its impact does not stop at the airways. For many people, flu is a short-lived illness of fever, cough, fatigue, and muscle aches. For others, particularly those with underlying metabolic disease, it can become a serious systemic infection.

One of the clearest examples is diabetes mellitus. People with diabetes are consistently recognised as being at increased risk of severe influenza outcomes, including pneumonia, hospitalisation, and death. In recent seasons, around 30% of adults hospitalised with influenza have had diabetes, a striking overrepresentation that points to something fundamental about how metabolic disease reshapes the host-pathogen interaction.

The answer lies in immunometabolism: the study of how metabolism and immune defence are deeply interconnected.

Why Diabetes Makes Influenza More Dangerous

Diabetes is not simply a disorder of high blood glucose. It is also associated with chronic low-grade inflammation, altered innate and adaptive immunity, vascular dysfunction, oxidative stress, and impaired tissue repair. These changes can shape how the body responds to viral infection.

Influenza infection itself is metabolically demanding. When the virus infects epithelial cells of the respiratory tract, it triggers interferons (early-warning signalling proteins that switch on the cell’s antiviral defences), inflammatory cytokines, immune-cell recruitment, fever, and increased energy consumption. In a metabolically healthy person, this response is usually tightly regulated. In diabetes, that regulation may be compromised.

A 2023 systematic review and meta-analysis (Dicembrini et al., 2023) confirmed that influenza causes more severe complications in people with diabetes, and several mechanisms help explain this vulnerability.

1. High glucose can impair antiviral immune responses

Effective control of influenza depends heavily on the early innate immune response. Cells infected with influenza should rapidly produce type I and type III interferons, which help restrict viral replication and warn neighbouring cells.

In diabetes, especially when blood glucose is poorly controlled, several immune functions can be impaired. Hyperglycaemia has been associated with reduced neutrophil function, altered macrophage activity, impaired chemotaxis, and dysregulated cytokine production. The practical result is delayed viral clearance, giving the virus a greater chance to spread deeper into the lungs before the immune system responds effectively.

2. Diabetes is a chronic inflammatory state

Type 2 diabetes is accompanied by chronic low-grade inflammation driven by insulin resistance, endothelial stress, and altered lipid metabolism.

This matters in influenza because severe disease is often caused not only by viral replication, but also by an excessive or poorly controlled inflammatory response. Too little antiviral immunity early in infection can allow the virus to expand; too much inflammation later can damage lung tissue. That combination (delayed viral control followed by exaggerated inflammation) is what makes it dangerous.

3. Hyperglycaemia may create a more favourable environment for viral replication

Viruses depend on host-cell metabolism. Influenza-infected cells rewire their energy and biosynthetic pathways to produce new viral particles, relying heavily on glucose metabolism. Elevated glucose availability and altered cellular metabolism in diabetes may influence how efficiently this replication proceeds.

This is one reason diabetes should be viewed not just as a “risk factor” but as an immunometabolic condition that changes the host-pathogen interaction.

4. Influenza can destabilise glucose control

The relationship also works in the opposite direction: influenza can worsen diabetes management.

During acute infection, stress hormones such as cortisol and adrenaline rise. These hormones increase hepatic glucose production and promote insulin resistance. Fever, dehydration, reduced appetite, and altered food intake can further destabilise blood glucose.

As the CDC notes, flu can make blood sugar harder to manage: glucose may rise because of infection stress, but it may also fall if someone is unable to eat or drink normally. The relationship between the two conditions is therefore self-reinforcing. Diabetes increases the risk of severe influenza, which in turn worsens glycaemic control, and poor glycaemic control further impairs immune function, driving the risk of complications higher still.

5. Diabetes often coexists with other influenza risk factors

Many people with diabetes also have other conditions that independently increase flu risk, such as cardiovascular disease, chronic kidney disease, obesity, older age, or hypertension. These comorbidities can compound vulnerability.

Metformin: A Diabetes Drug with Immunometabolic Effects

Metformin has been used for decades as a first-line therapy for type 2 diabetes. Its best-known effect is reducing hepatic glucose production and improving insulin sensitivity. But metformin also affects cellular energy sensing, inflammation, mitochondrial metabolism, oxidative stress, and immune-cell function.

This does not make metformin an antiviral drug in the conventional sense. It does not directly target influenza neuraminidase like oseltamivir, nor does it block the viral polymerase like baloxavir. Instead, metformin may act on the host environment that influenza depends on. It is this host-directed angle that makes it scientifically interesting.

How might metformin help during influenza?

Metformin may influence influenza outcomes through several interconnected mechanisms. Better glycaemic control alone could meaningfully restore immune function, since hyperglycaemia impairs neutrophil activity, macrophage responses, and cytokine regulation. Beyond glucose, metformin reduces NF-κB signalling and inflammatory cytokines, potentially preventing the immune response from damaging lung tissue. At the cellular level, its effects on mTOR further disrupt the nutrient-sensing pathways viruses exploit (Halabitska et al., 2024). There may also be a downstream benefit to lung protection, given metformin’s influence on endothelial function and oxidative stress, though this remains under active investigation (Zhang et al., 2022).

The Path Ahead

Metabolism is proving fundamental to how we respond to disease, even viral disease. The soil shapes the outcome: diabetes is a powerful reminder that the same infection can follow very different courses depending on the metabolic health of the host. Host-directed approaches such as metformin remain unproven against influenza, but they point to a wider shift in thinking, from targeting the virus alone to reshaping the host environment it depends on.

How VRS Can Help

At VRS, we work with both influenza A and B using always-updated, currently circulating strains. Whether the goal is evaluating antiviral compounds through antiviral drug screening, testing host-directed strategies such as metabolic modulators, or supporting vaccine development with neutralisation assays, we can provide the right tools and expertise to move the work forward. Get in touch to discuss how we can support your research.

References

1. Dicembrini I, et al. Influenza: diabetes as a risk factor for severe related-outcomes and the effectiveness of vaccination in the diabetic population. A meta-analysis of observational studies. *Nutrition, Metabolism and Cardiovascular Diseases*. 2023;33(6):1099-1110. doi: [10.1016/j.numecd.2023.03.016](https://doi.org/10.1016/j.numecd.2023.03.016)

2. Halabitska I, et al. Metformin in antiviral therapy: evidence and perspectives. *Viruses*. 2024;16(12):1938. doi: [10.3390/v16121938](https://doi.org/10.3390/v16121938)

3. Zhang Y, et al. Metformin alleviates LPS-induced acute lung injury by regulating the SIRT1/NF-κB/NLRP3 pathway and inhibiting endothelial cell pyroptosis. *Frontiers in Pharmacology*. 2022;13:801337. doi: [10.3389/fphar.2022.801337](https://doi.org/10.3389/fphar.2022.801337)