Question: What are some of the mechanisms by which diabetes increases the severity of flu symptoms and risk of mortality?
Takeaway: This mouse study found that, when infected with the same dose of flu virus as controls, diabetic mice mounted a greater inflammatory response alongside impaired viral clearance and impaired macrophage recruitment. While 100% of diabetic mice were dead within 10 days, only 60% of control mice died. This suggests diabetes directly impairs the immune response to flu infection.
Research has indicated diabetics have two to three times higher risk of infectious disease mortality than otherwise similar nondiabetics (1). Hyperglycemia (i.e., elevated blood glucose levels) has been hypothesized to specifically interfere with macrophage recruitment and effective immune response (2). This 2015 mouse study sought to understand the specific mechanisms by which diabetes increases mortality.
Diabetic and control mice were both infected with H1N1 influenza at an LD50 dose — that is, a dose expected to kill at least 50% of control mice. Over the next 10 days, 100% of diabetic mice died, compared to 60% of controls.
Notably, when other doses were tested, the estimated LD50 for diabetic mice was 1/100th that of control mice. In other words, the majority of diabetic mice would be killed when exposed to a dose 1/100th the size of that required to kill the majority of control mice.
Closer inspection revealed profound differences in how diabetic and control mice responded to the infection. Compared to controls, inflammation levels were higher in diabetic mice at all checkpoints. Diabetic mice also failed to recruit macrophages to the lung — specifically, lung macrophage levels were constant at all checkpoints in diabetic mice, whereas controls exhibited a large increase in macrophage levels soon after infection. The viral load in the lungs increased similarly in diabetic and control mice over the first three days, but where control mice saw viral loads peak and then gradually decrease, viral clearance was significantly impaired in diabetic mice. These differences are illustrated in the figures below.
Figure 1: Inflammation levels were consistently higher in diabetic than nondiabetic mice.
Figure 2: Control mice (squares) recruited additional macrophages to the lung soon after infection, with macrophage levels decreasing back to baseline alongside decreasing viral load. Diabetic mice (circles) did not exhibit macrophage recruitment despite a similar increase in viral load. (See Figure 3)
Figure 3: Viral load increased similarly over the first three days in control and diabetic mice. After day three, viral load decreased in control mice (squares) while remaining elevated in diabetic mice (circles).
Taken together, this data demonstrates diabetic mice failed to mobilize macrophages in response to the infection, failed to clear virus from the lungs, and mounted a greater inflammatory response. While this is a mouse study and the results cannot be directly extrapolated to humans, it nevertheless reveals direct mechanisms by which diabetes may interfere with the body’s ability to have an effective response to viral infection and by extension demonstrates why diabetes increases risk of viral mortality.
Notes
- Diabetes and the risk of infection-related mortality in the U.S. diabetes care
- Impaired leucocyte functions in diabetic patients; Effects of hyperglycemia on C3 and Candida albicans; Innate immune response mechanisms in non-insulin dependent diabetes mellitus patients assessed by flow cytoenzymology; Pattern recognition receptors and inflammation; Pulmonary complications of diabetes mellitus
Comments on Pathogenesis of the Influenza Virus in Diabetes Model Mice
These studies are important to underscore the point: if a body is taxed dealing with an ongoing ailment it will have a harder time fighting any acute illnesses. But, the problem is we--as a society--seem to prefer acute problems to chronic ones. We have stopped the economy, our children's educations, healthcare for the masses, etc all for the a few acute cases of traumatic illness for those who are already ill. Wouldn't it be wise to see this as an opportunity to look under the hood and ask how we got ourselves into this mess? The real opportunity here is to address the larger issue: we are a sick nation.
In a healthy individual, a virus is a way to strengthen the immune system, and in turn, improve the long-term health of the population of people infected and armed with antibodies. Viruses make strong populations stronger. Our problem is our population is not strong.
It is a tragedy that a third of the US is considered pre-diabetic, according to the CDC, a number that is only expected to exponentially increase in coming years. Sick has become status quo.
Despite billions spent on research, cancer death rates are the same as they were in the 70s when Nixon declared his war on the disease. When you statistically back out the decrease in smoking rates, which accounted for a high number of cancer deaths in the past, it becomes easy to argue we're worse off today, even with all our fancy interventions. If chronic illnesses are all manifestations of metabolic dysfunction, as many on this thread will attest, then this all becomes more infuriating, because despite the complexity of the problems there is just one simple solution: off the carbs, off the couch.
Knowing that the solution exists, it is accessible to all and yet most will not utilize it can feel demoralizing.
Most of the world is distracted by the complexities, the new shiny technology that will sequence the cancer cell's genome, the anti viral vaccine that will that will not actually stop the cytokine storms... I get it, that's all fascinating and mind blowing that we can look at parts of life in such detail, but what about backing out and helping to restore the simple dignity of preventing someone of needing those treatments? I'm reminded over and over with this pandemic how we focus on treatment rather than prevention. We see this with the attention and money spent to turn every American factory into a mask producing facility and the race for a vaccine--rather than a wide spread effort to test which should have happened months ago! And we see this with the money and support going to treating and preventing the spread of COVID19, but not the conversation about sugar and carbs and the deleterious effects of the American diet on the health and economy of our population.
The real killer here is the underlying metabolic derangement that leads to chronic illness. This story is not that a new virus swept the world killing healthy people. It is that the world has become so unhealthy its people can no longer withstand the stress of viral mutations, of which there will surely be more.
To drive this point home, in my household we are carefully tracking COVID19 deaths, there has only been ONE DEATH in NYC of a person without an underlying illness over the age of 75! That means we could argue age is actually not a risk factor here! Likewise, there were only 4 deaths in NYC of people ages 65-74 who didn't have underlying conditions... Whereas there were 6,266 deaths of people ages 65 and older who had underlying health conditions.
Try to shine a light on ways to save people from a global pandemic... crickets... criticize hokey vegan propaganda films... message board explosion!!... equal parts sad and stupid. Thank you CrossFit for continuing to be some of the only people shining a light on this underlying issue. Even if the majority of humanity doesn't learn from these findings the fit can be 'safe on the island' as Greg put it, and we as coaches can continue to do our best to keep saving the people who wash up on shore.
Pathogenesis of the Influenza Virus in Diabetes Model Mice
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