Insulin Receptor Determines Behavior of Immune Cells
And pathogens like to exploit that — increasing insulin resistance and driving obesity and diabetes.
Insulin resistance means a cell’s insulin receptor has difficulty responding to insulin. An insulin-resistant cell is thus unable to uptake glucose properly. What happens to immune cells that can’t uptake glucose properly? They do nothing and let foreign invaders roam free.
Immune Cells Need Responsive Insulin Receptors
A 2018 study in Cell Metabolism showed that engineered T-cells without insulin receptors failed to proliferate and kill the influenza H1N1 infection in mice. Those T-cells did not die but did not do anything either. Whereas insulin-responsive T-cells swiftly eliminated the influenza virus.
Analyzing the T-cells, they found that an activated insulin receptor is required to stimulate its glucose transporters and growth signalling pathways. The insulin receptor is, therefore, decisive if T-cells could do its job in killing cells that should be killed.
T-cells belong to the adaptive arm of the immune system. They mount a specific killing response towards cancerous or infected cells, including cells harbouring SARS-CoV-2.
Later in 2019, researchers found the same applies to macrophages, the innate arm of the immune system that engulfs a broad range of pathogens. In this study, they overfed mice with glucose to make them insulin resistant. Isolating their macrophages showed that it behaved similarly to macrophages without insulin receptors. These insulin-resistant macrophages were unable “to clear pathogens in the context of polymicrobial sepsis,” they wrote.
What do immune cells without insulin receptors resemble? Insulin-resistant immune cells.
Do these studies mean we have to consume glucose to raise insulin for immune cells to work? No. The pancreas is always releasing small amounts of insulin, even when not eating. This is to help cells uptake glucose — from gluconeogenesis — in times of fasting.
Insulin Resistance and Infections
The above two studies showed that immune cells without insulin receptors failed miserably. They cannot clear infections. What do immune cells without insulin receptors resemble? Insulin-resistant immune cells.
“We document, for the first time, the immune consequences of T cell-specific insulin resistance during severe H1N1 infection,” authors of the 2018 study in Cell Metabolism wrote. Insulin-resistant immune cells could help explain why insulin-related diseases like obesity is a risk factor for infections, cancer, and vaccine inefficacy, they noted.
Diabetes and obesity support a plethora of infections — be it respiratory, gastrointestinal, urinary, liver, skin, etc.
Prediabetics have a weaker response to respiratory viral infections too, as shown by a 2019 study in Nature. “The healthy folks went through what we saw as a pretty normal immune response,” said Professor Michael Snyder, a director of genomics and personalized medicine at Stanford University. “But the insulin-resistant folks — not so much. Their immune systems seemed to be somewhat deficient in launching a proper immune response to infection.”
It’s not only respiratory viral infections, but diabetes and obesity are known to support a plethora of infections — be it respiratory, urinary, gastrointestinal, liver, skin, head and neck, etc. In the current context of SARS-CoV-2, diabetes, biomarker of insulin resistance, poor blood sugar control, and obesity are all known risk factors for severe Covid-19.
Pathogens Can Induce Insulin Resistance
If the insulin receptor is mandatory for proper immune function, it makes sense for some pathogens to evolve mechanisms to exploit it. And indeed, provoking insulin resistance is one of the ways by which human pathogens — be it bacteria or viruses infecting the brain, respiratory or gastrointestinal tracts — overwhelm the immune system.
The infamous Staphylococcus aureus, for example, makes insulin-binding proteins that block the insulin receptor and glucose uptake of immune cells. Viruses like cytomegalovirus or influenza can stimulate interferons that downregulate the expression of insulin receptors.
Other examples include herpes simplex viruses 1 and 2, enteroviruses, C. pneumoniae, Helicobacter pylori and adenovirus-36 that messed up the insulin-signalling system.
Provoking insulin resistance is a common way by which pathogens overwhelm the immune system.
As some pathogens can induce insulin resistance, scientists have suggested they contribute to the development of insulin-related chronic diseases, especially when the infection becomes chronic or persistent. This is particularly true with S. aureus and adenovirus-36 with evidence pointing its causal role, as I have written, in type-2 diabetes and obesity, respectively.
Chicken or the Egg?
But people with insulin-resistance — such as being diabetic and obese — are more vulnerable to infections. Are infections, therefore, a sign but not cause of diabetes or obesity? It can be both, but insulin resistance probably comes first.
Repairing insulin resistance would arrest or attenuate the vicious cycle.
Immune cells with sensitive insulin receptors should be able to deal with the infection properly. Only when infections are poorly controlled, it would worsen existing insulin resistance. And then comes the vicious cycle. As follows, repairing insulin resistance would break the cycle.
