Many infections, including sepsis, trigger insulin resistance and hyperglycemia. Chronic viral and atypical bacterial infections, such as HSV-2 and Chlamydia pneumonia, are associated with high blood sugar and insulin resistance. Other viral illnesses, including hepatitis C infection and HIV also induce insulin resistance. In the case of HIV, research suggests that these findings may be attributable to metabolic endotoxemia and translocation of gut bacteria.

Recent experience shows that SARS-CoV-2 is a particularly manipulative actor that causes metabolic derangement. The virus responsible for COVID-19 encodes a peptide that has sequence homology to Semi-SWEET, a prokaryotic glucose transporter. The SARS-CoV-2  Semi-SWEET peptide homolog may promote transmission of the virus by importing glucose into infected cells. Hence a strategy of the virus is to make glucose more available to infected cells. SARS-CoV-2 also reduces insulin production by pancreatic islet cells, inducing a pre-diabetic state. Patients with active infection and survivors of the virus are prone to insulin resistance and diabetes, as this large scale observational study published in the journal Nature showed.

Some infections have an anti-diabetic effect. Human adenovirus 36 (Ad-36) increases insulin sensitivity, leading some to advocate for infection with this virus as a way to control diabetes. Unfortunately, Ad-36 also leads to obesity, in part by making fat cells more insulin sensitive and apt to take up glucose. Even if it were helpful to reverse diabetic symptoms with Ad-36, most people would not be keen to get an infection that encourages weight gain. Why does Ad-36 increases glucose uptake? It happens that Ad-36 primarily infects human skeletal muscle, for which insulin sensitivity might increase glucose delivery to infected cells.

Even though Ad-36 seems to be something of a special case, it follows the general pattern of other viruses in commandeering energy resources from the host. These include viruses that engage in lipid hijacking, and glucose hijacking, a feat accomplished by upregulating glucose transporters in infected cells. Myriad viruses induce expression of glucose transporters, including Kaposi’s sarcoma-associated herpesvirus, HIV, Human cytomegalovirus, influenza and, as mentioned above, SARS-CoV-2.

Of course, it is not just viruses that are linked with insulin resistance. The microbiome plays a role in insulin resistance leading some to argue that insulin resistance co-evolved with gut microbiota. In 2004, Backhed and colleagues first demonstrated that the insulin resistant phenotype could be transferred from one animal to another by transferring the fecal microbiota. Other gut microbes, such as Helicobacter pylori, the causative organism in peptic ulcers, also are associated with an increased risk of diabetes.

What these observations tell us is that insulin resistance is tightly linked with immune activation and with infection. From my vantage point, it seems that insulin resistance is the outcome of genetic conflict, usually between host and pathogen genes. (It is notable that other kinds of genetic conflicts can cause IR, for instance in pregnancy, in which the conflict is between human genes of maternal and paternal origin. IR can also be a feature of many malignancies, in which the conflict may lie between mutated cancer lineages and healthy cells.)

It makes sense to me that fighting over glucose is expected from manipulative genetic elements. This notion raises an important question that is often overlooked in evolutionary medicine: Who, or what genes, benefit? For changes in glucose metabolism, one needs to identify whether it benefits the pathogen, does it benefit neither – being simply bystander damage, or does it benefit the host (see Crespi and Alcock for more). It can be hard to tease apart these competing alternatives, even more so if the observer is blind to the possibility that those options even exist. A key tell that a genetic conflict exists, however, is that we should see phenotypes being pulled in opposite directions. That is, there should be evidence of a tug of war.

Glucose metabolism has all the hallmarks of an epic tug of war, playing out over evolutionary timescales. Even if we humans gain the upper hand in the tug of war, we need to be attuned to the possibility that a novel pathogen, like SARS-CoV-2 can re-direct a previously adaptive trait and make it maladaptive for us. Take the case of ACE receptors that that the virus uses to gain access to human cells. The ACE receptor did not evolve to give the virus a way to invade host cells. The interaction between human ACE receptors and viral spike is decidedly maladaptive for hosts. These can be particularly difficult for hosts to deal with, since the toolkit we use to fight invaders can be repurposed to harm us when we are dealing with a rapidly evolving pathogen like SARS-CoV-2.

With this complexity, we need to prospectively test how medical interventions affect the outcome of infections. As we discussed recently, insulin worsens outcomes in sepsis and in COVID-19. The anti diabetic drug metformin, which we will explore in a future post, improves COVID-19 outcomes, and may have other benefits in other infections.

For more on insulin resistance and its evolution see these previous posts. Insulin has a dark side. Blood sugar and the microbiome. Too sweet or just right. The microbiome and insulin resistance.

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine