A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2

The sugar question !

Today I might do two short posts. This post is tangentially related to the one below, among the dozens of other papers on the subject of glucose and SARS-CoV-2, possibly hundreds with glucose and other viral infections.

Glycaemic control is associated SARS-CoV-2 breakthrough infections in vaccinated with type 2 diabetes

A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2

However, the underlying causes for increased susceptibility to viral infection in patients with diabetes is not fully understood. Here we identify several small-molecule metabolites from human blood with effective antiviral activity against SARS-CoV-2, one of which, 1,5-anhydro-D-glucitol (1,5-AG), is associated with diabetes mellitus. The serum 1,5-AG level is significantly lower in patients with diabetes. In vitro, the level of SARS-CoV-2 replication is higher in the presence of serum from patients with diabetes than from healthy individuals and this is counteracted by supplementation of 1,5-AG to the serum from patients. Diabetic (db/db) mice undergo SARS-CoV-2 infection accompanied by much higher viral loads and more severe respiratory tissue damage when compared to wild-type mice. Sustained supplementation of 1,5-AG in diabetic mice reduces SARS-CoV-2 loads and disease severity to similar levels in nondiabetic mice. Mechanistically, 1,5-AG directly binds the S2 subunit of the SARS-CoV-2 spike protein, thereby interrupting spike-mediated virus–host membrane fusion. Our results reveal a mechanism that contributes to COVID-19 pathogenesis in the diabetic population and suggest that 1,5-AG supplementation may be beneficial to diabetic patients against severe COVID-19.

A metabolite is a byproduct of…well…metabolizing something. Here the authors found that a specific metabolite 1,5-AG is significantly lower in infected patients with diabetes, they refer to a 2020 paper where authors put virus with blood with a lot of glucose and without, and SARS-CoV-2 replicated faster. Back then it was the first paper to actually show it, even though in theory it is pretty obvious.

What actually happens (the mechanistically word) is 1,5-AG directly binds (glues) to the S2 part of the Spike protein, and interrupts the virus-host cell membrane fusion (how the virus enters cells).

1,5-anhydro-D-glucitol is an anhydro sugar of D-glucitol. D-Glucitol is another name for Sorbitol.

Its sugar alcohol found in fruits and plants with diuretic, laxative and cathartic property. Unabsorbed sorbitol retains water in the large intestine through osmotic pressure thereby stimulating peristalsis of the intestine and exerting its diuretic, laxative and cathartic effect. In addition, sorbitol has one-third fewer calories and 60 % the sweetening activity of sucrose and is used as a sugar replacement in diabetes.

Following the paper itself.

The amount of viral RNA was significantly reduced in cells treated with the serum filtrates compared to the infected control…A total of 298 small-molecule metabolites were identified for further investigation; notably, 222 were commercially available We incubated Vero cells with 100 μM solutions of each metabolite and then infected them with SARS-CoV-2. Seven metabolites reduced the amount of viral RNA with an inhibition rate higher than 95%

Three metabolites, 1,5-AG, chenodeoxycholic acid (CDCA) and 5-methoxytryptophol (5-MT), are known as endogenous metabolites that can be synthesized by human cells

We investigated whether the levels of endogenous metabolites were correlated with and accounted for the differential antiviral activities between the healthy and diabetic groups. The significant increase in fasting glucose indicated that the serum from patients with diabetes was tied to hyperglycemia. In fact, we found that the 1,5-AG serum level was much lower in patients with diabetes than that in healthy donors whereas the CDCA and 5-MT levels. The urinary excretion of 1,5-AG is increased by the competitive inhibition of glucose in patients with diabetes with glycosuria, resulting in a significant reduction of 1,5-AG in the serum of patients with diabetes.

The amount of viral RNA was much higher in Vero cells treated with the sera from patients with diabetes than in cells treated with sera from healthy donors. Notably, 1,5-AG supplementation of the sera from patients with diabetes reduced the amount of viral RNA

The authors decided to measure hundreds of such metabolites, with achieving antiviral capabilities, seven of these had viral RNA inhibitory rate higher than 95%, basically stopping most of the viral infection in these cell lines. 3 of these metabolites are produced inside your own body, 1,5-AG being one of them.

They go to further tests, to see if these metabolites were responsible for the different antiviral properties inside people with diabetes and healthy people. They went to find what a decent body of literature on the subject already did, that levels of 1,5-AG are lower in patients with diabetes. In a state of too much glucose inside you, your body literally pees away 1,5-AG.

Supplementation with 1,5-AG restored this antiviral function even in diabetic people. Nice graph below, more red = more virus.

They go to test different mechanisms to verify the exact mechanism by which 1,5-AG interferes with the virus, meaningful finding was the following.

A recent study suggested that elevated glucose levels and sustained aerobic glycolysis in human monocytes directly promote SARS-CoV-2 infection31. Nonetheless, treating with 1,5-AG did not affect the glycolysis, glycolytic capacity or glycolytic reserve in the Vero cells

To assess the stage of SARS-CoV-2 infection inhibited by 1,5-AG, we treated Caco-2 cells with 1,5-AG 1 h before (pre), simultaneously with (co), or 1 h after (post) SARS-CoV-2 inoculation to further identify the stage of SARS-CoV-2 infection in which 1,5-AG acts ). The post-treatment showed no effect, while the pre-treatment slightly reduced the amount of viral RNA. Notably, the co-treatment led to a dramatic reduction in the amount of viral RNA , indicating that 1,5-AG may exert its maximal antiviral effect during viral entry.

An important distinction in which 1,5-AG does not influence the virus metabolism (or hijacking of your own metabolism), and the most effective time to “use” 1,5-AG was during the infection not before, or after in these settings. They went to test against other viruses and found that 1,5-AG is specifically potent against coronaviruses, and not other types of viruses. As I mentioned a couple of years ago, this family of viruses, and this one specifically is a glucose-hungry beast.

1,5-AG, a glucose-like pyranoid polyol in the human body, presents an effective anti-SARS-CoV-2 activity by binding to the S2 subunit of the SARS-CoV-2 spike protein, thereby interrupting spike-mediated virus–host membrane fusion. 1,5-AG is a short-term marker of glycemic control and serum levels of 1,5-AG are significantly lower in patients with diabetes than the healthy individuals11. Our results suggest that a low level of 1,5-AG in diabetic people might, in part, underlie a high risk for severe COVID-19, therefore revealing the importance of 1,5-AG-mediated metabolic homeostasis in COVID-19 pathogenesis and suggesting that 1,5-AG supplementation and amelioration of hyperglycemia in patients with diabetes might help to reduce the incidence and/or prevent severe COVID-19.

The end of the paper is self-evident, they just discuss their, important in my opinion, finding. So, should you just buy a bucket of Sorbitol ? No, this paper is more related to this mechanism and parallel to hyperglycemia and diabetes, with too much sugar floating around.

What you can easily do is… limiting carbohydrates, since it has been found in quite a few trials under a glycemic peak, your 1,5-AG levels also drop, and it is not directly related to a diabetic state, but more to your glycemic levels and overall metabolism after your meals.

If there wasn’t enough reason for your to exercise, fast, and eat more protein and fewer carbohydrates to achieve the best health state you could, here is another one.

Have a nice night!