Effects of Glucose Supply on Infections

Using proteomic and metabolic screening of patients with sepsis, an extreme reaction state to infections, a study reported that glucose, fatty acids, and beta-oxidation pathways are critical in differentiating between survivors and non-survivors to infections in intensive care units [1].

This study highlights the key role of the host metabolism, which provides essential nutrients to pathogens, in determining the viability of bacteria and viruses and influencing infected patients’ capacity to combat infections.

However, the type of nutrients that are generated by the host metabolism may promote or inhibit infections depending on whether the infection is bacterial or viral. In this regard, glucose supply has been shown to protect or promote infections according to the type of infection [2].

However, before discussing this further, it is essential to provide an overview of glucose metabolism during fasting and non-fasting conditions.

Glucose Metabolism

In non-fasting conditions, glucose is used by the mitochondria to generate energy in the form of ATP through a cellular metabolic process known as the aerobic pathway, a process that is necessary for the function of cells, tissues, and organs.

During fasting, the level of blood sugar is very low, and therefore, to compensate for the lack of energy our body will rely on other metabolic pathways such as gluconeogenesis and glycogenolysis to generate energy from glucose or lipolysis, and protein catabolism to generate energy from lipids and protein breakdowns.

In gluconeogenesis, glucose is generated from non-carbohydrate substrates such as lactate, glycerol, and glucogenic amino acids. Glycogenolysis produces glucose from glycogen that is stored in the liver and muscles. During lipolysis, energy is produced from the breakdown of lipids (triacylglycerols) into fatty acids and glycerol through a metabolic process known as ketosis.

Fatty acids and glycerol are transported to the liver where they are transformed into ketones for the generation of energy. During protein catabolism, energy is generated from turning amino acids into molecules that can be used for the generation of energy [2].

Glucose Metabolism and Bacterial Infections

During bacterial infection, and particularly during bacterial sepsis, studies have shown that the production of energy relies on lipolysis via the breakdown of fatty acids and ketones and that the production of energy through glucose metabolism is limited.

Therefore, a shift from glucose to KB/FFA utilization would help bacterial sepsis to thrive [3]. The mechanism by which this shift occurs appears to be associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ), a regulator of adipocytes (cells that store lipids) differentiation and ketogenesis (production of ketones).

The pharmacological inhibition of PPAR-γ (Gemfibrozil) has been found to reduce the severity of bacterial sepsis [4]. Thus, that treatment aimed at normalizing the glucose level in blood would benefit patients by promoting glucose metabolism instead of lipolysis [1].

Glucose Metabolism and Viral Infections

Unlike bacterial infections, glucose appears to be necessary for viral infections. Glucose, supplied to cells and tissues through the blood, is used by the glycolytic pathway to generate acetyl Co-A and NADPH.

These metabolic products are used to generate fatty acids and energy that are used by diverse viruses such as HCMV, dengue virus (DV), and Hepatitis C virus (HCV) to increase the production of intracellular membranes that are necessary for their assembly and to increase energy supply for their replication [5][6].

The mechanisms involved in the generation of fatty acids and energy are mediated by the conversion of acetyl Co-A into fatty acid palmitate via successive metabolic reactions, comprising acetyl Co-A carboxylase and fatty acid synthase.

Conclusion

During bacterial infections, lipolysis is used to generate the energy that is essential for their survival which does not require glucose supply; however, during viral infections glycolysis is used instead, and therefore, requires glucose supply.

Thus, manipulating glucose intake according to the type of infection may be used to treat bacterial or viral infections through glucose supplementation or deprivation, respectively.

References

[1] Nice-Sugar Study Investigators, 2009. Intensive versus conventional glucose control in critically ill patients. New England Journal of Medicine, 360(13), pp.1283-1297.

[2]https://accesspharmacy.mhmedical.com/content.aspx?bookid=2492&sectionid=204926001

[3] Agwunobi, A.O., Reid, C., Maycock, P., Little, R.A. and Carlson, G.L., 2000. Insulin resistance and substrate utilization in human endotoxemia. The Journal of Clinical Endocrinology & Metabolism, 85(10), pp.3770-3778.

[4] Cámara‑Lemarroy, C.R., Cordero‑Perez, P., Ibarra‑Hernandez, J.M., Muñoz‑Espinosa, L.E. and Fernandez‑Garza, N.E., 2015. Gemfibrozil attenuates the inflammatory response and protects rats from abdominal sepsis. Experimental and therapeutic medicine, 9(3), pp.1018-1022.

[5] Liu, H., Liu, J.Y., Wu, X. and Zhang, J.T., 2010. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. International journal of biochemistry and molecular biology, 1(1), p.69.[6] Greseth, M.D. and Traktman, P., 2014. De novo fatty acid biosynthesis contributes significantly to establishment of a bioenergetically favorable environment for vaccinia virus infection. PLoS pathogens, 10(3), p.e1004021.