O Glycosylation and Insulin Resistance

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In a previous post, Soeters and Soeters proposed that IR adjusts glucose metabolism, favoring the pentose phosphate pathway instead of glycolysis. Another alternate glucose metabolic pathway also exists. This is the hexosamine shunt.

Insulin resistance is tightly linked to diversion of glucose to the hexosamine shunt. Hexosamine results in a monosaccharide (UDP-GlcNAc) which, in turn, is the substrate for post-translational modification of proteins. The O-linked glycosylation of polypeptides results in O-glycans, important in both health and disease.

The rate limiting step in O-glycosylation is activity of glutamine fructose 6-phosphate amidotransferase (GFAT), which is increased in IR, increasing the production of O-glycans.

How are O-glycans important? It turns out O-glycosylation is vitally important feature of host defense, as described by Chatham and colleagues (2008). O-glycans improve cell survival during stress, a key feature during the high-stakes contest between pathogen and host. O-glycosylation improves survival during trauma, and may play a critical role in survival during sepsis. Thus, the inhibition of glycolysis during IR diverts glucose to the hexosamine metabolic pathway, with implications for host survival during acute threats.

Chatham and colleagues write the following about glyceraldehyde 3-phosphate dehydrogenase inhibition, which occurs in IR:

Glyceraldehyde 3-phosphate dehydrogenase serves as a control point for the entry of glucose into glycolysis and oxidative phosphorylation; thus, its inhibition results in glucose units being channeled into other pathways, including the pentose phosphate shunt and, of particular interest to this review, the HBP, which, we propose, has profound ramifications to various aspects of cell survival.”

In addition to protecting host cells from bystander damage during inflammation, O-glycosylation is necessary for the production of antimicrobial mucin, which prevents microbial colonization of the intestinal epithelium, thus preventing bacterial translocation and invasion. O-glycosylation is also requisite step in the production of antimicrobial peptides, known as defensins. Loss of O-glycan defense results in widespread infection of the colon or colitis. Clearly, O-glycosylation is an important part of the immune toolbox that provides a bulwark against invasive pathogens. Indeed, this general cellular defense mechanism is so effective that it has been co-opted by some pathogens to provide them a measure of protection from the immune system.

Unfortunately, non-enzymatic glycosylation is also the event that produces advanced glycated end products (AGE),  which are thought to exacerbate arterial inflammation. One of these glycated proteins, Hemoglobin A1C, is a measure used by clinicians to assess the severity of diabetes. These observations show that the addition of a sugar moiety to proteins can either be good or bad, depending on circumstances.

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