Diabetes and chronic cellular stress

Diabetes, to my surprise, results from chronic cellular stress. The source of the stress is both legion and not really important to understanding what diabetes is. It all begins with the endoplasmic reticulum, an organelle inside every cell in our body.

The Endoplasmic Reticulum

The endoplasmic reticulum (ER) is an organelle in every cell in the body that is responsible for the folding, sorting and transport of proteins. On the surface of the ER are ribosomes that sequence amino acids into peptides and stuff the peptides through holes in the ER. Once inside the ER, chaperone proteins oversee the correct folding of the peptides into proteins, sometimes making small modifications to the peptides in the process.

If a peptide misfolds, the chaperones may help in refolding the protein or they may transport the misfolded protein to a location where it will be torn back down into its basic amino acids.

Physically, the ER looks like a series of boxes and tubes. It has been recently discovered that some of those tubes actually pass through the cell’s nucleus.

ER Stress

ER Stress, a sudden demand for increased protein production, occurs as a response to environmental situations such as wound healing. ER Stress is usually short lived and normal.

The Unfolded Protein Response

On the surface of the ER, sticking out like hairs, are strands of the protein ATF6a. If ER Stress occurs for an extended period of time or is severe, the ER may run low on chaperone proteins and unfolded peptides begin backing up in the ER. This condition is detected by the ER and produces the Unfolded Protein Response (UPR). UPR is simply the cleaving of ATF6a from the surface of the ER. Upon entering the nucleus of the cell, ATF6a causes the nucleus to call for increased production of chaperones; that is, it causes the genes for producing chaperones to be turned on.

I liken this to a factory that has more orders to do the final assembly work on proteins than it can handle. It requests from management more workers to fill the orders. In this case, the factory would also be manufacturing the additional workers, the chaperones.

Chronic ER Stress

When ER Stress occurs for protracted lengths of time, the ER starts running out of ATF6a; that is, the production of new chaperones decreases despite the continued need for them. This results in a cascade of events that result in the cell becoming increasingly insensitive to insulin. This is a protective response.

If you think of the factory analogy, this would be the case where the factory cannot obtain enough workers to keep up with the work load and the factory is filling up with unfinished product (unfolded proteins). The logical response at this point would be to slow down the arrival of peptides needing folding.

Because a cell’s response to insulin is not only the taking in of glucose but also the taking in of amino acids, insulin resistance slows the production by the ribosomes of peptides. That reduces ER Stress, but does not cure it unless the stressor that led to the state is removed. If the stressor is not removed, it will either be a holding action or a war lost.

Apoptosis

If the condition of the ER continues to degrade, once again the cell changes response. At this point the cell appears to its own apparatus to be irreparably damaged and orderly cell death (apoptosis) is initiated.

The Cure

Chronic ER Stress can result from innumerable environmental conditions – the internal environment of the body. Excessive glucose, lipids, toxins, chronic infections, and inflammatory cytokines are among the most common environmental conditions that lead to diabetes. Anything that requires the continuous, never-ending need to produce structural or secretory proteins will cause chronic ER Stress. This is why the “cause of diabetes” was so elusive.

To cure diabetes (and many other old age illnesses) it is necessary to reinforce, to actually grow, the ER so that it can handle the stress. At the same time, it is necessary to remove as many stressors as possible.

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