Diabetes, steroids and hypoglycemia

Following alloxan induction of diabetes, rats overexpress glucocorticoids. This in turn depletes the mast cell populations in the skin, lungs and intestines. Glucocorticoids interfere with production and expression of tissue cytokines and stem cell factor, a growth factor for mast cells.

Several experiments have definitively proven that these steroids are responsible for downregulating mast cell growth and activity. Treating diabetic rats with the steroid receptor blocker RU486 or removing adrenal glands on both sides of the animal causes an increase in intestinal mast cell numbers and IgE formation.

The mechanism by which steroids confer these effects is thought to involve insulin. Glucocorticoids inhibit secretion of insulin in the pancreas. In turn, insulin release decreases systemic glucocorticoids. Additionally, insulin also activates mast cell signaling pathways. In the presence of insulin, antigen induced mast cell degranulation and survival is upregulated. In diabetic rats, administration of insulin recruits mast cells and increases response to antigen. Insulin treatment can reverse the reductions in mast cell populations, histamine production and IgE release seen following alloxan administration.

Increased activity of the HPA axis is often seen in type I and II diabetics, resulting in elevated cortisol. One study showed that appropriate activity can be restored with insulin treatment. This is achieved by a complex mechanism in which expression of glucocorticoid receptor mRNA is elevated in the pituitary, facilitating glucocorticoids to suppress expression of ACTH release.


Can hypoglycemia cause mast cell degranulation?

Yes. Activation of histamine 1 and 2 receptors as a result of insulin or hypoglycemia causes release of ACTH. Hypoglycemia (low blood sugar, which can also be induced after administration of insulin) normally increases ACTH levels in the blood. However, higher than normal histamine levels in the blood can interfere with the action of ACTH, which would normally address hypoglycemia via production of glucocorticoids. One study found that this effect can be mostly ameliorated by pretreating with antihistamines, though I suspect in mast cell patients, this may not achieve the full response seen in non-mast cell patients.


Can anaphylaxis cause hypoglycemia?

Yes. In instances of severe stress (emotional or physical), corticotropin-releasing hormone (CRH), neurotensin and substance P are released. Among other things, CRH can induce mast cell degranulation (of note, CRH does not directly induce histamine release via degranulation). CRH also causes increased expression of the IgE receptor on mast cells, which increases the likelihood of being stimulated and thus degranulation (this may cause histamine release). In tandem, neurotensin and substance P increases the expression of the CRHR-1 receptor for CRH on mast cells so that they are more sensitive to CRH. Likewise, neurotensin and substance P act on mast cells via receptors to induce degranulation (this causes histamine release). As a result of this degranulation, histamine and other mediators are present to inhibit the action of ACTH, which would otherwise increase blood sugar (via the production of cortisol, epinephrine, and norepinephrine).



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