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Diabetes, mast cells and allergic disease

Patients with either type I or II diabetes mellitus demonstrate unusual physiology pertaining to hypersensitivity and mast cell activation. This was first described in 1962, when a paper reported that diabetic animals do not experience anaphylactic shock.   Despite the amount of time that has passed, the reasons for this are still being unraveled.

The role of mast cells in type II diabetes mellitus is more straightforward. When mice are made obese through dietary manipulation, they normally develop glucose intolerance or insulin resistance. If the mice are mast cell deficient, they do not develop these conditions. Transfer of mast cells to mast cel deficient mice was shown to reverse this protection against these complications.

In mice without established type Ii diabetes that were given manipulated diets to induce obesity, treatment with mast cell stabilizers actually prevented the development of type II diabetes. In mice with pre-established type II diabetes, treatment with mast cell stabilizers cromolyn or ketotifen protected against glucose intolerance and insulin resistance. These findings have been replicated in at least one patient, a type II diabetic who had normalized plasma glucose and A1C after six months on cromolyn.

The relationship between mast cells and type I diabetes is far more intricate.   This is mostly understood through a diabetic rat model. It is possible to induce type I diabetes in rats by administering a chemical called alloxan. Triggering diabetes in this way causes a variety of mast cell changes in these animals. The same changes can be seen when causing diabetes via administration of another chemical, streptozotocin.

Diabetic rats have less vascular response to the action of histamine and reduced mast cell degranulation. These animals are resistant to both local and systemic allergic responses, including anaphylaxis.   Mast cell populations become depleted and less likely to activate. When exposed to antigen, diabetic rats have 50% less degranulated mast cells and histamine release compared to non-diabetic controls.

IgE production is also suppressed in diabetic rats, both antigen specific IgE and total IgE. If you transfer mast cells from the spleen and lymph nodes of non-diabetic rats to diabetic rats, IgE production is diminished. Likewise, if mast cells from diabetic rats are transferred into non-diabetic animals, IgE production is restored.

This protection from allergic processes is well established in animals, but also translates to humans. Children with type I diabetes, and their siblings, are less likely to develop asthma. The incidence of bronchial asthma, rhinitis, and atopic dermatitis is lower than predicted in patients with diabetes mellitus.   Risk of death due to anaphylactic shock is significantly reduced in diabetes. This has been attributed to both the depletion of mast cell populations in diabetics, but also to the overproduction of corticosteroids in the body.

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.