Type 1 diabetes (T1D) results from autoimmune-mediated loss of insulin-producing beta-cells.
Neuronal hypothesis
Events controlling T1D development are not only immunological, but also neuronal in nature.
In the non-obese diabetic (NOD) mouse model of T1D, a mutant sensory neuron channel, TRPV1, initiates chronic, progressive beta-cell stress, inducing islet cell inflammation.
This novel mechanism of organ-specific damage requires a permissive, autoimmune-prone host, but ascribes tissue specificity to the local secretory dysfunction of sensory afferent neurons.
In NOD mice, normalizing this neuronal function by administration of the neurotransmitter substance P clears islet cell inflammation, reduces insulin resistance and restores normoglycemia.
Susceptibility loci
IL4R
IL4
IL13
4q27 (17999365)
Reviews
Kaneto H, Matsuoka TA, Katakami N, Kawamori D, Miyatsuka T, Yoshiuchi K, Yasuda T, Sakamoto K, Yamasaki Y, Matsuhisa M. Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. Curr Mol Med. 2007 Nov;7(7):674-86. PMID: 18045145
Tsui H, Razavi R, Chan Y, Yantha J, Dosch HM. ’Sensing’ autoimmunity in type 1 diabetes. Trends Mol Med. 2007 Oct;13(10):405-13. PMID: 17900987
Wong FS. Insulin—a primary autoantigen in type 1 diabetes? Trends Mol Med. 2005 Oct;11(10):445-8. PMID: 16150642
Wong FS, Wen L. The study of HLA class II and autoimmune diabetes. Curr Mol Med. 2003 Feb;3(1):1-15. PMID: 12558070
Adorini L, Gregori S, Harrison LC. Understanding autoimmune diabetes: insights from mouse models. Trends Mol Med. 2002 Jan;8(1):31-8. PMID: 11796264
Todd JA, Farrall M. Panning for gold: genome-wide scanning for linkage in type 1 diabetes. Hum Mol Genet. 1996;5 Spec No:1443-8. PMID: 8875250
References
Zhernakova A, Alizadeh BZ, Bevova M, Leeuwen MA, Coenen MJ, Franke B, Franke L, Posthumus MD, Heel DA, Steege G, Radstake TR, Barrera P, Roep BO, Koeleman BP, Wijmenga C.Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases.Am J Hum Genet. 2007 Dec;81(6):1284-8. PMID: 17999365