Hypotheses on the etiology of type 1 diabetes

[jcc]

Putting the pieces of the puzzle together - a series of hypotheses on the etiology and pathogenesis of type 1 diabetes. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17045415&itool=pubmed_DocSum) PMID: 17045415 Oct 2006


This paper presents a series of 10 hypotheses on the etiology of type 1 diabetes. We begin with the hypothesis that wheat gluten is one of the elusive environmental triggers in type 1 diabetes. Habitual consumption of wheat gluten increases the intestinal synthesis of dipeptidyl peptidase IV. This enzyme helps to shape the repertoire of peptides released into the small intestine following the ingestion of wheat gluten by catalyzing the release of X-Pro dipeptides from the N-terminus of the proline-rich glutenins and gliadins in wheat gluten. The release of gluten-derived peptides causes the tight junctions of the small intestine to open through a zonulin-dependent mechanism, which allows these peptides to enter the lamina propria where they get presented as antigens by HLA-DQ, -DR and CD1d molecules. Binding of one or more gluten peptides by CD1d leads to abrogation of oral tolerance, and a marked increase in peripheral immune responses to wheat proteins. Furthermore, it is our contention, that in response to beta cell apoptosis during normal remodeling of the pancreas and CCL19/CCL21 expression within the pancreatic lymph nodes (PLNs), gluten-loaded dendritic cells migrate from the small intestine to the PLNs. These dendritic cells present gluten-derived antigens on the surface of the PLNs, which leads to migration of CD4(-)CD8(-) gammadelta and CD4(-)CD8(+) alphabeta T cells to the pancreas where they mediate Fas and perforin dependent cytotoxicity. We also hypothesize that at least one of the type 1 diabetes associated HLA-DR molecules that bind and present wheat-derived peptide(s) also bind and present an islet cell antigen(s), activating plasma cell synthesis of islet cell autoantibodies and irrevocable, complement-dependent destruction of islet cells. Our final two hypotheses state that type 1 diabetes morbidity is reduced in those areas of globe where genetically susceptible individuals get adequate amounts of vitamin D, in the diet and/or through exposure to sunlight, and in areas where people are exposed to bacterial, viral, or parasitic infections in early childhood.
PMID: 17045415

[annelb]

What jumped out at me from this abstract was Our final two hypotheses state that type 1 diabetes morbidity is reduced in those areas of globe where genetically susceptible individuals get adequate amounts of vitamin D, in the diet and/or through exposure to sunlight, and in areas where people are exposed to bacterial, viral, or parasitic infections in early childhood.

I have heard about the Zonulin, leaky gut and infection connections but I don't think I have heard about the vitamin D connection.

There is a recent post here about the TB/CD/vitamin D connection here (http://brain.hastypastry.net/forums/showthread.php?t=1884).
Anne

[jcc]

I know on MS-Direct site that Vitamin D is a big issue there, too, for MS.

http://www.direct-ms.org/journalarticles.html

Cara

[FoolsGold]

I have heard about the Zonulin, leaky gut and infection connections but I don't think I have heard about the vitamin D connection.Any disease with distinct variations by lattitude is usually one that is thought to be vitamin D related.

[annelb]

I think this new abstract needs to be added to this thread. Dr Fasano has found elevated Zonulin in diabetics.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17053448&query_hl=4&itool=pubmed_docsum

Curr Opin Gastroenterol. 2006 Nov;22(6):674-9.
Systemic autoimmune disorders in celiac disease.

* Fasano A.

Center for Celiac Research and Mucosal Biology Research Center and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

PURPOSE OF REVIEW: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established. RECENT FINDINGS: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease. SUMMARY: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

PMID: 17053448 [PubMed - in process]

Here are the articles about zonulin and DMT1. Both have free full text :)
Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16644703&query_hl=1&itool=pubmed_docsum

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2916-21. Epub 2005 Feb 14.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15710870&query_hl=1&itool=pubmed_docsum
Anne

[jcc]

This article references another article that I have missed in the past...from 2002. One that shows:

We report on a 15-y-old adolescent boy affected by silent coeliac disease, abnormalities in glycoregulation and with autoantibodies specific to diabetes mellitus type 1 (ICA: islet cell antibodies) and GAD 65 (autoantibodies against glutamic acid decarboxylase), in whom normalization of glycoregulation and disappearance of the immunological markers of pre-diabetes were observed after 6 mo on a gluten-free diet. The patient was followed-up for 36 mo and showed a normal insulin response to an intravenous glucose tolerance test and no markers of autoimmunity. It is possible that undiagnosed coeliac disease over a long period could lead to a direct autoimmune mechanism against pancreatic beta cells. Conclusion: Our findings seem to confirm the theory that undiagnosed coeliac disease can induce an autoimmune process against the pancreatic beta cells and that, following a gluten-free diet, the immunological markers for diabetes mellitus type 1 will disappear.
Regression of autoimmunity and abnormal glucose homeostasis in an adolescent boy with silent coeliac disease. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12434905&query_hl=3&itool=pubmed_docsum)PMID: 12434905 2002


It also discusses several other rat studies and human studies that show intestinal permeability and gluten plays a role. Other studies have shown casein sensitivity, as well. So interesting.

Gosh...this intestinal permeability stuff seems to be so crucial!

Cara

[annelb]

Wonder what would happen if all newly diagnosed T1D's were put on a GF diet.

Anne

[The_One]

I found this link that may support one of your findings about zonulin and puts together your hypotesis that "The release of gluten-derived peptides causes the tight junctions of the small intestine to open through a zonulin-dependent mechanism, which allows these peptides to enter the lamina propria where they get presented as antigens by HLA-DQ, -DR and CD1d molecules."

The article talks about celiacs having a higher amount of zonulin protein in ther bodies allowing gluten and other allergens to get to the immune system.

Anyways, I wanted to say this is a great post.

http://www.celiac.com/st_prod.html?p_prodid=66

[NancyM]

Just coincidentally I was reading how lectins bind to vitamin D, making it unavailable. How much rickets there was in heavy wheat eating cultures. And wheat has a lot of lectins in it.

Copied from a PDF, so it looks a bit odd
http://www.thepaleodiet.com/newsletter/newsletters/PaleoNewsletterVol2Issue1.pdf

The EGF-R, WGA and Rickets
Mechanistically, scientists have never
really understood why excessive consumption of
whole grains, particularly wheat, could cause
rickets. However, with the recent discovery that
WGA gains access to the systemic circulation by
binding the EGF-R in the gut, it became increas-
ingly clear that WGA and similar whole grain
lectins could impair vitamin D metabolism.
Because of its affinity to the EGF-R,
WGA circulating in the bloodstream has the ca-
pacity to gain entry into any cell expressing the
EGF-R. It should be noted that epithelial cells
located in skin tissue express the EGF-R. Conse-
quently the keratinocytes within the epidermis,
because of their expression of the EGF-R will
internalize WGA if it is present in peripheral
blood. Keratinocytes are also the site of vitamin
D synthesis upon ultraviolet (sunlight) irradiation
of 7-dehydrocholesterol in the cell.
Once within skin keratinocytes, WGA
blocks the nuclear pore (22, 23), a structure that
normally allows passage of certain cellular hor-
mones and large molecules into the nucleus
which then cause gene transcription. In particu-
lar, WGA blocks the cellular transport of the vita-
min D receptor and its endogenous ligand
(vitamin D) to the nucleus (24, 25) which may
result in impaired vitamin D utilization, and sys-
temically increases the risk for rickets.

[Zonulin]

Great link - a leaky gut (too much Zonulin) allows toxins to run rampant through our bodies (and through the brain/blood barrier), causing our immune systems to go haywire.

And it's not just our diets (filled with hybridized wheat products in nearly all processed foods), but toxins in the air, chlorine and fluoride in our water, poisons in our furniture and carpet - :eek: And I just read this in in January/February 2007 issue of Well Being Journal: "Thirty years ago, children received a total of four vaccines, but today a fully vaccinated child receives a whopping 37 - 50 vaccines during the early, formative years of life, when his developing immune system is most vulnerable. Even an adult immune system would be challenged by so many vaccines given during such a short period of time."

So it makes sense to control what we can - and we CAN control what we EAT :D

Karen