Genetic "cause" of diabetes

[LC FP]

It's hard to envision that any epidemic could have a genetic origin. Your genes are probably the most stable organic molecules in the universe. But some people keep trying to prove that type 2 diabetes is "genetic".

I grant you that some people are more likely to develop diabetes than others, if you feed them the wrong diet. That's called variation, and it's the basis of selection, which I believe everyone can agree about, (without getting into religious stuff).

It seems like these guys are looking to find the gene "responsible" for T2D, no doubt to find a patentable way to manipulate it.

The old study they based this on is one of the best ever done, which compared metformin vs diet and exercise in the prevention of diabetes in people with pre-diabetes. Of course diet and exercise was quite effective, twice as effective as metformin. And they even used the wrong diet (LF)!

From this week's NEJM:

TCF7L2 Polymorphisms and Progression to Diabetes in the Diabetes Prevention Program

Jose C. Florez, M.D., Ph.D., Kathleen A. Jablonski, Ph.D., Nick Bayley, B.A., Toni I. Pollin, Ph.D., Paul I.W. de Bakker, Ph.D., Alan R. Shuldiner, M.D., William C. Knowler, M.D., Dr.P.H., David M. Nathan, M.D., David Altshuler, M.D., Ph.D., for the Diabetes Prevention Program Research Group

ABSTRACT

Background Common polymorphisms of the transcription factor 7–like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo.

Methods We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year.

Results Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.

Conclusions Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992 [ClinicalTrials.gov] .)

Source Information

From the Diabetes Prevention Program Outcomes Study Coordinating Center, George Washington University, Rockville, Md.

The bolded text says that even if you have the "wrong genes", your odds of developing diabetes aren't significantly high, as long as you take a relatively ineffective medication or you exercise and eat the wrong diet.

I bet if they ate the right diet, nobody would have developed diabetes. That would shake up the dieticians.

[Nancy LC]

Yeah, I know what you mean. I'm following some of the research on Zonulin and gluten intolerance. I read recently that anyone eating wheat (gliadin) has an increase in zonulin production, which causes the tight junctions in the intestines to open somewhat. In people with severe gluten intolerance, the effect lasts longer and is more severe. But that it happens to some extent in just about everyone.... makes you kind of wonder that we're eating food we should be leaving to creatures with more stomachs than we have.

http://www.medscape.com/medline/abstract/16635908?queryText=gliadin

[LC FP]

Nancy, interesting subject. I haven't looked at it much. I think developing celiac disease has similarities to developing diabetes.

Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues.
Pre-CD kinda like pre-T2D.

And then:

Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression
I think this means that you down-regulate the number or strength of tight junctions with chronic gliadin exposure.

[Nancy LC]

There's a lot of overlap in excess zonulin production and autoimmune diabetes too. Of course, there's a lot of thinking that it might be intestinal permeability behind all sorts of autoimmune diseases.

I'm looking forward to the day when we can measure this easily in people. Both so that we can see if this is what is causing all these autoimmune issues and also to see if their is other stuff that also causes it to happen. And, I'd love to know if my TJ's will ever slam shut again, or are they stuck open forever?

But one thing I wonder about, what purpose does opening the tight junctions serve? There must be a reason we have that hormone working at times. Of course, the research is going into developing a drug to close them up again in celiacs. Again, treating the response to crummy diet rather than pointing out that perhaps the food shouldn't be eaten.

[ItsTheWooo]

There's a lot of overlap in excess zonulin production and autoimmune diabetes too. Of course, there's a lot of thinking that it might be intestinal permeability behind all sorts of autoimmune diseases.

I'm looking forward to the day when we can measure this easily in people. Both so that we can see if this is what is causing all these autoimmune issues and also to see if their is other stuff that also causes it to happen. And, I'd love to know if my TJ's will ever slam shut again, or are they stuck open forever?

But one thing I wonder about, what purpose does opening the tight junctions serve? There must be a reason we have that hormone working at times. Of course, the research is going into developing a drug to close them up again in celiacs. Again, treating the response to crummy diet rather than pointing out that perhaps the food shouldn't be eaten.
http://gut.bmjjournals.com/cgi/reprint/49/2/159

A century ago, TJs were conceptualised
as a secreted extracellular cement forming an
absolute and unregulated barrier within the paracellular
space.3 Biological studies of the past several decades have
shown that TJs are dynamic structures subjected to structural
changes that dictate their functional status under a
variety of developmental,4–6 physiological,7–10 and pathological
circumstances.11–13 To meet the many diverse physiological
challenges to which the epithelial and endothelial
barriers are subjected, TJs must be capable of rapid and
coordinated responses. This requires the presence of a
complex regulatory system that orchestrates the state of
assembly of the TJ multiprotein network.
....
The Zonulin System
The physiological role of the zonulin system remains to be
established but it is likely that this system is involved in
several functions, including TJ regulation responsible for
the movement of fluid, macromolecules, and leucocytes
between the bloodstream and the intestinal lumen and vice
versa. Another possible physiological role of the intestinal
zonulin is protection against microorganism colonisation.24
In the absence of enteric infections, the mammalian small
intestine is virtually sterile. Colonisation of the proximal
gut by enteric microorganisms (even without apparent
mucosal damage or elaboration of specific toxins) may lead
to a leaky intestine25 but the mechanism(s) by which this
disturbed physiological regulation of intestinal TJ permeability
secondary to proximal bacterial contamination
occurs remains unclear.

So it used to be thought that TJs were like structural bonds/barriers (that were supposed to stay shut, unchanging) but now we know they have a functional role, opening/closing to regulate normal physiology - passing fluids, and, keeping bugs out of the small intestine, which in normal physiology is sterile in mamals.

These results
suggest that the presence of enteric microorganisms in the
small intestine (but not in the colon, where the zonulin
system is not operative15 18 19) induces a host dependent
mucosal response that leads to luminal secretion of zonulin.
...
The fact that the interaction of bacteria with the intestinal
mucosa induces zonulin release, irrespective of their
pathogenic traits or viability, can be interpreted as a bacteria
independent mechanism of defense of the host that
reacts to the abnormal presence of microorganisms on the
surface of the small intestine.Following zonulin induced
opening of TJs, water is secreted into the intestinal lumen
following hydrostatic pressure gradients19 and bacteria are
“flushed out” from the small intestine.

.
Elevated zonulin reflects a condition which is likely subjecting your small intestine to an abnormal amount of microorganisms trying to make a home there.

It is how eating carbohydrate in excess leads the body to make too much insulin, which then results in diseases. Once we get to the "high insulin" part of maintaining normal physiology after eating a krispy kreams donut... the body just kinda scratches it's head, playing catchup with all the imbalances that result. It has no genetic concept of a condition that can produce chronic high blood sugar, therefore, it has no way of responding to it other than making more and more insulin. Imbalance, then disease results.

This is likely with the elevated zonulin - a response to, and a symptom of the celiac disease. The body doesn't genetically understand of such a condition as wheat, causing problems which lead to real high level of bugs trying to live where they shouldn't. The zonulin becomes abnormally high as a way of trying to maintain physiology in the only way it knows how - flushing out the bacteria by breaking down TJ with zonulin.

[Nancy LC]

This is likely with the elevated zonulin - a response to, and a symptom of the celiac disease.Except it also does in non-celiacs too, though not quite so much. At least, that's how I'm reading that article.

Where do the "flushed out" bacteria go? The blood stream? I wonder if the badly leaking gut is letting stuff get into the blood stream that shouldn't be there. I think that is the case.


Elevated zonulin reflects a condition which is likely subjecting your small intestine to an abnormal amount of microorganisms trying to make a home there.
I think the opposite is happening. Stuff that shouldn't be escaping the gut, autoantibodies, perhaps even bacteria, is getting out. They're finding some evidence of antibodies to intestinal bacteria in synovial fluid in RA patients.

Zonulin was discovered when a guy was trying to come up with cholera vaccination. Here's a pretty readable article: http://sciencenews.org/articles/20000422/bob8.asp

The neat thing is it also works on the blood/brain barrier.

Anyway, this also directly links to diabetes:

They also speculate that the leaky tight junctions in a person with celiac disease may allow molecules to leak from the intestine into the blood and trigger autoimmune reactions. To support this idea, Fasano has examined laboratory rats that spontaneously develop diabetes because their immune systems begin attacking insulin-producing cells in the pancreas. These rodents, he finds, always have an increase in intestinal permeability several weeks before the diabetes symptoms appear.

But anyway, the reason I posted about this in the first place is, wheat (and some other foods) might end up being a food that was a just a bad move for the human race to start eating. And as time has gone on, we've been eating it more and more.

[LC FP]

This is interesting stuff, thanks for the references wooo.

Where do the "flushed out" bacteria go? The blood stream?

I think in the normal system the presence of bacteria in the small intestine opens up the TJs, and water from the intersitital (between-the-cells) space leaks into the lumen (inside) of the intestine, and causes "diarrhea" which flushes the bacteria into the large intestine, where they belong.

such a condition as wheat, causing problems which lead to real high level of bugs trying to live where they shouldn't
Again I think wheat doesn't cause bugs to invade the small intestine, the wheat protein gliadin "simulates" the presence of bugs in the small intestine and causes the same result, diarrhea and inflammation, and malabsorption etc. As long as you continue to eat wheat, you fool your intestine into thinking it's invaded with bacteria, and it continues to loosen the TJs and you essentially have the equivalent of cholera.

[bigpeach]

It's the same crap as saying fatness is genetic. What? Your parents ate buckets of fried chicken as snacks too? Your fatness is genetic. Logical, eh?

[SunnyCarol]

I bet if they ate the right diet, nobody would have developed diabetes. That would shake up the dieticians.

I would have to disagree. My daughter died almost two years ago (8-8-2004) from complications of diabetes. She was 31 years old. She was never overweight and only weighed in at just over 100 pounds, at 5 feet four inches tall, one time in her life--the day she delivered her 7 pound 2 ounce son. She weighed 104 pounds that day. The only 'bad' food she consumed was too much coffee. She was my kid that loved her veggies and chicken and turkey. She loved spinach, broccoli and Brussels sprouts like other kids like candy. I never had junk food and sodas growing up and I didn't feed that to my kids. She didn't like sweets at all. She used to want to buy a candy bar with her allowance and she would take one bite and put it in the fridge for 'later,' only later never came and I would throw it away when I cleaned the fridge. One of my favorite memories was when she'd cook a 10 ounce package of frozen petite Brussels sprouts and politely ask you if you'd like some with such a look of "please don't want any," on her face, that you just had to laugh. She didn't eat a lot of red meat, but did enjoy steak and hamburgers. She did eat a lot of fish, seafood, and fowl. She could eat you under the table on steamed shrimp and crab legs.

There is no diabetes on my side of the family, but her paternal grandfather was severely diabetic. He was not overweight, either, being slim until HIS death from complications of diabetes. His father died at a young age from diabetes. The only picture of him I ever saw showed a normal size man.

So--if not genetics, then how do you explain her having diabetes when she ate very healthy and was never overweight and was very active? You can't blame everything on diet alone.

[2bthinner!]

I have heard of evidence that a virus can cause it... Let me see if I can google anything.. My BIL is diabetic, but his diet wasn't good. And a friend of my daughter's became diabetic..

http://www.diabetes123.com/d_0n_120.htm

This is what happened to my daughter's friend. His parents thought he was faking it. He had a friend who had just been diagnosed with diabetes too, and they thought he felt he had diabetes because of his friend.
http://www.scripps.edu/newsandviews/e_20010702/nora1.html

Google search results
http://www.google.com/search?hl=en&q=diabetes+virus&btnG=Google+Search

[Nancy LC]

Carol, I'm so sorry you lost your daugther. :(

There are two types of diabetes. One where the immune system attacks the pancreatic cells and destroys them, which is called Type 1. It is an autoimmune disease. These folks are often skinny.

The other is Type 2 where your body produces insulin but not enough or else their bodies don't use it correctly. This is the sort usually associated with diet and obesity.

I once would have said Type 1 isn't caused by diet, and probably isn't in all cases, but I've got my suspicions that food intolerances cause a lot of autoimmune diseases. There sure is a strong association between gluten sensitivity and diabetes.

But also, there might be pathogens we get that also cause intestinal permeability and conditions that cause the body to react to antibodies, that eventually leads to Type 1 diabetes.

Carol, did your daughter have Type 1?

[SunnyCarol]

Carol, did your daughter have Type 1?

No, she was Type II and didn't get diagnosed until she was a teenager, because she was so small and otherwise healthy--except for the ongoing, never ending UTIs and kidney infections and insatiable thirst! They were shocked at the results; so much so that she was put in the hospital on dialysis within hours of the test. With her sugar that high, they didn't know how she was not in a coma. I had told them of the family history and they were still shocked. Since there was nothing they could do with diet, because she ate healthy and only weighed 85 pounds, she had to go on insulin. Her kidneys were so compromised at this point, that she frequently had to be hospitalized. Her doctor at that time was her life-long pediatrician, but we never went back to him. He had been treating these urinary problems as cystitis for a couple of years, blaming them on towels left damp in the gym lockers and the fact that she swam at least three times a day in the summer.

Her grandfather was Type II, as well. He wasn't diagnosed until an adult and was insulin dependent after an attempt at diet, which he actually didn't need. He lost both legs below the knee a few years ago.

[bigpeach]

Adults can develop type 1 and it is often misdiagnosed only because of their age.
http://www.healthatoz.com/healthatoz/Atoz/dc/caz/diab/dia1/alert08052003.jsp

[SunnyCarol]

Adults can develop type 1 and it is often misdiagnosed only because of their age.
http://www.healthatoz.com/healthatoz/Atoz/dc/caz/diab/dia1/alert08052003.jsp


From the link provided:

"For a long time, we thought type 1 mostly happened to children. Now we know that in older people its symptoms can develop at a slower rate - four to five years. With children, it seems to happen almost overnight," says Eugene J. Barrett, M.D., former president of the American Diabetes Association, professor of internal medicine and pediatrics at the University of Virginia Health System in Charlottesville.

This is where my daughter was treated and diagnosed as Type II. She spent over two months in the Kluge Children's Center, a part of UVA Health Systems, when she was 16 years old. She was seen several times by Dr. Barrett.