most common T2D gene implicated in LADA

[foxl]

Diabetologia. 2011 Nov 23. [Epub ahead of print]
The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study.
Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P.
Source

1st Department of Paediatrics, Semmelweis University, Bókay u 53-54, 1083, Budapest, Hungary, krisztinalukacs@hotmail.com.
Abstract
AIMS/HYPOTHESIS:

The variants of transcription factor 7-like 2 (TCF7L2) gene have been proposed to be associated with latent autoimmune diabetes in adults (LADA). We sought to confirm the possible association in Europeans and to examine the interaction between one gene variant and clinical data.
METHODS:

The TCF7L2 rs7903146 C-to-T polymorphism was genotyped in 211 LADA, 1,297 type 2 diabetic, 545 type 1 diabetic and 1,497 control individuals from Hungary. A meta-analysis of our and previously published studies was performed to evaluate the size and the heterogeneity of the gene effect.
RESULTS:

The meta-analysis yielded a significant effect of TCF7L2 T allele (OR 1.28; p < 0.0001) on LADA risk without heterogeneity among Europeans. The T allele conferred equally strong susceptibility to LADA and type 2 diabetes. In the Hungarian dataset, the T allele was associated with LADA and type 2 diabetes, but not with type 1 diabetes. T allele carriers had significantly lower BMI than patients with the CC genotype in the LADA and type 2 diabetes groups (p = 0.0021 and p = 0.0013, respectively). In both diseases, the diabetes risk was significantly higher in the non-overweight than in the overweight BMI category (p = 0.0013 and p < 0.0001, respectively); susceptibility to LADA was increased by 2.84-fold in non-overweight individuals compared with overweight ones.
CONCLUSIONS/INTERPRETATION:

The meta-analysis demonstrates that TCF7L2 rs7903146 polymorphism is a population-independent susceptibility locus for LADA in Europeans. The effect size is similar for LADA and type 2 diabetes. The gene effect on diabetes risk may be modulated by BMI, such that the lower the BMI, the higher the gene effect.

[foxl]

Intriguing ... not one mention of IR.

"which is involved in beta
cell proliferation and insulin secretion. One putative
effect of TCF7L2 gene may be a further decrease of
insulin secretion via non-autoimmunity-mediated beta
cell dysfunction."

[Tribbles]

Intriguing ... not one mention of IR.

"which is involved in beta
cell proliferation and insulin secretion. One putative
effect of TCF7L2 gene may be a further decrease of
insulin secretion via non-autoimmunity-mediated beta
cell dysfunction."

They have come around to the idea now that decreased insulin secretion is a key flaw in Type 2 diabetes. There were results coming out of work done on islet transplants where they found that donated beta cells from Type 2s barely reacted to glucose. In theory they should behave normally - this was a bit of a blow because it reduced the available islets for transplant. It may turn out that malfunctioning beta cells and not IR is the defining characteristic of Type 2.

[foxl]

They have come around to the idea now that decreased insulin secretion is a key flaw in Type 2 diabetes. There were results coming out of work done on islet transplants where they found that donated beta cells from Type 2s barely reacted to glucose. In theory they should behave normally - this was a bit of a blow because it reduced the available islets for transplant. It may turn out that malfunctioning beta cells and not IR is the defining characteristic of Type 2.

They (researchers) might have, but the press have not jumped on this one ... obviously. But the fact that there are in use several medications addressing this issue should tell us something ... along with a host of c-peptide results!

[VeeJay]

It's my understanding that IR doesn't necessarily mean diabetes. There are plenty of "normal" people who have IR but their pancreas regenerates beta cells at a rate that compensates. A T2 diabetic does not, and their regeneration rate does not keep up with the IR. What the meds do is to reduce the IR, allowing the available insulin to be used more efficiently.

Many T2s need to supplement with insulin. Is it because their IR is too great, or because their beta cells are insufficient. This study would seem to indicate the latter.

[Daytona]

Interesting study, thanks for sharing. I too lean towards thinking that for many T2 the issue is not enough insulin secretion vs blaming everything on insulin resistance. That may just be my own personal bias showing though.

[Tribbles]

Have a look at a post I made in the Scientific Studies section - Interesting stuff in itunes. It references a seminar that is available on itunes and items 13 and 15 which are the slides and audio respectively. The seminar is on beta cells in Type 2. Some of the interesting things they found were:
- Some T2s have IR but all T2s have insufficient insulin secretion.
- There are loads of genetic links.
- Beta cells do not regrow (as opposed to regenerate). The idea they did came from the mouse model where they were looking at young mice, when they looked at older mice they found this had stopped - they confirmed the behaviour in humans as well. If you are an adult and lose beta cells they are gone for good.
- An interesting reference to Amyloid deposits. Sounds like they have got further with that.

The slides alone are worth looking at but the audio is interesting because there is some elaboration on the slides.

Beta cells

[Peter_V]

They have come around to the idea now that decreased insulin secretion is a key flaw in Type 2 diabetes. There were results coming out of work done on islet transplants where they found that donated beta cells from Type 2s barely reacted to glucose. In theory they should behave normally - this was a bit of a blow because it reduced the available islets for transplant. It may turn out that malfunctioning beta cells and not IR is the defining characteristic of Type 2.

Who is "they"?
Everything I've read says that Type 2s generally produce excessive amounts of insulin, not deficient amounts. Well I guess technically it's deficient because even though they produce way more than average it's not enough to overcome the insulin resistance.
Do you have any links to studies saying this? It might help explain some of the inconsistencies with my diabetes. I gather that if you are over 40 when you become diabetic the vast majority of doctors don't even test to see if you're insulin resistant they just assume that you are.

[foxl]

Peter, read the article I posted ... this is an indication that most T2D is NOT resistance, it is a signalling defect.

If you have antibodies, or have had T2D for a long time, though, I have a feeling that drugs stimulating the signalling might not be a good idea for beta cell preservation, though ....

[Peter_V]

Peter, read the article I posted ... this is an indication that most T2D is NOT resistance, it is a signalling defect.

If you have antibodies, or have had T2D for a long time, though, I have a feeling that drugs stimulating the signalling might not be a good idea for beta cell preservation, though ....

Well, you didn't post the article or a link to it, so I can only go by the extracts you posted.

And that is not what they say,
"one putative" could be one of many,
"may" means that it may or may not
and it also doesn't say that this applies to all or even most type 2s

Do you have a link to the actual study?

[foxl]

I do, but I cannot share it, and it is $35.00 to purchase ... sorry.

However, my understanding of IR is that it leads to insulin levels many times the normal level; I would expect this to be reflected by a c-peptide also of many times normal level.

I do not know too many people who have stated they have that. I have read a few people online who do, though. But, that is anecdotal ...

The "fashion" as of the 80's was to assume all Type 2 was caused by IR and The Metabolic Syndrome, though. I think the mere point that Januvia, byetta, and Victoza are all intended to deal with the signalling problem is an indication that there is more to it than IR in the liver, or the muscles.

[Peter_V]

I should also point out that by definition ALL types of diabetes are caused by insufficient insulin production, even insulin resistant diabetes.
When the insulin resistance gets so high that even though your pancreas is producing 4-5 times the normal amount of insulin, it can't produce enough to overcome the insulin resistance so you become diabetic.

So you have insufficient insulin production even though you are producing MUCH more than normal.

[Tribbles]

I should also point out that by definition ALL types of diabetes are caused by insufficient insulin production, even insulin resistant diabetes.
When the insulin resistance gets so high that even though your pancreas is producing 4-5 times the normal amount of insulin, it can't produce enough to overcome the insulin resistance so you become diabetic.

So you have insufficient insulin production even though you are producing MUCH more than normal.

The problem lies in with the mechanism that builds extra beta cells as you gain weight (insulin resistance) and that replaces cells as they age. In Type 2 it gets the numbers wrong and builds less than required. This takes a while to show since you usually need a 40% beta cell shortfall before you become diabetic (rats can manage with a 60% shortfall!). Eventually you hit that threshold and the train comes off the rails.

Weight creates insulin resistance, but this isn't normally a problem since the body adapts. By losing weight a diabetic can get below that magic 40% threshold and minimise the shortfall but the clock is still ticking. The bad news is that when you lose weight your body scraps beta cells because it no longer thinks in needs them although the improved insulin resistance offsets this for a while.

The upshot is that if you put two people side by side with the same overweight BMI the diabetic may be producing much more insulin than a normal BMI person, but the non-diabetic will be producing even more insulin. Consequently the non-diabetic remains in range and the diabetic goes high which kills beta cells (so there is less insulin, higher levels, more dead beta cells,...)

I recommend this paper which I dug up from a past post for another post today - The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity.

[Peter_V]

The problem lies in with the mechanism that builds extra beta cells as you gain weight (insulin resistance) and that replaces cells as they age. In Type 2 it gets the numbers wrong and builds less than required. This takes a while to show since you usually need a 40% beta cell shortfall before you become diabetic (rats can manage with a 60% shortfall!). Eventually you hit that threshold and the train comes off the rails.

Weight creates insulin resistance, but this isn't normally a problem since the body adapts. By losing weight a diabetic can get below that magic 40% threshold and minimise the shortfall but the clock is still ticking. The bad news is that when you lose weight your body scraps beta cells because it no longer thinks in needs them although the improved insulin resistance offsets this for a while.

The upshot is that if you put two people side by side with the same overweight BMI the diabetic may be producing much more insulin than a normal BMI person, but the non-diabetic will be producing even more insulin. Consequently the non-diabetic remains in range and the diabetic goes high which kills beta cells (so there is less insulin, higher levels, more dead beta cells,...)

I recommend this paper which I dug up from a past post for another post today - The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity.

There are couple problems with your explanation.

First: not everyone that is over weight is insulin resistant, and not everyone that is insulin resistant is overweight.

Second: from what I've been reading people don't build and scrap beta cells like you describe. They thought for a while that they did because of some earlier studies on rats, but it turns out they were looking at juvenile rats and not adult rats. Adult rats don't build new beta cells, and from what they are seeing now neither do adult humans.

Finally, you are STILL appear to be saying (and this I agree with) that insulin resistant people produce MORE insulin than NON-insulin resistant people, this is pretty much the definition of insulin resistance. When an insulin resistant person initially becomes diabetic they STILL have higher than normal insulin levels, they don't typically produce less than normal until they've been diabetic for 10-15 years.
So again the problem (for insulin resistant diabetics) is NOT that they produce less than normal amounts of insulin, at least not initially.
Given that insulin resistant diabetics make up something like 75% of all diabetics and 85-90% of Type 2 diabetics, the statement that "decreased insulin secretion is a key flaw in Type 2 diabetes" would appear to be incorrect.

Unless of course you mean that their insulin production has decreased from "extremely" high levels to merely "very" high levels. I suppose this is possible, but I haven't come across any studies that indicate this, have you? Can you post a link?
So the statement "decreased insulin secretion is a key flaw" appears to be

[Tribbles]

There are couple problems with your explanation.

First: not everyone that is over weight is insulin resistant, and not everyone that is insulin resistant is overweight.

Actually if you are overweight you *will* have insulin resistance, that's what triggers the beta cell build out (or rather the hyperglycemia caused by the IR will). In non-diabetics the build out scales though so the IR is invisible.

Second: from what I've been reading people don't build and scrap beta cells like you describe. They thought for a while that they did because of some earlier studies on rats, but it turns out they were looking at juvenile rats and not adult rats. Adult rats don't build new beta cells, and from what they are seeing now neither do adult humans.

Yup, there was a slide set I cited elsewhere from a seminar at Columbia that talked about that. This is the finding that adult rats do not regrow beta cells when they are destroyed whereas earlier research was done on juvenile rats that can regrow beta cells. If I understand what you are saying then you are confusing the mechanism that controls the build out (this mechanism needs to be triggered by weight gain) with what the seminar was talking about - the ability to spontaneously regrow beta cells as in juvenile rats. If build out did not work for adults all obese adults would be diabetic.

Finally, you are STILL appear to be saying (and this I agree with) that insulin resistant people produce MORE insulin than NON-insulin resistant people, this is pretty much the definition of insulin resistance. When an insulin resistant person initially becomes diabetic they STILL have higher than normal insulin levels, they don't typically produce less than normal until they've been diabetic for 10-15 years.

That depends on a lot of factors including the variety of Type 2 they have. Basically it comes down to the rate of decline of their beta cell function as that seminar at Columbia pointed out. The issue is that without doing a clamp there is no way to know the level of IR and hence whether the apparent insulin levels are due to a lack of IR, or an absolute deficiency.

So again the problem (for insulin resistant diabetics) is NOT that they produce less than normal amounts of insulin, at least not initially.
Given that insulin resistant diabetics make up something like 75% of all diabetics and 85-90% of Type 2 diabetics, the statement that "decreased insulin secretion is a key flaw in Type 2 diabetes" would appear to be incorrect.

Maybe as recently as even five years ago that was the perceived answer but a slew of medical researchers would disagree with you these days.