Stem Cells and Diabetes

*I would like to start with a disclaimer. My laptop is broken (AGAIN), and until I invest in a new harddrive, I am going to have to write all the posts on this little netbook, Ruby, who, while intrepid, can’t do JACK when it comes to images. Which means I’ll have to add the images in the AM. My apologies.

Sci found this paper today and immediately had to run around showing it to people and saying “OMG isn’t this COOL!!” At first, it was so cool that I thought I should save it for a special occasion, but dangit, I’m feeling celebratory. Anyway, I wanted to blog it NOW.

And since this is Sci’s blog, what Sci wants, Sci gets.

And I love this paper.

ResearchBlogging.org Alipio, et al. “Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic β-like cells” PNAS, 2010.

So first, let’s talk a little about diabetes.

Sci has posted a bit about diabetes previously, but I’ll recap here a little bit.

Basically, diabetes is a disorder where your body lacks insulin, which you probably already know. Insulin, which is a protein produced from the beta cells in the pancreas, is a molecule which allows your cells to take up glucose. Glucose, as you know, is a potent form of energy that we get from food, and your body is very hard put to survive without it. So you really need insulin to get your glucose into your cells, or your cells will literally begin to starve to death.

And now we get to diabetes:

Type I

What happens in Type I diabetes is that your body destroys and rejects the beta-cells which make your insulin in the pancreas. Without beta cells you produce no insulin, and so the only cure at the moment is to supplement insulin in diabetic patients on a daily basis. While Type I diabetes only affects about 3.5 percent of the total population, giving insulin in not a cure, and it has significant impacts on quality of life, as well as having a lot of side effects associated with it which can shorten the lifespan.

Type II

Some scientists are starting to think of type II diabetes as a precursor to type I, as many patients with type II will go on to develop type I and become insulin dependent. Type II diabetes is not an inability to make insulin, instead, it is either a condition of not making enough, or not being sensitive enough to what you DO make. Sometimes this can be managed with lifestyle (when some people gain too much weight they become insensitive to insulin) or with some drugs, but many patients with Type II diabetes will also end up having to dose with insulin. This type of diabetes is much more widespread, affecting up to 7% of the population.

So now we get to the issue of this paper, the issue of the beta cells.

Type I diabetes, as I mentioned up there, occurs because of the destruction of the beta cells which produce insulin. So the idea is, if you could get the body to REMAKE the beta cells, you could cure diabetes. Sounds simple right? Well, not really. Previous ideas to get this effect have been tried with pancreas transplants or trying to get beta cells reintroduced, but often the body will reject the donation. Other methods tried using beta cells that have been induced from bone marrow cells, but the cells coming from there don’t differentiate into beta cells very well, and don’t really produce a lot of insulin.

But what about pluripotent stem cells?

An induced pluripotent stem cell (called an iPS) is a stem cell (a cell that can become lots of different things) that is deliberately induced from an already-differentiated adult cell. You can do this by reprogramming the cells using viruses to transfer the DNA that you need. They are very similar to the embryonic stem cells of controversial fame, but are derived from adult cells that are already in your body. This is a good thing, because if it’s a part of your body, you can’t reject it.

In this case, the scientists took mice, and made two models of diabetes. The first one is a type II diabetes model, which shows low levels of insulin production. The second was a mouse given streptozotocin, which is a chemical that kills beta cells in the pancreas, giving the mouse type I diabetes.

They took skin cells from mice and made them into iPS cells using viruses. The cells were also labeled with GFP, so they knew what they were looking at by the glow. After treatment with the viruses, the former skin cells differentiated into muscle and gut and all sorts of other things. They then differentiated them into beta cells, and checked to see how they did with glucose.

You can see above the beta cells exposed to glucose. And they behaved just like beta cells should, pumping out insulin in response to the glucose.

But the question is, would it work in the mice? They injected the new beta cells into the livers of the diabetic mice and looked.

And it did. You can see up there four lines. The two top lines are the fasting glucose levels of untreated type 2 diabetic mice and mice treated with a fake injection of cells. The two bottom lines are a mouse with no diabetes and a mouse treated with the stem cells. You can see the stem cell treated mice look just like a normal mouse. What’s happening here is that in the diabetic mice, there is no insulin to make the glucose in the blood go into the tissues, and so their blood glucose levels are HIGH. In the normal mice (and the stem cell treated mice) there is enough insulin being produced to get glucose from the blood to the tissues, and so glucose levels are LOW!

And here you can see mice that have type I diabetes, who have no beta cells at all. The top line are the controls, and the bottom line is the diabetic mice treated with iPS cells. You can see that the treated mice had a dramatic decrease in blood glucose, showing that the stem cells they received became beta cells and were pumping out insulin like they should.

While the treatment didn’t work in all of the mice (two of the type 2 diabetic mice had high blood sugar levels soon after), this paper could be GREAT news to people with type I and type II diabetes. If we can induce human cells to produce iPS cells, we could put them back into the humans and potentially reduce their blood sugar levels. Not only that, the stem cells also produced alpha cells in addition to beta cells. Alpha cells produce glucagon, which is a very important part of the insulin response, and type I diabetes destroys both alpha and beta cells. So having them both back would be even better than having just one, as the two types could work in concert.

However, you have to keep in mind that we aren’t there yet. This was in mice, and iPS cells aren’t as well characterized in humans. Not only that, a lot of type I diabetes and later stages of type II diabetes has an IMMUNE COMPONENT. This means that the body will continue to try and make beta cells, and it will also reject and destroy them, even though they are normal cells and not an invasion. So it’s possible that these cells could still be rejected.

But despite the caveats, this is a big step in the right direction, and it gives Sci hope that a cure for diabetes may come sooner rather than later.

Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, & Ma Y (2010). Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic {beta}-like cells. Proceedings of the National Academy of Sciences of the United States of America PMID: 20616080

7 Responses

  1. I’d be more excited if they grew up some t-regs in vitro and cured it that way.
    Though I wonder about tolerance in the liver. Maybe injecting a boatload of cells all at once could get you some nice t-regs anyway.

    Question about that first graph- is that normal? Do all beta cells have a narrow optimal-function range like that (20mM)? Cause that says… unsettling things about my tendency to eat giant ice cream sundaes.

    Also- the iPS made beta cells. And alpha cells. And… anything else? Mice in this study didn’t live long enough to get cancer, but that has to be looked at.

    • Actually, they did look at the mice several months out. The good news is that only two of them regressed, and all of the type I diabetic mice retained normal function. One type II mouse DID get a tumor, but it wasn’t GFP positive, indicating that it didn’t arise from the iPS.

      And yeah, in my experience glucose tolerance curves are supposed to by sigmoidal, but this WAS in vitro and that could have something to do with it.

  2. [...] Go here to review a rest: Stem Cells as well as Diabetes « Are we Scicurious? [...]

  3. Dr Denise Faustman’s research into curing type 1 diabetes is much farther along(completed phase 1 clinical trials in humans). http://www.faustmanlab.org/ for the details.

  4. I thought that in type-II diabetes, the primary problem wasn’t insulin quantity – it’s insulin resistance. That’s why oral hypoglycemics are so effective in treating early-stage type II -they counter the cells resistance to metabolizing the insulin. In fact, from what I recall from family, many type-II diabetics have unusually high insulin levels – it’s just that the cells don’t use the insulin.

    So is this a bad model of type II? Or is my understanding of type II just all wrong?

    • Mark, I think the presence of insulin in end stage type 2 diabetics varies. Some type 2 diabetics do take insulin in combination with the oral medications.

      I don’t understand how restoring insulin production would return the blood sugar in the type 2 mice to a normal range. If they are indeed type 2 they should have significant insulin resistance.

  5. Hello :)

    Although many people with Type 2 diabetes will use insulin to manage their glucose levels this doesn’t mean that their diabetes has turned into Type 1 (which is largely an autoimmune disorder). Certainly there’s plenty of discussion as to how different or similar these two types of diabetes are and whether there’s some sort of continuum… but Type 2 doesn’t become Type 1. I mention this in particular as many people with the condition have been given confusing information as to the type of diabetes they have (and it’s certainly not always easy to be sure, and even when it’s fairly clear antibody tests can be ambiguous)… and people with Type 1 diabetes can be insulin resistant too, and of course things can be complicated further by the less common form such as MODY and LADA to consider.

    The recently published report from the Royal College of General Practitioners and NHS Diabetes, called Coding, Classification and Diagnosis of Diabetes considered the impact of misdiagnosis (and of miscoding into NHS patient databases which is a separate problem) – page 9 of this doc looks at the effect on the patient.

    http://www.diabetes.nhs.uk/document.php?o=2063

    Streptozotocin certainlys seems to kill off beta cells rather effectively, and produce a form of diabetes that’s very similar to Type 1 (in that there are no cells producing insulin) but I don’t think this model has the underlying autoimmunity issue that features in the natural form of the disease process.

    I’m speculating a bit here but I think that if replacement beta cells are given to an animal after its original ones have been destroyed by STZ – but that the STZ treatment is not ongoing, ie withdrawn – then those beta cells could well survive. Where the animal has a persistent autoimmune attack on beta cells I suspect this isn’t going to be the case.

    Something similar-ish is seen I think in the ‘honeymoon period’ which can occur shortly after diagnosis of Type 1 diabetes and the start of insulin therapy. The patient could well have presented with their diabetes when about 90 per cent of the beta mass has been lost and the remaining 10 per cent have admitted defeat under the onslaught of rising glucose levels. Injected insulin restores glucose levels to something nearer to normal and the remaining beta cells seem to rally a little and start producing some of their own (often the person finds they can significantly reduce their insulin dose though they are generally advised to maintain a small dose to support their beta cells for longer). This restarting of endogenous insulin production appears to alert the immune system (I’m afraid I can’t pretend to understand the technicalities of this!) which then goes on the attack once more and these remaining beta cells are lost.

    I’m not convinced that the immune system of someone with Type 1 diabetes would treat any more kindly these new stem cell-derived beta cells (from the person’s own bone marrow / iPS / other adult stem cells) having already dispatched the person’s previous (well matched) beta cells.

    Happy to be disagreed with on all of this – always keen to learn more about diabetes as I spend a large portion of my day answering questions about it :)

    I work as a Science Information Officer for Diabetes UK but my comments here are my own views.

    Best wishes,
    Jo

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