July 13, 2009

Research Gives Insight into How to Measure Beta Cell Mass in Living People

Expensive diabetes drugs are being sold with the claim that they rejuvenate beta cells. Avandia, Actos, Januvia and Byetta are all promoted this way, and because they believe these claims doctors often insist their Type 2 patients stay on these costly drugs even when they aren't having any discernible effect on their blood sugar.

One reason the drug makers can make this claim is that it is difficult to disprove. That's because there is currently no way to measure the beta cell mass in a pancreas located inside a living person. Imaging fails because the size of the pancreas doesn't tell you anything about the density of beta cells. So researchers base their claim either on rodent studies--though rodents have very different blood sugar metabolisms than humans--or they estimate the beta cell mass of humans taking their drugs by measuring insulin or c-peptide levels and applying a formula, HOMA, to compute a number they believe represents the beta cell mass.

HOMA stands for "Homeostatic model assessment". The formula was created back in 1985 long before we had reliable measures of blood sugar variables or any way to measure beta cell mass. To learn the details of how HOMA is computed, read this essay:

Diabetes in Control: HOMA: Often Mentioned, Rarely Defined.

I have blogged before on how HOMA calculations fail to distinguish between insulin resistance and insulin deficiency and how this measure gave doctors the erroneous belief that Type 2s are largely insulin resistant, rather than, as turns out to be the case, insulin deficient.

I am particularly sensitive to this problem because when I plugged my numbers into the Oxford HOMA calculator some years ago, it told me I was seriously insulin resistant. It was only when I injected insulin that I discovered that I was very insulin sensitive--two or three units of fast acting insulin will cover 40-60 grams of carbohydrate for me, and I can hypo on 8 units of Lantus. So I felt vindicated when I learned that the HOMA formula labels many people "insulin resistant" who, in fact, are insulin deficient.

Now a new study takes another look at how the HOMA formula is used to estimate beta cell mass and finds it defective there, too. This is important because it is the HOMA calculation that is often used to support claims that various drugs are increasing beta cell mass.

The study is:

Functional Assessment of Pancreatic β-Cell Area in Humans. Juris J. Meier et al. Diabetes. July 2009, vol. 58, no. 7, 1595-1603. doi: 10.2337/db08-1611

The researchers here rounded up a group of unfortunate people who, because of serious medical problems, were about to have their pancreata removed. These subjects had a wide range of pancreatic function before surgery as they had different diseases some of which killed beta cells and some of which did not. The researchers gave them each a Glucose Tolerance Tests with C-peptide measurements before surgery.

After surgery their pancreases were carefully examined to find out exactly what their beta cell mass might be. This is not easily done because as soon as a pancreas is removed the enzymes it contains start to digest the pancreatic tissue. It is only over the past decade that techniques have been devised that allow researchers to examine beta cells shortly after death or after surgical excision of the pancreas.

What the researchers found was this:
β-Cell area was related to fasting glucose concentrations in an inverse linear fashion (r = −0.53, P = 0.0014) and to 120-min postchallenge glycemia in an inverse exponential fashion (r = −0.89)
To give you a feeling for the difference between an "inverse linear" relationship and an "inverse exponential" relationship, let's look at a hypothetical example. In the linear relationship, if your fasting glucose was up, say, 3% then your beta cell mass would be down that same 3%. If the fasting glucose rose by 6%, your beta mass would go down 6%.

With the exponential relationship that applies to the two hour glucose tolerance test result, if the two hour reading was up 3% your beta cell mass would be down 9% but if the 2 hour reading was up 6% your beta mass would be down 36%, if it was up 9% your beta mass might be down 81%. That gives you some idea of how much more intense an exponential relationship is compared to a linear relationship.

This suggests, too, why the glucose tolerance test and/or post-meal tests are so much more important than the fasting glucose test for diagnosing diabetes. Because small changes in the two hour test result point to larger changes in your beta cell mass.

What the researchers found in this study was that the blood test measure that best predicted the actual beta cell mass that they found when they examined the pancreas, was, "the C-peptide-to-glucose ratio determined 15 minutes after the glucose drink".

This is very interesting indeed, because until now we have been told because of earlier research that the 15-minute glucose tolerance test result was not predictive of anything and that only the 30 minute result was useful. That may be true if you look only at glucose levels, but this study makes it clear that it is not true if you include C-peptide levels.

Unfortunately, because of the belief that the 15 minutes result isn't useful, you will have to look long and hard to find other studies that measure 15 minutes C-peptide. Invariably when C-peptide is measured at all it is measured, fasting, at 1/2 hour intervals, and often only at the 2 hour mark.

The researchers also found that "a fasting C-peptide–to–glucose ratio already yielded a reasonably close correlation." It wasn't as good as the oral glucose tolerance test 15 minute measure, as shown by the "r" values. The lower the "r" value the better the correlation with an inverse result. The r value for the 15-minutes result was -.72 (-1.00 would have been perfect correlation and 0 would have been no correlation.). The r value for the fasting c-peptide/glucose ratio was -.63.

But here's the kicker. The researchers add "Homeostasis model assessment (HOMA) β-cell function was unrelated to β-cell area.

This is the same HOMA calculation drug company researchers are prone to use to support claims that their drugs are increasing beta cell mass.

I have long doubted that any oral drug can make a significant improvement in anyone's beta cell mass for several reasons. Long term studies show that over several years, after an initial improvement, the blood sugar control of people taking these drugs starts to declines. It does not improve the way it would if they had more beta cells cranking out insulin. This suggests that these drugs either stimulate insulin secretion--which is true of Januvia and Byetta--or make the same amount of insulin more effective, as is the case with Actos and Avandia.

But when you take people off all these drugs, within weeks their blood sugar control goes back to where it was before they started the drug, except in the case of the people for whom Byetta causes dramatic weight loss, who may have been blood sugars because they have 100 lbs less body weight and hence are more insulin sensitive.

Were a drug to actually regenerate beta cells, you'd expect to see blood sugar control increase over the long term and you'd also expect to see sustained better blood sugar control when the person stopped taking the drug. That neither of these effects occurs makes it very unlikely that these drugs are having this effect.

One cannot but wonder if perhaps there are similar studies to this one kept locked in drug company files, studies run to "prove" that Januvia or Byetta increased beta mass, whose publication was suppressed when the result was not found. The drug companies have been pushing this claim so hard for these drugs, that you would expect to see autopsy studies by now, years after the drug has been in use. And we know for a fact that drug companies have a long history of hiding or suppressing the publication of studies whose findings might lessen sales.

In any case, if you wonder about how your own beta cell mass is doing--and who doesn't--it would be nice to get that 15 minutes oral glucose tolerance test with C-peptide measurement that might give you a good read on this, but you won't. It isn't a standard lab test and doctors aren't likely to notice this particular research study since, because it doesn't promote a drug or confirm a strongly held belief, no one is going to bring it to their attention.

But what you can do is this: You can ask for a fasting C-peptide with glucose measurement every year, compute the C-peptide/glucose ratio, and track how it is progressing over time. This should give you some sense of how your beta mass is holding up.

If your doctor insists that you take Januvia or Byetta to "regrow your beta cells" insist on getting the fasting C-peptide test with fasting glucose measurement before you start the drug and then a year later. If you don't see improvement in the C-peptide/glucose ratio, you will know that the drug company claim is false. Then, if the drug hasn't made a significant improvement in your blood sugars, you'll know there is no reason for you--or your insurance company--to keep spending almost $200 a month on the drug.

Of course, if you have a personal history of cancer or a strong family history of cancer, you should not be taking Januvia, but that's another issue. Details here: Januvia and Cancer.

 

12 comments:

Anonymous said...

doctors are not swayed by rhetoric. If there are human studies showing regeneration then doctors will believe it. But as you point out there are no such studies. To say that drug companies push their product with a blatantly false claim would be illegal and cause for severe fines by the FDA. Maybe these claims are being misinterpreted? It would be insulting to doctors to suggest they buy into such claims of regeneration without any human proof...

Jenny said...

All I know is that I get a steady stream of mail from people who tell me that their doctors insist they take Januvia because it will rejuvenate their beta cells. Even when the drug is not doing much for their blood sugars.

The rejuventation claim is being made based on rodent and test tube studies. It was made for years for Avandia and Actos, which is one reason why so many doctors put people on them though it didn't do much for their blood sugar and caused weight gain.

The rejuvenation claim for Avandia was debunked in the DREAM study follow up, but many doctors did not hear about this as the drug reps who sold them rejuvenation were not about to point it out.

The FDA has no staff for or inclination to prosecute drug companies for what their reps tell doctor.

Jim Purdy said...

If, as Anonymous said, "doctors are not swayed by rhetoric," then what are they swayed by?

I've had so many adverse reactions to prescription drugs that I barely trust any medical professionals any more.

Your blog does a great job of raising good questions.

Anonymous said...

You said - The FDA has no staff for or inclination to prosecute drug companies for what their reps tell doctor.

The FDA does not have authority to prosecute anyone. Only US District Attorneys do that. They may work with the FDA but I don't know how they get their cases started.

The most active office has been the DA in Boston. See this powerpoint presentation.
http://www.ehcca.com/presentations/pharmaaudio20071126/loucks.pdf

Over 100 cases yielding 8 billion in fines in the four years ending 2006.

The problem with the Januvia claim is that it proabably not false legally. They have studies showing it rejuvenates beta cells.

Trinkwasser said...

This is fascinating! Obviously the defect at 15 minutes would be Phase 1 insulin response, so this lends more credence to the theory that (in certain forms of Type 2 anyway) the Phase 1 craps out long before the Phase 2 is affected. Which is exactly what I have found, though without the benefit of tests to prove my theory, just the fact my BG will bounce up high given enough carbs but then be pulled down rapidly when the Phase 2 comes on stream.

My insulin resistance was also a factor but much less now it is under control: that hasn't brought back the missing Phase 1 though.

This *could* be a relatively easy test which may determine "prediabetes" long before the FBG or 2 hour postprandials go south and offer patients the chance to control things before irreversible damage accrues, and likely to be more useful than waiting until A1c has passed 6.5

Anonymous said...

Jenny--

What happened to your article titled: "ADA Journals Add An Interesting Disclaimer." I saved it to a file, but wanted to direct a friend to your post . . . it wasn't there! What gives?

Jenny said...

Anonymous 12:11,

I had no sooner posted that blog post than someone reminded me that I had already blogged about the identical article some months ago. It turned out to have been published twice--one e-pub and once in paper, and I'd already blogged about it when it came out the first time e-pub.

That should teach me not to blog first thing in the morning before I have had my coffee!

Anonymous said...

a few qualifying points:
-No drug has human regeneration data- if they did it would be on the front page of every newspaper
-the beta cell "mass" should really be termed beta cell volume as none of the researchers are placing the pancreas on a scale. They are measuring area
-the concept behind the benefits of branded drugs, namely the glitazones and to a lesser extent, glp1 analogues is their ability to "mummify" the beta cell. metformin and sulfonylureas do nothing to slow progression of disease as demonstrated in the UKPDS, DPP and ADOPT trials. Nothing works forever but some will surely work better- particularly if the patient is caught early enough to actually have some volume worth saving (slowing).

dr j said...

Jenny,
superb post, no wonder your penmanship led to the authoring offer!

On checking wiki re c peptide I found this and these people might have a dialogue with you

A company based in Stockholm, Sweden called Creative Peptides has secured manufacturing and other patents in a number of countries for C-peptide, and aims to commercialize it as a therapeutic. It is now undergoing human clinical trials. However since C-Peptide was discovered in 1967, patenting the peptide itself is not possible, only the processes to create it. This makes it very difficult to obtain research dollars from pharmaceutical companies to conduct research. Creative Pepides solution is to patent processes to create C-Peptide, thus making the product more profitable to invest in for pharmaceutical companies.

After delays due to lack of funding, Creative Peptides has now obtained funding based on a process that will make it possible to inject C-peptide once a week instead of daily. Stage 3 Clinical Trials are set for late 2009.

best
john
australia

Jenny said...

Injectible C-peptide is very good news for people with type 1, but for a reason that has nothing to do with making beta cells more functional.

The reason people have been demanding it is that other research suggests C-peptide plays a role in preventing neuropathy. I have blogged about that HERE.

Unfortunately, other research implicates C-peptide with cardiovascular disease:

Read it HERE

Jenny said...

Anonymous,

All the UKPDS showed was that using drugs to achieve A1cs of near 7.0% guarantees progression.

Since we know blood sugars over 140 mg/dl damage organs, and since the A1c over 7.0% ensures people spend many hours a day over 140 mg/dl, this would be predicted.


What would you think of a study that "proved" that not smoking did not prevent lung cancer, and then defined "not smoking" as only smoking 10 cigarettes a day? That's what UKPDS did with the dangerously high blood sugar level it defined as "tight control."

Use Metformin or carefully titrated insulin along with a lower carb diet that keeps your blood sugar in the normal range at all times (always under 140 mg/dl and lower if possible) and you see a dramatic difference in progression.

I know hundreds of people who have done this, many for over a decade, and their health is excellent, with no neuropathy, retinopathy or kidney changes. I'm a month away from 11 years of diagnosis and 10.9 years of carb restriction and have perfect eyes and kidneys. The only neuropathies I have come from burst vertebral discs, but I have none that are symmetrical diabetic neuropathy.

trinkwasser said...

I've only been doing it for five years but not only have NOT progressed but have reversed several symptoms. Not uncommon.

The other day I read of someone who has been Type 2 and low carbing for 39 years, also with no progression. He was lucky enough to have been diagnosed when low carb was recommended, and somehow in the meantime no-one saw fit to change his diet.