December 26, 2011

Mitochondrial Diabetes: Another Non-Insulin Resistant Adult Onset Diabetes

I've been reading up on mitochondria this month, in the writings of Nick Lane, Power, Sex, Suicide: Mitochondria and the Meaning of Life, and Oxygen: The Molecule That Made the World. There was a lot of interesting information in both books, but because at times Lane writes in a confused way about the relationship of diabetes and mitochondrial dysfunction, I became curious about what is actually known about mitochondrial failure and diabetes and started reading up on the subject.

It turns out that there is a distinct genetic form of diabetes caused by the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. It causes an adult onset form of diabetes that can be misdiagnosed as either Type 1 or Type 2 depending on how late the onset is. Some people get it in their 20s, while others only develop it in middle age. The average age of onset is 38 years. Whatever the time of onset, 100% of those who have this gene will eventually become diabetic, with a form of diabetes characterized by failure to secrete insulin, rather than insulin resistance.

Like all the genetic forms of diabetes, this is another case where the actual expression of the gene defect can range from very mild to severe. Some people who carry it won't develop diabetes until they are in their 60s, while others may get it in their teens and be misdiagnosed as Type 1 (though the person with it will not show the characteristic antibodies associated with autoimmune Type 1.) The actual percentage of mitochondria carrying the mutation in various tissues will vary from person to person diagnosed with it, and that may have something to do with the severity of the diabetes, as well as whether other damaging effects of the gene are present (discussed below.)

A very severe condition caused by this gene mutation is called MELAS syndrome and reading about its symptoms can be scary, as they include stroke, and a shortened life. But the good news is that now that gene testing is more widely available, scientists are now finding that many people with the same mutation have far less severe manifestations that go undetected until they are gene tested, though these other carriers may have various health problems that seem like the usual wear and tear that are actually byproducts of the gene.

Also, and very interestingly, people with this gene defect, who tend to be thin and at times shorter than their peers, prior to becoming diabetic will have completely normal C-peptide and glucose tolerance tests. However as the gene expresses in their beta cells it apparently causes the mitochondria in the beta cells to fail, leading to the death of the beta cells.

This gene is found in varying frequencies in different ethnic populations. It was found in almost 3% of a Japanese diabetic population, and in about 1% of a group of Dutch people with diabetes. The incidence was lower in those participating in the UKPDS, and in a French population--roughly .5%.

Because mitochondrial genes are passed only from the mother, the family pattern of this genetic form of diabetes appears strictly in the maternal line. Men can get it if their mothers have it, but they cannot pass it on to their children.

This gene defect also appears occasionally spontaneously, so it is possible to have it without a family history but this is very rare.

This gene defect also causes hearing loss in the higher frequency ranges which often becomes evident shortly before the diabetes appears. For that reason this kind of diabetes is also called MIDD (Maternally Inherited Diabetes with Deafness.)

People with this gene may also have a hard-to-detect problem with their heart muscles--asymptomatic cardiomyopathy--which makes it very important that they avoid Avandia and Actos, which have been proven to increase the risk of heart failure in people who take them. The sulfonylurea drugs except gliclazide are also problematic since they also seem to have a negative effect on the heart.

Changes in retinal pigmentation also present in many carriers of the A3243G mutation and they may be more prone than others to develop retinopathy, though it appears that controlling blood sugar will lessen the risk of this happening. Other symptoms which are related to the gene defect can include problems with the digestive tract including diarrhea, obstruction, and severe heartburn.

This gene defect can also cause problems with kidneys that will show up as protein in the urine but are not necessarily linked to high blood sugars, as is typical in diabetes, but are another outcome of the failing mitochondria.

In some people with this gene defect there are other manifestations of mitochondrial failure throughout the body including the inability to tolerate exercise and a frequent migraines. A smaller number have strokes at a young age. This is one reason why you would want to be screened for this gene if you do have the history of diabetes running down the maternal line of your family in conjunction with deafness.

Because mitochondrial failure can cause a rise in lactic acid, people with this form of diabetes should not take metformin as they are at risk for lactic acidosis.

If your family and personal history are suggestive of this kind of diabetes, demand that it be ruled out. It is very possible that your family doctor will NOT have heard of it, so you may have to educate him or her. If you encounter resistance (such as the doctor responding to your showing him one of the articles below by saying, "Where did you earn your M.D.?") find another doctor. This kind of diabetes because it may come with other organ problems requires that you find the support of a very good, up-to-date medical team.

The appropriate treatment for mitochondrial diabetes is insulin, as it brings about the progressive loss of beta cells over time, so it won't be fully controlled by diet. The better you control your blood sugars, the less stress you are putting on those beta cells that remain, so it's likely that very tight control--as close to normal as possible--will have some effect, and of course, it will help prevent the development of the classic diabetic complications.

I have heard from one person diagnosed with MELAS whose diabetes was being controlled with insulin but who was having trouble with her control. She reported that following the "Test test test" strategy this site recommends was helpful for improving her control. You can read about it HERE.

Though I read recommendations online that it is possible to treat milder versions with sulfonylurea drugs, this is probably a bad idea given the recent findings (published after these articles were written) that sulfonylurea drugs can harm the heart.

If you have the symptoms of this form of diabetes you should get your heart checked out by a talented cardiologist--ideally one who practices in a teaching hospital who might have heard of this syndrome, rather than one of the hacks who practices out of a community hospital and prescribes statins to everyone who walks through the door.

As is too often the case with oddball forms of diabetes, most of what you find in scanning the research is diagnostic, rather than information about how to treat the condition. That is probably because it is rare and no one will get rich treating it. If you do have this kind of diabetes it is likely that like everyone else with some form of diabetes your overall health will be better if you keep your blood sugar as close to normal as possible, which even with insulin usually requires keeping a close eye on carbohydrate intake and ratcheting it down until you are avoiding the blood sugar spikes over 140 mg/dl (7.7 mmol/L) that are known to cause the classic diabetic complications.

RESOURCES FOR LEARNING ABOUT MITOCHONDRIAL DIABETES

Mitochondrial Diabetes Molecular Mechanisms and Clinical Presentation.
J. Antonie Maassen et al.Diabetes .53.2007.S103 Diabetes February 2004 vol. 53 no. suppl 1 S103-S109 doi: 10.2337/

Epidemiology and Treatment of Mitochondrial Disorders. Patrick M Chinnery, et al. American Journal of Medical Genetics (Semin. Med. Genet.) 106:94±101 (2001)

Markedly different clinical features in 2 diabetes mellitus patients with extremely high tissue levels of the mitochondrial DNA A3243G mutation. Shinji Harihara. Gerontologia (2008) Volume: 54, Issue: 3, Pages: 168-172

Protean Phenotypic Features of the A3243G Mitochondrial DNA Mutation. Petra Kaufmann et al. Archive of Neurology VOL 66 (NO. 1), JAN 2009

December 19, 2011

Another Dangrously Misleading Study Promoting High A1cs as Healthy

A presentation given at the recent 44th annual meeting of the American Society of Nephrology claims that patients on dialysis have better outcomes when they have higher A1cs. As reported in Medscape, the chief researcher says, "The range from 6% to 9% seems to be the lower range of risk. There's even an impression that you could say that from 7% to 9% is the lowest risk."

You can read the report of the presentation here. It also got some play in the medical news and newsletters directed to doctors and appears summarized on quite a few diabetes sites. The Medscape article gives the best summary. Signing up is free:

Medscape:Diabetics on Dialysis Do Better With Higher Hemoglobin A1c.

It is all too likely that busy family doctors who encounter this information will add it to the rest of the bad research that has convinced them that it's dangerous for people with Type 2 Diabetes to lower their blood sugars to normal levels. (You can read about how misinterpreted studies have led this toxic recommendation HERE.)

To understand the real meaning of the paper given at American Society of Nephrology you have to know that other research looking into the blood sugars of people on dialysis has found that because of the impact of dialysis on their red blood cells, the A1cs of people on dialysis do not correlate to their blood sugars.

In a published review of the research that discovered the inapplicability of the A1c test to people on dialysis, the author writes
We expected maybe the hemoglobin A1c would be slightly impacted by the shortened red cell survival when we went into the study, but the results were shocking to us in that the hemoglobin A1c levels were significantly lower to where they would affect patient care and outcomes.
You can read this report here:

HbA1c Inaccurate in Diabetic Patients on Hemodialysis, Study Says Hogan, Michelle. Nephrology Times: April 2008 - Volume 1 - Issue 4. doi: 10.1097/01.NEP.0000334255.74897.99

The crucial findings of this study were:
Compared with patients who did not have kidney disease, patients with end-stage renal disease had higher mean serum glucose concentrations-172 mg/dL vs 146 mg/dL-and higher percent glycated albumin-18.7% vs 15.3%-but lower hemoglobin A1c-6.8% vs 7.3%.

For a glucose level of 150 mg/dL, for example, hemoglobin A1c was about 6.5% in the dialysis group but 7.5% in the normal renal function group.
There is another test that gives a better idea of blood sugar control over a longer time period, but it isn't available in the U.S.. What is available is testing with your blood sugar meter--which is more accurate in predicting health outcomes than the A1c ever was.

Test your blood sugar 1 hour after eating. If your level is under 140 mg/dl (7.7 mmol/L) you are in the range that research suggests will avoid diabetic complications. If you are staying over 140 mg/dl (7.7 mmol/L) for more than an hour or two you are raising your risk of complications. The more time spent over that level, the more likely it is that you are damaging your organs.

The damage doesn't start immediately, and most of us will see occasional readings over that level from time to time that, if they are isolated events, aren't likely to cause damage. But if we are seeing them every day, it's time to take action.

If you are on dialysis, you will want to rely on what you see when you test your blood sugar after meals, not the A1c, to ensure that you aren't worsening whatever other diabetic complications you already have by maintaining damaging high blood sugar levels.

And if you aren't on dialysis and want to keep your nerves, kidneys, eyes and heart healthy, don't let any doctor tell you that it's dangerous to lower your A1c below 6.5%. The evidence suggests that it is not only safe, but very healthy to lower your blood sugar to normal levels, as long as you aren't doing it using Avandia, Actos, Glipizide or Glimiperide all of which have been shown to damage the heart.. The one other "dangerous" way to lower blood sugar is to use insulin in such a way that you balance high blood sugars with hypos. If you are using insulin but never see hypos below 60 mg/dl (3.3 mmol/L) you have nothing to fear.

If you avoid these known dangerous drugs and use carb restriction, metformin, and/or insulin dosed correctly to lower your blood sugar, especially if you start close to diagnosis (or in the pre-diabetic stage) before long term exposure to high blood sugars have damaged your heart, nerves, and blood vessels, your long term outlook should be very good.

And if your doctor disagrees, find a new doctor. Only doctors whose knowledge of diabetes is gleaned only from dumbed down one-paragraph newsletter summaries--or from perky drug company reps who encourage doctors to keep patients at high A1cs because their expensive new drugs only achieve higher than normal A1cs--believe that lowering A1c to normal levels is dangerous.