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.


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


Zoe said...

Thanks so much for this posting. It sounds a lot like me, my sister and my grandmother, who died young from a stroke. We all got diabetes in our early 40's. How would I go about getting the genetic test done?

Jenny said...


You'd probably need to see an endocrinologist who practices out of a major teaching hospital as my experience is that many local doctors have never heard of these rarer forms of diabetes.

You might try supplementing with Coenzyme Q10. The CVS brand has been tested and found to contain the chemical and it's reasonably priced. Someone with mitochondrial diabetes posted on my Blood Sugar 101 FaceBook page that the NHS in England pays for CoQ10 for people diagnosed with mitochondrial diabetes and that it seems to help.

Other than that, you need to do the same things other people do with diabetes--strive to get normal blood sugars, which you can do by cutting back on your carbohydrate intake. Strokes are not uncommon among people with regular Type 2, but lowering your blood sugar with diet rather than drugs might be very helpful in avoiding them.

Zoe said...

Hello again.
One other question. If I tested positive for having the antibodies typically associated with Type 1 diabetes, would this rule out this mitochondrial diabetes? Also I have had diabetes for 12 years and my hearing is fine...
Are there any places to lead me to further research my kind of female inherited adult onset variety?
Today, I discovered your blog and today I have ordered your book. I feel like a lucky woman.

Jenny said...


If you have the antibodies for Type 1, you have Type 1. There wouldn't be any antibodies in Mitochondrial diabetes as it is not caused by an attack on the beta cells but by failure of the mitochondria to burn glucose properly.