August 9, 2006

STOP-NIDDM Research on HNF4-alpha and Type 2 Diabetes

A while back, I discussed the HNF4-a gene which is implicated both in one of the MODY forms of diabetes and in the Type 2 diabetes found among Ashkenazi Jews. I speculated that because researchers were only looking at people with Type 2 diabetes diagnosed with fasting glucose tests they were missing a lot of people with HNF4-a diabetes.

This is because, from what I can determine from the MODY research I've read, defects in this gene cause beta cells not to respond correctly to incoming glucose, pushing up post-prandial blood sugars. But because the problem first surfaces in post prandial blood sugars, in milder cases the fasting blood sugar may stay below the level used to diagnose diabetes for many years while very high blood sugars follow every meal--and destroy organs. Only when the PP control is completely gone does the fasting blood sugar start to rise.

Well, what do you know? An alert reader sent me notice of a newly published research paper which found that, in fact, women in the STOP-NIDDM trial who had a defective HNF4-a gene were almost twice as likely to become diabetic over the course of the study as those who lacked it.

The paper is "The Single nucleotide polymorphisms of the HNF4-a gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial." Andrulionyte L, Laukkanen O, Chiasson JL, Laakso M.

These are researchers from the Department of Medicine, University of Kuopio, Kuopio, Finland, who earlier published an important study linking polymorphisms of this gene to Type 2 diabetes.

What does this mean for you? Just another bit of evidence that not all diabetes is necessarily caused by insulin resistance. The HNF4-a gene causes a secretory defect, rather than causing or increasing insulin resistance.

It also points out the importance of looking at your post-prandial blood sugars from time to time. Even if your doctor tells you that you are "fine" based on a fasting blood test, you need to make sure your blood sugars aren't going into the diabetic range years before your fasting blood sugars are high enough to diagnose you. By then, you'll have damaged your heart, your nerves, and possibly your eyes and kidneys.

On a related note: A visitor stopped by to post a comment saying that as a person with Type 1 diabetes he was offended that I didn't "understand" that all type 2 diabetes is caused by insulin resistance. I just want to make my point here very clear. I do not question that many type 2s are insulin resistant. But it turns out that many are not. Indeed, there is increasing evidence that secretory defects are an equal cause of type 2 diabetes, and that insulin resistance is NOT necessarily the major cause in a significant amount of type 2.

The best explanation of this is in a wonderful paper
The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity by John Gerich.

I invite anyone who still thinks all Type 2 is caused by insulin resistance to read this article and bring themselves up-to-date on what the researchers are finding.

The reason that I focus on Type 2s who are not significantly insulin resistant is because, since I started writing about this on my web site and on the newsgroup, I've heard from a surprising number of people diagnosed as Type 2, who, like me, are not overweight and who have found when they use insulin or sulf drugs that they are not insulin resistant. Since something like 20% of all type 2s are not overweight, I often wonder just how big the pool of Type 2s with secretory defects like that caused by HNF4a might be.


Lili said...

You are absolutely right. Before your website, I had never heard of MODY. Now I am pretty sure I have some form of it. The only reasons I discovered my postprandial blood sugars were abnormal are (1) I apparently have a really low tolerance for differences in blood sugar and (2) I live with a Type 1 diabetic. That was March of 2005.

Even though I came in with proof that this was happening, doctors kept saying I wasn't diabetic because my fasting blood sugar was normal. It seems that a more modern approach of looking at postprandial numbers instead of only fasting hasn't quite caught on yet. It was only through dogged persistence that I was able to get medication. Sure enough, my postprandial numbers got higher and higher. The highest has been 280 - that was on Metformin and Actos. I'm now only on NovoLog and doing great. Nothing else worked. Still, I am told at least once a week (by doctors, pharmacists, friends, strangers) that I shouldn't be on insulin because I'm a Type 2. I could scream.

I'm going to be moving soon and I'm apprehensive about having to find another endo that doesn't have their head firmly planted in the past.