A1c, glycation problems and DKA

This might be a bit of a mess but I wanted to get this information out and I figure I can clean it up a bit later.

You might have noted that I keep adding on to the ethnic KPD list. You might have also noticed the strong representation of people of color in this list. It is tempting to think that there is some aspect of melanin involved in KPD but I seriously doubt it. I tend to see color as an indicator of certain things. The first thing it indicates is global location. Fairer people tend to live in more temperate climes. Darker skinned people tend to be located in more tropical regions.

What is it about those regions. One thing is parasites and malaria. It is known that genetic tests tend to show that people with protection against malaria also seem to have higher rates of kpd. I won’t go into the genetics but typically the same genes tend to be cited and they all tend to give an advantage in handling malaria. Here’s a listing of G6PD deficiency.

Table 1. Common Hemoglobinopathies: Populations Affected, Prevalence, and Outcomes
Hemoglobin (Hb) Variant	Populations Affected	Prevalence (in the United States unless otherwise noted)	Outcome with One Abnormal Gene and One Normal Gene (Heterozygous State)	Outcome with Two Abnormal Genes (Homozygous State)
Hemoglobin S (HbS)	African Americans Hispanic Americans/Latinos Also found in East India, the Mediterranean, and the Middle East	About one in 12 African Americans has sickle cell trait 1 About one in 100 Hispanic Americans/Latinos has sickle cell trait 2 Sickle cell anemia occurs in one of every 500 African American births 1 Sickle cell anemia occurs in one of every 1,000 to 1,400 Hispanic American/Latino births 1	Sickle cell trait (also called HbAS): usually asymptomatic	Sickle cell anemia (also called HbSS disease): sickled red blood cells that interfere with circulation and decrease life span of red blood cells; can result in hemolytic, splenic sequestration, and aplastic crises and multiple complications
Hemoglobin C (HbC)	African Americans People of West African descent	About 2.3 percent of African Americans have HbC trait 3	HbC trait (also called HbAC): asymptomatic	HbC disease (also called HbCC disease): mild hemolytic anemia, mild to moderate enlargement of the spleen
Hemoglobin E (HbE)	Asian Americans, especially those of Southeast Asian descent Common in Cambodia, Indonesia, Laos, Malaysia, Thailand, and Vietnam. Also seen in southern China, India, the Philippines, and Turkey	Prevalence of HbE may be 30 percent in Southeast Asia 3	HbE trait (also called HbAE): asymptomatic	HbE disease (also called HbEE disease): mild hemolytic anemia, microcytosis, and mild enlargement of the spleen
Hemoglobin SC (HbSC)	African Americans and people of West African descent Also found in East India, the Mediterranean, and the Middle East		N/A	HbSC disease (also called sickle-hemoglobin C disease): mild hemolytic anemia and moderate enlargement of the spleen; may have blocking of blood vessels as in sickle cell anemia but milder symptoms
Hemoglobin F (HbF) elevated	Occurs in patients with hereditary persistence of fetal hemoglobin, sickle cell anemia, severe anemias, leukemia, and other conditions	About 1.5 percent have more than 2 percent HbF but some groups may have concentrations as high as 12 percent 3	N/A	Those with elevated HbF and sickle cell anemia may have a milder form of sickle cell anemia

¹ National Heart, Lung, and Blood Institute, NIH. Sickle cell anemia. Available at: www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_All.html. Posted May 2007. Accessed June 27, 2007.

² National Human Genome Research Institute, NIH. Learning about sickle cell disease. Available at: www.genome.gov/10001219. Posted February 2007. Accessed July 3, 2007.

³ Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clinical Chemistry. 2001;47(2):153–163.

http://diabetes.niddk.nih.gov/dm/pubs/hemovari-A1C/

Unless you are totally blind, you will recognize that all this information matches up with who gets KPD. It also matches up with Malaria.

Now the reason for bringing this up is about the tendency of these issues to affect the A1c. They can cause an over estimation of A1c but most typically they will cause and under reading for A1c. This is because the A1c is a measure of glycation. (basically carmelized blood cells)This measure, however, assumes that the average blood cell will be around for 90 days. What if the cell has a shorter life as it tends to have with these two issues? The number for glycation is going to be lower simply because the blood cell hasn’t been around long enough to get glycated as much. The A1c will appear to be lower.

I have already written about the ADA, diabetes and the danger to KPD’s. This needs to be tossed in. We are in serious trouble with the ADA guidelines since they sit right at the point of DKA for us but what if the test is off? We shouldn’t be anywhere near an A1c of 6.3 for safety sake. The A1c number could be 5.8 but, in truth, we could be at 6.5, which is trouble.

Here is what that trouble means. It means a continual rise in DKA admissions to hospitals with all the attendant costs. As has been noted before, there isn’t any real way to separate out KPD’s from Type 2’s but the suspicion is that greater than 50% of new onset DKA admissions are KPD’s and for all we know a good many of the Type 2’s are KPD, as well.

DKA’s Admissions per year

This graph shows a doubling of admissions in the last 25 years, basically 60,000 more than 25 years ago and it is rising. KPD’s are probably a little better than half this number. If you add the blood glycation problem with the ADA recommendations you can see how this might be the case.

Things aren’t getting any better for us and they won't get better anytime soon because they are now going to make the A1c the diagnostic tool for diabetes. For us, this is a really really bad idea.

The A1c tipping point

Whilst looking for correlations on some other things, I fell across this important information that didn't make an impression on me then but it certainly does now. I guess it shows that it's a good practice to go back with the new ideas that you've gained and look at the data again.

Even though, by my estimates, there are millions of Ketosis Prone Diabetics out there, we remain the "mystery meat" of diabetics. There is very little research about its genesis. There is no way to identify a KPD before a diabetic emergency occurs. In fact, as far as I know, very few people are diagnosed as KPD even after they have had an extreme glycemic event and recovered. We don't even know what the numbers are for KPD. I tend to believe that an A1c greater than 10 with spikes above 300 is a good indicator, especially if the fasting blood sugar was less than 140 in the previous year. That thinking and two bucks might get you a cup of coffee.

We aren't high on anybody's list of things to do. So, I think it's important to glean what facts I can from whatever data is out there to help people deal with KPD. This brings up this little fact. It has to do with the tipping point or when does KPD go from being just a type of diabetes to something that can be deadly.

Ketosis-Prone Type 2 Diabetes in Patients of Sub-Saharan African Origin

Clinical Pathophysiology and Natural History of -Cell Dysfunction and Insulin Resistance

Franck Mauvais-Jarvis,1 Eugene Sobngwi,1 Raphae¨ l Porcher,2 Jean-Pierre Riveline,3

Jean-Philippe Kevorkian,4 Christian Vaisse,5 Guillaume Charpentier,3 Pierre-Jean Guillausseau,4

Patrick Vexiau,1 and Jean-Francois Gautier1

http://diabetes.diabetesjournals.org/content/53/3/645.full.pdf

This is a study that tracks KPD's over ten years and compares them to regular Type 2's and Ketosis Prone Type 1's. This study is out of Paris done on emigrants who come mostly from Sub-Saharan Africa. I have talked or corresponded with people who question the relevance of this research to them because they aren't remotely African or descended from Africans. As I said before, this syndrome has been documented almost every. The research is very spare and I've had to cobble data from all over the world. I suggest that beggars can't be choosy. My position is that anything that says anything about KPD is relevant to all KPD's  irrespective of color or origin.


ADA Criteria for the diagnosis of diabetes
1. A1C 6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*
OR
2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
OR
3. Two-hour plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT.

Standards of Medical Care in Diabetes—2010

http://care.diabetesjournals.org/content/33/Supplement_1/S11.full.pdf+html


That being said, let's get on with it. Above I have copied the ADA guidelines for diabetes diagnosis. It's important to keep these numbers in mind. It is especially important because, as I've said, most docs have no idea about how this works so you need to look out after your needs or those you know.

Buried in the KPD paper is a graph that describes the path that relapse takes in KPD's. Though it describes relapse, I am looking at it as just the course which KPD's take before their blood sugars go awry. What is my evidence for this. Well, there is one thing but I'll get to that later. Of course, A KPD, by definition, has already been diagnosed so it very definitely pertains to those.

What they found was that the course before relapse could be predicted by A1c over a years time.  I tried to get this but it wouldn't copy. You can find it on page 650. Here's what they had to say.


The median duration between the development of hyperglycemia (HbA1c 6.3%) and the onset of a ketotic relapse was 12 months (95% CI, 6–21, Kaplan-Meier). During this period, the insulin secretory reserve, measured before the onset of hyperglycemia and during readmission for relapse, dramatically deteriorated ( C-peptide, 2.88 0.21 vs. 0.19 0.08 ng/ml; P 0.05). There was no precipitating illness other than hyperglycemia. The increase in HbA1c 6.3% was associated with an increased risk of ketotic relapse with an HR of 38 (95% CI, 5–286; P 0.0004). Thus, hyperglycemia preceded and was strongly associated with
the subsequent development of an insulin-deficient, ketotic relapse.


The chart is pretty clear. It tracks the A1c for 40 months. The A1c stays steady at around 6.3% and at about 12 months before relapse takes a slight jog up. At 6 months, it takes another jog up to about 6.6 %. From this point on, the curve becomes steep.

What you can see is that below 6.3% blood sugars remained steady. Above that number events go bad very quickly. The 6.3% averages out to a blood sugar of 134. The first jog up appears to be about 6.5%, which averages to daily blood sugar of 140. This 140 is not a random number. It is thought to be the point at which blood sugars become damaging and bring on long term complications.

My thought on this as occurring before the first episode is from some reading, which I can't find, that said it was frequent, that previous to diagnosis, a KPD would have a normal or near normal blood sugars 6 months before. This graph shows something similar. We have no idea what causes this catastrophe but the fact that its beginnings sit at this critical juncture seems to suggest that something gets broken here. What you have to recognize is that this is for people who've already broke down then gone into remission, so whatever got broken got fixed once the blood sugars were brought down.

Now look at the ADA guidelines. They've tightened them up but look how close they are to the KPD danger point. This guideline is really for T2's. Would you give this as a guideline for KPD's knowing that they can crash very quickly? If you are a KPD should you feel safe with these guidelines?

If you showed up at a doc with these numbers, the ADA recommends that the physician should inform you that you're prediabetic and that maybe you should start making adjustments with diet and exercise. You would be asked to return in 6 months for a checkup to see how things were going. This wouldn't be a problem for a Type 2 because onset isn't abrupt and acute but for a KPD these numbers should be sending off all types of alarms because in 6 months you could very well be hospitalized or at worse, dead.

Until there is a diagnostic test for KPD, we will continue to windup in emergency. For those who already know what they are; keep and eye on your blood sugars because, unlike a T2, whose numbers trend steadily, you can go off the rails very quickly.