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.

Increased weight and insulin resistance revisited

This relates to a baffling previous post.Here This was puzzling because it involved KPD diabetics gaining weight after a DKA event and becoming normoglycemic. I've discussed remission in KPD's before and though the mechanism isn't well understood, it is known to be common enough to be considered a part of the KPD syndrome. No, what upset the apple cart here was that thin KPD's did not do as well as the ones who gained weight. This seems counter to all the advice about weight loss that is given to diabetics. Almost the first thing a doctor will say to a patient is to lose weight. If a KPD followed this advice their blood sugars would rise and lowering blood sugars is central tenet of all things diabetic. What the heck is going on here?

I am now going to put forth an idea that popped into my head after reading a post by Ned Kock over at Health Correlator. Here What got my attention were people who were heavy but were more insulin sensitive then their control group. What was even better: once they received medication they began to lose weight but became more insulin resistant with a rise in blood sugar.

Insulin Resistance is very much at the heart of obesity and thinness as far as I can see but it is also one of the central aspects of Ketosis Prone Type 2 diabetes. Pal Jabekk speaks of the fact that insulin resistance is a body wide behavior. I agree given insulin's importance in energy metabolism obviously everything has critical involvement with it. This doesn't, however, mean that insulin is used at the same rate through out the body all the time. At any given moment, there will always be some systems that are more or less resistant.

This brings me back to the puzzle of KPD weight gain while at the same time reaching near normal blood sugars. First of all KPD's are infamous in the fact that weight is not an issue. Just as many KPD's are thin as obese. Some have separated this along the lines of those who lack sufficient insulin so that they become thin and those who have plenty so they become fat.

When the DKA or severe ketosis event occurs KPD's, who recover, are shown to have a low normal reading of C-peptides. The cut off that has been cited is .9. In six months, it is common for this to go back into the normal range and higher. It is also known that KPD's recover near normal blood sugars even though their measurable IR isn't reduced one jot. It should be noted, as well, that the best blood sugars tend to go to the heavier KPD's and not the thin ones.

Given that the IR is still high, the  C-pep is normal or above and the blood sugars have normalized, we have to assume that there is relatively enough insulin present. What is the difference between thin and obese?

Now the leap of faith. It has to be relative insulin sensitivity issues. We can see with a thin person that insulin is putting relatively more energy in other systems besides fat. What those systems are we really don't know. What we can tell, however, is those systems on the whole are more sensitive to insulin than fat. Likewise, if the person is putting on weight then their adipose is relatively more sensitive to insulin than other body systems.

Now my thinking about the KPD's gaining weight with better A1c's. I believe fat works better for glucose storage then muscle or other systems. You can look at obesity as the body's way to reacting to high amounts of glucose. This is why I believe there are so many heavy people. Obviously, the body is sending glucose everywhere but the fat cells seem to get more. If we make this about controlling blood sugar then the fat cells become like the catch basin for the extra glucose in the system.

A thin KPD is relatively more insulin resistant in the fat cells, and this is why I say fat works better, sending glucose to other systems with fat lower down on the list doesn't normalize blood sugars as well as those who can send it to fat. So thin KPD's are typically not going to have blood sugars as good as heavier KPD's. This would also say that thin KPD's are more at risk of relapse to DKA then heavier KPD's. I would also add that this probably isn't how normal people work but we have broken metabolisms. Our livers are pretty much blind to insulin.

Multi-Tissue resistance in KPD's

I've been away doing research and other things but now I'm back.

KPD's don't have enough insulin therefore the body hovers at a high bg level. I originally was going to write another piece about the oddness of KPD and weight gain and then obtaining acceptable levels of blood sugar but I thought I had published this piece.  Sorry, I'm doing it now.

It has been noted that insulin resistance is a big part of being Type 2. This is why many Type 2's have high insulin numbers because the pancreas has to put out more insulin to overcome this resistance. KPD is Type 2, at least most of the time. What they have found to be different about KPD's is that all systems in the body seem to have relatively high insulin resistance.

This is the first investigation of diabetic patients in a metabolic state close to normoglycemia without insulin treatment. The multiorgan insulin resistance observed in near-normoglycemia suggests that these defects are primary rather than secondary to the diabetic state.
Multitissue Insulin Resistance Despite Near-Normoglycemic Remission in Africans With Ketosis-Prone Diabetes
SIMEON-PIERRE CHOUKEM, MD, EUGENE SOBNGWI, MD, PHD, LILA-SABRINA FETITA, MD, PHILIPPE BOUDOU, PHD, ERIC DE KERVILER, MD, YVES BOIRIE, MD, PHD, ISABELLE HAINAULT, PHD, PATRICK VEXIAU, MD, FRANCK MAUVAIS-JARVIS, MD, PHD, FABIEN CALVO, MD, PHD, JEAN-FRANC¸ OIS GAUTIER, MD, PHD
DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008
http://care.diabetesjournals.org/content/31/12/2332.full

Table 2—

Metabolic parameters and indexes of insulin action

	KPD	Control subjects	P
Fasting plasma glucose (mmol/l)	6.3 ± 0.2	4.9 ± 0.1	<0.001
Fasting plasma insulin (μU/ml)	9.4 ± 1.9	6.7 ± 1.0	0.33
Insulinogenic index (mU/mmol)	4.6 ± 0.9	21.3 ± 5.4	0.001
HOMA-IR	3.1 ± 0.6	1.1 ± 0.2	0.005
SSPI1 (μU/ml)	20.9 ± 3.3	17.4 ± 1.2	0.82
SSPI2 (μU/ml)	189.6 ± 20.5	181.5 ± 14.8	0.89
TGD (mg · kg−1 · min−1)	7.5 ± 0.8	10.5 ± 0.9	0.018
TGD × insulinogenic index	28.1 ± 4.0	193.3 ± 46.1	<0.001
bEGP (mg · kg−1 · min−1)	4.0 ± 0.3	3.0 ± 0.1	0.001
rEGP1 (mg · kg−1 · min−1)	1.6 ± 0.2	0.6 ± 0.1	0.004
bEGP × FPI (mg · kg−1 · min−1 · mU · l−1)	35.9 ± 7.2	20.7 ± 3.6	0.04
rEGP1 × SSPI1 (mg · kg−1 · min−1 · mU · l−1)	33.2 ± 7.2	10.9 ± 2.8	0.006
rEGP2 × SSPI2 (mg · kg−1 · min−1 · mU · l−1)	50.3 ± 22.1	0	0.007
Fasting NEFA (μmol/l)	1,936.7 ± 161.4	1,230.0 ± 174.1	0.002
SSNEFA1 (μmol/l)	706.6 ± 96.5	381.6 ± 55.9	0.015
SSNEFA2 (μmol/l)	187.8 ± 27.7	116.1 ± 11.2	0.05
Fasting IRNEFA (103 · μmol · mU · l−2)	17.7 ± 3.2	8.0 ± 1.7	0.009
IRNEFA1 (103 · μmol · mU · l−2)	17.4 ± 4.6	6.9 ± 1.4	0.05
IRNEFA2 (103 · μmol · mU · l−2)	40.2 ± 9.2	21.2 ± 2.6	0.06

• 
  
  Data are means ± SE. SSNEFA, steady-state nonesterified fatty acid; IR_NEFA, insulin resistance index to NEFA disappearance (₁ and ₂denote the last 20 min of the first and second steps of the glucose clamp, respectively).

I'm not going to go through all these numbers but they are meant to represent calculated indexes of insulin resistance. It would have been nice, if the comparison had been made to regular Type 2's. It would have been great, if they could have tested this before people went DKA but, as you know, there is no way to distinguish KPD before it occurs. It suffices to say that, metabolically, we aren't the most normal group on the planet.
If you look at these numbers and toss in glucose toxicity, you can get an idea of why we go DKA quickly. 


Despite an increasing number of reports of ketoacidosis in populations with Type 2 diabetes mellitus, the pathophysiology of the ketoacidosis in these patients is unclear. We therefore tested the roles of three possible mechanisms: elevated stress hormones, increased free fatty acids (FFA), and suppressed insulin secretion.
Conclusions  At the time of hospital presentation, the predominant mechanism for ketosis in KPDM2 is likely to be greater insulinopenia.


Pathophysiology of ketoacidosis in Type 2 diabetes mellitus
P. Linfoot , C. Bergstrom and E. Ipp    Diabetic Medicine   Volume 22 Issue 10, Pages 1414 - 1419

http://www.ncbi.nlm.nih.gov/pubmed/16176205


The question I have is: when did this start? Is this part and parcel of our lives as youths? Have we always been KPD and it took bad diet to get us here. There is plenty of documentation that this is present in the young. 

Emerging Epidemic of Type 2 Diabetes in Youth,  but once 

again more research needs to be done.


Purely from an anecdotal perspective, looking back at my childhood and viewing my present day symptoms, I would say they were present then. The problem is we really don't know what KPD is. It is described by its most dramatic symptom, which is its acute presentation. What is going on before that? Is it the same syndrome in children? How insidious is it? What is the continuum of its behavior?