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What is disease? Diabetes, diagnosis, and real science

ResearchBlogging.orgOne of the concepts we often discuss around here is “what is disease?” As we’ve seen in the discussion of Lyme disease and so-called Morgellons syndrome, this is not always an easy question to answer. Knowing what states are disease states does not always yield a black-or-white answer. The first step is usually to define what a disease is. The next problem is to decide who in fact has that disease. The first question is hard enough, especially in disease states that we don’t understand too well. The second question can be equally tricky. To explore the scientific and philosophical issues of diagnosing an illness we will use as a model diabetes mellitus (DM). This won’t be quite as boring as you think, so don’t click away yet. (Most of the information here refers more specifically to type II diabetes, but most of it is valid for type I as well.)More…

Diabetes

Diabetes is a metabolic disorder characterized by elevated blood sugar levels. Sometimes very high sugar levels can lead to illness and death, such as in diabetic ketoacidosis. These days, however, people rarely die from having a high blood sugar. The elevated blood sugars of diabetes cause a host of changes in the body over time, leading to two main types of problems: microvascular complications such as blindness and kidney failure, and macrovascular complications such as heart attack and stroke. The macrovascular problems are not unique to diabetics, but the microvascular complications, such as diabetic retinopathy (DR) are unique, and a good ophthalmologist can identify a likely diabetic without even checking a blood sugar level. But blood sugar levels are how we designate someone as being diabetic.

Who is diabetic?

Having diabetes puts you at high risk for the medical complications listed above. Intervening medically can reduce these risks, so knowing who is and is not diabetic is rather important. But knowing who is diabetic is not immediately obvious. Currently, the most accepted way of diagnosing someone as being diabetic is by checking a fasting blood sugar level. But blood sugar levels a very labile. It’s not clear how well blood sugar levels correlate to the risks of diabetes. This week, the journal Diabetes Care released new guidelines from the International Expert Committee which has been tasked with examining how we decide who is, in fact, diabetic.

The damage done by high blood sugars happens over time, but a blood sugar level is a brief snapshot. What clever researchers have done in the past is evaluate patients for a common complication, diabetic retinopathy, and correlate this with blood sugar values. These studies have helped us to decide who is diabetic, as they have shown us that above a certain level, a doctor can see the retinal changes of diabetes. But using a single blood sugar measurement can miss many people who are at risk for diabetes complications.

A test we’ve used for years to monitor the long-term control of blood sugar is the glycosylated hemoglobin level (HbA1C). Hemoglobin, the molecule in red blood cells that carries oxygen, will change when exposed to high blood sugar levels. Normally, about 5% of your hemoglobin is glycosylated, that is, attached to sugar molecules. These A1C molecules reside in red blood cells whose average life span is 120 days, so A1C levels generally reflect about three months of blood sugar levels.

Studies have shown that A1C levels over 6.5-7.0% are associated with increasing complications from diabetes. The International Committee reviewed the data on blood sugar as it relates to A1C, and both A1C and blood sugar as they relate to DR. They found that an A1C of 6.5% and above is closely associated with DR. Therefore, they recommend defining diabetes as having an A1C of 6.5% or above.

Implications

Changing the way we diagnose diabetes does a few things. First, it recognizes that clinicians have been using A1C levels to “diagnose” diabetes for years. It then examines this practice and finds that what we’ve been doing likely prevents diabetic complications. The other effect it will have is to “increase” the number of diabetics as we capture more diabetics with improved testing.

This is a wonderful example of how science-based medicine works. First, a plausible hypothesis is formed (A1C levels should correlate with physical changes in diabetics), looks at the evidence (A1C levels correlate well with diabetic retinopathy), and then practice recommendations are made.

Most important, however, is the realization that practice must change if the evidence warrants. This ability to change is the fundamental difference between medicine based on science, and everything else.

References

The International Expert Committee (2009). International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes Diabetes Care DOI: 10.2337/dc09-9033

Posted in: Science and Medicine

Leave a Comment (28) ↓

28 thoughts on “What is disease? Diabetes, diagnosis, and real science

  1. Newcoaster says:

    Not boring at all, in fact, I guess I was expecting a part 2.

    Such as taking a favorite non-disease of the sCAM crowd..say, Adrenal Fatigue Syndrome, or Total Body Candidiasis…and then applying the same process to it to show why we know these are NOT real diseases that require treatment.

  2. AgnosticOracle says:

    What does th distribution curve for A1C look like across the population? Is there a bump in the distribution curve corresponding to the average level for people with a discreet condition? Or is this that sufficient deviation from the mean along a normal distribution starts to cause problem?

  3. Scepticon says:

    I was thinking that the new diagnostic criteria will now produce such an increase in cases of diabetes that the crank crowd will find a “Cause” to start campaining against a la Vaccination/Autism.

  4. Fred Dagg says:

    Well done on writing on this topic. Diabetes is one of the fastest growing preventable diseases in the developed world. Whilst diagnosis may be difficult, the management of it also has its problems. There is such a strong correlation between lifestyle, i.e. diet and exercise, to the incidence of diabetes. Expecting patients to change the lifestyle habits of a lifetime is fraught with problems. Well done on the article, I appreciate the effort.

  5. zen_arcade says:

    Many, many Americans could benefit from similar examples illustrating basic scientific methodology. Not only would it improve their understanding of reality but it also might impress upon them the elegance of good science.

    Would also love to see some posts about the misuse of statistics as this seems to be a very bad habit of the CAM/pseudoscience crowd.

  6. The Blind Watchmaker says:

    “I was thinking that the new diagnostic criteria will now produce such an increase in cases of diabetes”

    Great point! The epidemic will likely have a spike in 2009 as it will now be easier to define.

  7. daedalus2u says:

    This is an interesting post, and is a good starting point to point out some issues that I have with how medicine is understood, taught, talked about and practiced. Some of it is sloppy thinking, and sloppy speaking.

    “Diabetes” is defined as elevated blood glucose. Elevated blood sugar is a symptom, which can be used to try and understand the underlying physiology, infer a differential diagnosis and from that differential diagnosis determine a differential treatment.

    PalMD says “Sometimes very high sugar levels can lead to illness and death, such as in diabetic ketoacidosis.” I think what he actually means is that sometimes very high blood sugars are associated with illness and death, but it is not the very high blood sugars per se that are the cause of that illness and death in the case of diabetic ketoacidosis. Ketoacidosis occurs because there is insufficient glucose inside of cells, not because there is too much glucose outside of cells in the blood.

    Blood sugar is high because the cells don’t have enough glucose on the inside, so physiology is putting as much glucose as it can into the blood in the futile attempt to get it into cells. Lowering glucose levels in the blood per se, won’t improve diabetic ketoacidosis. If you put a person on dialysis and removed the excess glucose from their blood by dialysis that would not fix their diabetic ketoacidosis (it would likely make it worse). You could remove the ketoacids too, and increase the pH of their blood back to normal. Changing the glucose and ketone content of the blood back to “normal” by removing the excess would pretty quickly kill the patient.

    Giving insulin lowers blood glucose and fixes ketoacidosis. The fixing of the ketoacidosis comes from getting glucose inside of cells, and the insulin does that by increasing the number of glucose transporters in the cell membrane. With enough glucose inside of cells, the cells don’t need to use ketones, so the body stops producing them.

    The underlying problem in diabetes is not enough glucose inside of cells, but the glucose level inside of cells can’t be measured, so a surrogate marker is used, the glucose level in blood. The reason that works is because there are very strong regulatory pathways that increase blood glucose levels when cells don’t have enough and are having an energy crisis. We can use elevated glucose in the blood as a marker for not enough glucose in cells because those two things are highly coupled.

    Which comes to my major beef/rant with how diabetes is described; diabetes is not deranged regulation of blood glucose, it is deranged regulation of glucose inside of cells. The regulation of glucose in the blood is working just fine. Increase the level of glucose inside of cells by giving insulin, and blood glucose goes right down. Blood sugar is still being well regulated, it is good regulation around a bad setpoint. High blood glucose is the proper response to not enough glucose inside of cells. Every time physiology does raise glucose levels that is what it is trying to do, increase the glucose level inside of cells.

    The person with diabetes who has their glucose and ketone levels lowered by dialysis is made worse off. Their underlying problem (not enough glucose inside of cells) is made worse by removing glucose and ketones by dialysis. This shows the importance of rigorous and clear thinking in the face of incomplete information.

    I think the bad definition of diabetes as “deranged regulation of blood glucose” can lead to bad treatments, such as trying to lower glucose levels by dialysis. I think the emphasis on the right “blood sugar number” is misguided. A more important number is the glucose level inside of cells, but that can’t be measured. A better number would be the glucose concentration in the extravascular space next to the cells, but that can’t be measured either. If elevated blood sugar isn’t the “real” problem, maybe treatments that lower blood glucose by methods other than insulin are actually not helpful. I suspect that is why the trial that tried to get much tighter control of blood glucose (and a low HbA1C number) had a higher death rate. Some of the methods were non-insulin based methods. How you lower blood glucose may matter a lot more than what the level is.

    It is tempting to attribute symptoms to things that can be measured such as glucose levels, especially when those symptoms correlate very well with the things that are measured, such as microvascular damage. To me, the tortuous vessels of diabetic retinopathy just “scream” low NO (which causes the characteristic flow modulated morphology). Of course there is no technique to measure that NO, just as there is no technique to measure the glucose level inside of cells. (sorry if this raises issues that are too complex for this blog post)

  8. Newcoaster says:

    Daedalus2u

    I admire your restraint, you didn’t mention your version of the fundamentalists “god-did-it” (NO) until your 10th paragraph.
    That must have been difficult for you.

  9. Fred Dagg says:

    However, no one is really mentioning how to treat it. It is managable with lifestyle changes, to a certain extent. It relates to obesity, diet and lack of exercise.
    There needs to be concerted effort made to change peoples lifestyle choices along these lines. The sceptic in me says that we will spend lots of time talking about the problem, medical and pharmaceutical management, but no one has the guts to stand up and say, “America et al, eat correctly, exercise more often, reduce weight, less big mac’s and whopper burgers!!!!!!!!!!!!!”.
    There is a public responsibility to do this, as much as sit in ones ivory towers and eulogise on the wrongs of the healthcare system!!!!!!!!!!!!

  10. JayHawkDoc says:

    Fred…

    I feel like EVERYONE is saying “America et al….”

    http://www.aafp.org/afp/20040115/editorials.html

    http://www.diabetes.org/weightloss-and-exercise/exercise/overview.jsp

    http://www.cdc.gov/diabetes/faq/exercise.htm

    It just turns out that motivating your patients to change their lifestyle is one of the most challenging (And rewarding!!) parts of being a doctor.

    The current health system does not aid primary care physicians in attaining this goal.

  11. Mandos says:

    People are saying those things all the time. The effectiveness of saying them is another thing—and the effectiveness of people trying them is another. One thing that annoys me is the viewpoint that willpower is a bottomless resource, and we can and should be able to live with hunger, and we will live better for it—if only we were morally worthy…

  12. daedalus2u says:

    Many of the fundamental problems of diabetes are related to low basal NO, NO is the major signaling molecule, so when it is out of range then signaling by NO results in good regulation around a bad setpoint, the bad setpoint being due to the basal NO level being out of range for the physiological state the organism is in.

    I have a more extensive discussion of the role of NO in causing the tortuous vessels observed in diabetic retinopathy.

    http://daedalus2u.blogspot.com/2008/10/role-of-low-basal-no-in-capillary-and.html

    Very briefly, the morphology of the vessels takes on a tortuous morphology for the same reasons a stream develops a meander. The morphology becomes coupled to the flow, and that feedback results in the characteristic morphology. In a stream, high velocity flow on the outside erodes the bank, and then the eroded sediments deposit on the low velocity flow on the inside. In a vessel, high velocity accelerated flow causes red blood cells to move closer to the outside wall (because they are denser than plasma). To couple vessel morphology to the flow and cause the observed tortuous vessel morphology, the red blood cells must either be a source of something that causes a vessel to regress, or a sink for something that causes vessels to not regress.

    Red blood cells are the sink for NO, so as NO is removed faster, the low NO causes the vessel to regress. This is the generic mechanism for tortuous vessels, not just the tortuous vessels of diabetic retinopathy. The tortuous vessels observed in systemic sclerosis are due to this same mechanism and can occur with completely normal blood glucose. High blood sugar can lead to low NO because of activation of production of superoxide.

    NO is the normal signaling molecule that regulates capillary density. When basal NO is low, physiology acts as if there is sufficient blood flow in a volume (even when there isn’t) because the “signal” the body uses to determine if a region is diffusively close to oxyhemoglobin is the NO level. If the NO level is high, the body acts as if oxyhemoglobin is unavailable and initiates angiogenesis. If the NO level is low, the body acts as if oxyhemoglobin is close and ablates excess vasculature. This is one of the mechanisms for hypertension. Low NO leads to fewer capillaries which must have the same blood flow which requires higher pressure drop.

  13. mike150160 says:

    Glycated not glycosylated…

  14. Peter Lipson says:

    Both are correct.

  15. mike150160 says:

    Willing to be corrected but I understood that what hb1AC was measuring was the result of the non-enzymatic addition of glucose (Schiff’s base and re-arrangement) to the protein and glycosylation refers only to enzymatic addition

  16. Peter Lipson says:

    I suppose what I should have said is that the terms are used interchangeably, regardless of the correct chemistry : )

  17. mike150160 says:

    Fair enough

  18. LovleAnjel says:

    “Very briefly, the morphology of the vessels takes on a tortuous morphology for the same reasons a stream develops a meander. The morphology becomes coupled to the flow, and that feedback results in the characteristic morphology. In a stream, high velocity flow on the outside erodes the bank, and then the eroded sediments deposit on the low velocity flow on the inside.”

    The end result of this process is stream beheading– the channel will cut across the base of the meander, abandoning it and creating a lake.

    Are you suggesting something erodes and redeposits tissue in capillaries? That my capillaries will form stagnant pools of fluid? Is there a floodplain in my dermis? Do older people have wider capillaries, more abandoned vessels and wider floodplains? Does my mom look like the Mississippi under her skin, and I’m more like the Des Plaines?

  19. daedalus2u says:

    It is an analogy, where the flow of fluid in the stream modifies the geometry of the path that the fluid takes, as in a stream meander.

    http://en.wikipedia.org/wiki/Meander

    The tissue is not eroded by blood flow, but for the geometry of the vessels to be modified by the flow, there must be control pathways that couple the flow to the geometry.

    Low NO is known to be pro-apoptotic. The vasculature is “well formed”, that is when there is not enough, more is generated and when there is too much, the excess is ablated. Oxygen levels are insufficient to do both tasks because the O2 level “at rest” is set by the external air, not the amount of vasculature. There is no way for physiology to sense whether or not there is excess vasculature by O2 levels.

    NO levels are sufficient; with high NO indicating the tissue compartment is too far from oxyhemoglobin and so needs more vasculature. When NO is low, then physiology acts as if there is plenty of oxyhemoglobin around and ablates capillaries leading to capillary rarefaction, a common observation in hypertension, Raynaud’s, systemic sclerosis, end stage kidney failure, dilative cardiomyopathy and other disorders characterized by tortuous vessels and also by low NO. I think that low NO is the final common pathway linking tortuous morphology of blood vessels with degenerative diseases in essentially all tissue compartments.

  20. LovleAnjel says:

    You didn’t say it was analogy, you said they worked for the same reason:

    “Very briefly, the morphology of the vessels takes on a tortuous morphology for the same reasons a stream develops a meander.”

    Clearly they do not. Erosion and deposition plays no part in capillary morphology. And I doubt the growth and death of tissue is in any way analogous to sedimentary processes.

    I would suggest you refrain from drawing analogies from systems you do not understand.

  21. daedalus2u says:

    The reason they both take on a tortuous morphology is because in both cases the morphology is coupled to the flow. As the flow changes, it changes the morphology which feeds back and changes the flow. That coupling leads to the characteristic morphology of both meandering streams and tortuous vessels.

    They are analogous in that the flow affects the morphology. The mechanism by which the flow affects the morphology in the stream meander is known.

    There must be mechanism(s) by which the flow affects the morphology in a vessel. That mechanism must be distorted under conditions that lead to tortuous vessels such that tortuous vessels form.

  22. Wholly Father says:

    @ daedalus2u

    There is a considerable body of research of the subject, and contrary to your speculation, eyes with diabetic retinopathy have elevated levels of NO. The pathways mediated by NO such as inflammation, fibrous proliferation, and angiogenesis are all part of the very destructive process of proliferative diabetic retinopathy.

    As for the tortuosity of retinal vessels, this is probably mostly a passive response to hemodynamic forces in the eye. As the transluminal pressure in a flexible conduit increases, the caliber and length increase.

  23. LovleAnjel says:

    @ daedalus2u

    You seem to be assuming that flow is coupled to morphology in blood vessels. Just because two things look similar does not mean they share characteristics. The pathways of bark-boring beetles and snails grazing on algae also look suspiciously like river or stream shapes, but no one would suggest any similarity in mechanism.

    Flow in a blood vessel is constrained on all sides by the vessel walls, this in no way true of streams or rivers. You also have scale-dependent flow effects, such that Reynold’s number, viscosity and boundary layer would have a HUGE effect on flow within a capillary, and they have virtually no effect on a stream. You’re dealing with probably 100% laminar flow in a capillary (i.e., 100% of fluid experiencing a boundary layer interaction). Tortuosity in capillaries may have more to do with finding space to grow into and filling that space efficiently.

  24. daedalus2u says:

    Tortuous vessels fill space less efficiently. In the retina, the vessels are essentially constrained to be in a 2-D plane.

    What convinced me that the morphology is coupled to the flow was this paper.

    http://www.ncbi.nlm.nih.gov/pubmed/12417376

    The images are quite compelling to me. The “empty bag” morphology consists of a tortuous vessel in an empty void. The tissue surrounding the vessel has regressed and left no trace, no scarring. That means the tissue loss was due to apoptosis (they also found markers for apoptosis). Either the vessel is a source of a pro-apoptotic signal, or a sink of an anti-apoptotic signal. NO is an anti-apoptotic signal, and the red blood cells in vessels are a sink for it. NO is known to affect HIF-alpha, which regulates VEGF which regulates angiogenesis.

    Leukoaraiosis is observed in essentially all neurodegenerative diseases, which also happen to be characterized by reduced blood flow and reduced glucose consumption. Metabolism is known to be coupled to blood flow (that is the basis for fMRI BOLD imaging). There have been observations over time of the same individuals which have show progression of tortuousity.

    Another morphology that is extremely commonly observed in diabetic retinopathy is that of “nicking”. When vessels cross, often there is a reduction in cross section at the point of crossing. Either the vessels are sources of a signal that contracts them, or sinks of a signal that dilates them. It is known that shear in vessels produces NO, and this NO is important in setting the vessel diameter by causing dilation. We know that NO gradients on the order of vessel diameter are important in regulating vessel tone and vessel diameter.

    It is known that flow causes vessels to remodel. When vessels are occluded, vessels in parallel expand and increase flow bypassing the occlusion. For the remodeling to produce tortuous vessels, the flow-remodeling signal must change with a length scale comparable to the vessel diameter. The characteristic length scale of the tortuousity depends on the vessel diameter, implying that the signal is coupled to vessel diameter.

    In the paper I cite above, the tortuousity of the vessels inside the empty cavities is of a smaller length scale than the diameter of the cavity. The flow remodeling signal can’t come from outside the empty cavity and still have a length scale comparable to the vessel diameter, it has to come from inside. Blood moving inside a vessel with tortuousity would experience inertial effects which would result in segregation of red blood cells due to inertial effects. Modest changes in red blood cell concentration do have substantial effects on NO mediated vasodilation (as in isovolemic anemia). For the red blood cells to be a source of a diffusible pro-apoptotic signal, the rate of production of that pro-apoptotic signal would have to change (that is go on and go off) as a specific red blood cell moves the length of a vessel diameter.

    We know there is a signal that affects many of the pathways involved in angiogenesis, apoptosis, and vessel tone and that signal is known to be variable on length scales the order of the vessel diameter, and that changes in hemoglobin concentration affect the concentration of that signal, and when diseases characterized by less of that signal (i.e. hypertension, diabetes) are also characterized by what appear to be flow mediated vessel morphology. Control stability considerations require that the control schemes for vessel dilation must be compatible and continuous with the control schemes for vessel morphology.

    I think it is pretty clear that NO is a big player in vessel morphology, and is sufficient to explain what has been observed and reported in the literature regarding tortuous vessels.

  25. daedalus2u says:

    Wholly Father, do you have a citation for that? There is a lot of confusion in the NO literature, where people measure nitrite and nitrate levels and use that to infer NO levels (that is an incorrect inference).

    What nitrate plus nitrite levels indicate is the production rate of NO, which is independent of its concentration.

    Similarly, the presence of nitrotyrosine is not an indicator of high NO levels.

  26. Wholly Father says:

    daedalus2u

    I won’t continue to derail this post on this matter. You should have no difficulty finding numerous references with a simple Medline of Google scholar search.

  27. daedalus2u says:

    I am aware of multiple measurements of elevated nitrite plus nitrate that have been erroneously reported to show elevated NO.

    The presence of oxidative stress, asymmetrical dimethyl arginine, endothelial dysfunction, and inflammation strongly argue against increases in NO concentration.

    I am quite familiar with the NO literature as it pertains to retinopathy, and there has been no reported measurement of elevated NO that I am aware of. I thought there might have been something I missed. In checking the literature I found this study

    http://care.diabetesjournals.org/content/30/12/3048.long

    This pretty clearly shows reduced NO levels in the retina by a reduced vessel diameter response to light flicker.

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