- 00:00 Introduction
- 00:35 Random Glucose, Fasting Glucose, Glucose Tolerance Test
- 03:03 Hemoglobin A1c
- 08:26 Fructosamine and Glycated Albumin
- 10:50 Continuous Glucose Monitoring
- 15:44 The Overlooked Issue of Insulin Resistance
- 19:11 Summary
- On Measuring Glycemic Control:
- Hyperglycemia defines diabetes and drives microvascular disease, therefore we need to be able to accurately measure it.
- Many current techniques used for glucose measurement are flawed:
- Hemoglobin A1C:
- Hemoglobin A1C = Hemoglobin bound to glucose in a concentration-dependent fashion
- Hemoglobin A1C is influenced primarily by two variables:
- Glucose Concentration: The diabetes measure we actually WANT.
- Duration of exposure of hemoglobin to glucose: UNRELATED to diabetes but is impacted primarily by the “lifespan” of a hemoglobin molecule.
- For the average person, one molecule of hemoglobin lasts 120 days in circulation, the same lifespan as an RBC.
- Any process that impacts RBC turnover will thus alter the average lifespan of an RBC in circulation.
- Increased RBC production→ More new, unglycated RBCs in circulation → falsely LOWERS A1C
- Decreased RBC production → More old, glycated RBCs in circulation→ falsely INCREASES A1C
- Glycated Proteins: An Alternative to Hemoglobin A1C:
- Two assays used in clinical practice:
- Glycosylated protein measurement, like hemoglobin A1C, suffers from the similar flaw of being influenced both by glucose levels AND by its (protein) lifespan:
- States of protein loss, i.e, proteinuria, will result in increased protein production in the liver and decreased average circulating protein age, therefore falsely LOWER fructosamine levels.
- Continuous Glucose Monitors:
- Wearable device that measures glucose concentration every few minutes and can provide detailed data, including average, fasting, and post-prandial glucose.
- Superior to any other method for glycemic control measurement but often expensive and not adequately covered by insurance.
- CGM, as compared to usual care, has been shown to improve glycemic control in patients with Type 2 Diabetes on basal insulin.
- The Often Overlooked Issue of Hyperinsulinemia:
- Glycemic control can help reduce microvascular complications (retinopathy, neuropathy, nephropathy) of diabetes.
- Meanwhile, hyperinsulinemia and insulin resistance are associated with macrovascular/cardiovascular complications, whose rates are largely unaffected by achieving glucose control alone.
- Literature also suggests that hyperinsulinemia contributes to risk for cancer and Alzheimer’s disease
- Most of the traditional assays (random glucose, fasting glucose, A1c, glycated proteins, continuous glucose monitoring) discussed in this episode ONLY measure degree of hyperglycemia.
- The glucose tolerance test does help measure insulin resistance, but only indirectly. Again, it involves a tedious procedure often not performed in routine practice.
- Treating hyperinsulinemia involves lifestyle modification and possibly new pharmacological agents such as GLP1 agonists.
Dr. Cary Blum: Hi, I’m Carrie Blum. I’m a primary care doctor.
Dr. Greg Katz: And I’m Greg Katz. I’m a cardiologist and also like to think of myself as an internist.
Dr. Cary Blum: And welcome to mind the Gap on A1C and measurements of glucose control.
Dr. Greg Katz: Today we’re gonna briefly dive into the history of glucose measurements and how we came to use the hemoglobin a1c, and we’ll also unpack some of its limitations.
Dr. Cary Blum: And then we’ll talk about some of the newer kids on the block, fructosamine, glycosylated, albumin, and continuous glucose monitors.
Dr. Greg Katz: And lastly, we’ll get into a little bit about the big picture about what glucose measurement does and does not tell us. If you were to walk through, before hemoglobin a1c, what were the original mechanisms of deciding does this patient have diabetes, or does this patient not have diabetes?
Dr. Cary Blum: So in order to diagnose diabetes, it became clear that what we really needed to do was measure glucose. But the problem with that is that glucose fluctuates a lot. So there’s really three options you have. You can do a random glucose, you could do a fasting glucose, or you could do a glucose tolerance test. The problem with random glucose is that you need to do it a lot in order to get a sense of how high and how low it gets, you know, around mealtime. Fasting glucose, of course, is helpful but you only see half the picture, so you’re not gonna see how much hyperglycemia is in the postprandial state. And a glucose tolerance test can be very tedious because it involves having multiple blood tests over many hours. But it does provide good information in both a fasting and a postprandial glucose measurement.
Dr. Greg Katz: And I would also argue that the fasting glucose particularly will miss a fair amount of patients because that’s like the last thing that becomes abnormal, right? Right. You have have the postprandial hyperglycemia that very much precedes the fasting hyperglycemia for patients. And so if all you’re doing is checking a random fasting glucose, there’s a huge group of patients who will have really abnormal responses to a glucose load that are just not captured by that test.
Dr. Cary Blum: Yeah, that’s a really good point. That comes into medicine a lot. You know, like for example, when patients are on steroids which causes insulin resistance, the primary thing that you see is the postprandial spikes of glucose as opposed to fasting glucose elevations. And similarly, when you start a drug like a GLP one agonist, whose mechanism is primarily by reducing insulin resistance, the first thing you see is a reduction in the postprandial spikes. Sort of more than the fasting.
Dr. Greg Katz: As you’re talking about each one of these has benefits and drawbacks, it’s not surprising that we started to converge on on other tests that gave us a better sense of how this thing that bounces around over time was actually doing on average, rather than at these momentary snapshots.
Dr. Cary Blum: Right, because yeah, cuz if you could get all of the measurements just average together because we took a finger stick every minute you know, and then average those numbers together, then that would be a really helpful number to have. And, and hence the birth of hemoglobin a1c.
Dr. Cary Blum: And so we’re so used to taking the term A1C and using it to connote the average of how something has been over a period of time. And so you’ve probably heard a cardiologist refer to the left atrial size as the hemoglobin A1C of the heart. Or, or geriatrician, talk about toenail length as an hemoglobin A1C of functional independence. But understanding the limitations of an A1C is just insanely important. And so what else besides glucose should we be thinking about when we think about what that hemoglobin A1C value ends up being? We really should be thinking about any process that influences red blood cell lifespan. So you really have two sides of the coin here. You have decreased red blood cell lifespan, which happens when you’re losing red blood cells and your bone marrow is working hard to make new ones. You’re gonna have a lot of young red blood cells and circulation, and then they won’t have had enough time to get glucose attached to them. Uh, and then on the other side of the picture, you may have processes that slow down bone marrow production where your red blood cells are not being pumped out. You have, on average, slightly older red blood cells have been hanging out in circulation for a long time and have had more time to get glucose attached to them.
Dr. Greg Katz: So Carrie, walk us through some of the things that we need to understand that will affect what the hemoglobin A1C value is, and that may be in the realm of things that we need to ask our patients, or it also may be in the realm of things that we need to do a more thorough chart review to look for.
Dr. Cary Blum: Well, first you have to sort of think about processes that result in red blood cell destruction, right? So the classic ones are sort of bleeding and hemolysis, and as you might imagine, red blood cells being killed off by these processes, results in a compensatory reticulocytosis. And then, so on average, you’re gonna have a lot of young red blood cells in circulation under those circumstances. And even if you have high glucose, because that molecule of hemoglobin has not been around very long, your A1C is not gonna be super high. In fact, it’s gonna be falsely low.
Dr. Greg Katz: And then so you have false reassurance in those situations, right?
Dr. Cary Blum: Exactly. Yeah. So that and. I actually have a pretty good example of that. One of my residents was following a patient who had very longstanding, poorly controlled diabetes. She was on insulin but really had issues with adherence. Um, and was coming in with a lot of similar complaints as prior visit. Mostly complaining of fatigue that had been hypothesized to be related to her poor diabetes control cause she was telling us all about these finger sticks that were like in the 300. So we got an A1C, and when it came back much lower than her last one, like in the sixes, that ultimately led us to add on a CBC to the lavender top A1C that we drew. And low and behold, hemoglobin was newly, severely low, and that explained her her fatigue. After a little bit more workup, we diagnosed her with autoimmune hemolytic anemia, and unfortunately, she required steroids, which made her diabetes terrible, but at the end of the day, she ended up in remission from that. We got control of the diabetes again, and at the end of the day, the first sign of her having a new hemolytic anemia was an unexpectedly low A1C.
Dr. Greg Katz: It’s wild. Yeah. And so hemolysis, like you said, is certainly one of the things that commonly causes a falsely low A1C. And then on the flip side of that, it’s also the things that falsely raise the A1C.
Dr. Cary Blum: The classic one, I think, of the processes that lengthen the average red blood cell lifespan. Most red blood cells, you know, can’t live longer than 120 days because they get fragile and they die. But if you have a process such as like acute leukemia, that happens relatively quickly and results in bone marrow failure, then your reticulocyte number is gonna be rather low, and your average age of your circulating red blood cell will be greater than 60 days. Um, went actually saw a case of that when I was in residency working on the oncology service. That was a patient who transferred from a different hospital with a new diagnosis of acute leukemia. And as you sort of did a chart review going back, probably the first evidence of her having any process was that her A1C went when she went to her primary care doctor right before the hospitalization, about a month before actually. And I looked at the comments from the PCP and it was all about how the patient had actually been making a bunch of lifestyle changes to help control her diabetes better. So, you know, that story didn’t really make a lot of sense. You know, she’s dieting, she’s eating less candy, yet her A1C went from, you know, the mid sixes to the mid eights. And lo and behold, really the process that was driving that unfortunately was, was leukemia.
Dr. Greg Katz: If I had to summarize the key limitations of the hemoglobin A1C test, it’s that you need to understand the physiology of what that test shows, which is the exposure of hemoglobin to glucose over time. And so anything that changes the lifespan of hemoglobin or changes the levels of glucose is going to alter the hemoglobin A1C. And so you can often kind of think through the pathophysiology here in a way that helps the patient makes sense to you and understand what that A1C is actually reflecting.
Dr. Greg Katz: Thinking about the flaws with hemoglobin A1C has led other researchers and other clinicians to use other measurements like fructosamine and glycated albumin. And so help us understand fructosamine or glycated albumin
Dr. Cary Blum: Fructosamine and glycated albumin are basically the same thing as hemoglobin A1C in that they are ways to measure average glucose by seeing how much glucose binds to these proteins over time. So just like hemoglobin, if albumin is in circulation, you have high glucose levels, you’re gonna have more glycosylated albumin. Unfortunately also just like hemoglobin, processes that affect protein lifespan. For example, the classic one being nephrotic syndrome, where proteins are being lost and pumped out of the liver at a very high rate, you’re gonna have very young proteins in circulation, not enough time to bind to glucose, and a glycated albumin that is not reflective of the true average glucose.
Dr. Greg Katz: So, spell out some of the specific limitations of fructosamine and glycated albumin a little bit more.
Dr. Cary Blum: It is worth pointing out that fructosamine and glycated albumin reflect a shorter timeframe of average glucose because the average proteins only in circulation for about two to three weeks. So, therefore it really lacks the power to estimate over, over several months and you’re really looking at just a few weeks. That’s one issue. The other issue, of course, is that most studies have not looked at fructosamine or glycated albumin as cutoffs or as as markers, and so therefore there’s less evidence base supporting their use. There are sort of rough I guess conversions from hemoglobin A1C to fructosamine that can be used to sort of back calculate the patient’s average glucose. But it gets a little bit messy.
Dr. Greg Katz: Okay. So to summarize, fructosamine and glycated albumin are basically measuring glucose bound to protein. Fructosamine is this heterogeneous group of proteins and albumin is albumin. And the two issues here is that proteins have a shorter half-life, and so it reflects a shorter timeframe of average glucose than hemoglobin A1C. And just like A1C, these metrics are going to be affected by anything that changes the lifespan or production of proteins.
Dr. Cary Blum: You know, it’s possible, Greg, that in like 20, 30 years down the line, all the stuff that we’ve been talking about today so far with A1C and fructosamine, it’s all gonna be completely irrelevant. Cause now we have these continuous glucose monitors or CGMs as they’re known.
Dr. Greg Katz: It’s like doing a finger stick over and over and over and over again in infinitesimally, tiny intervals or otherwise, you’re measuring the glucose continuously from the interstitial space. And CGM you can always work backwards and you can impute an A1C from what the average glucose is. You can also see glucose excursions post-prandially and see what the impact of everything that you eat is on your serum glucose. But the A1C and the fructosamine and the glycated albumin, the finger stick, all of these things, these tools that we have are insanely limited. And what they’re, they’re trying to do is figure out exactly what a continuous glucose monitor gives you. And you know, Cary, there’s pretty good data that says a CGM is better than the tools that we have now.
Dr. Cary Blum: Yeah. And honestly, a CGM works just about as well as Januvia. You know, there was a randomized control trial that came out not too long ago where they randomized patients, on basal insulin to CGM versus no CGM. And the average A1C in the CGM group actually dropped by almost a point.
Dr. Greg Katz: Yeah. And so part of that is probably that folks can get a better sense of what their glucose is and then manage their insulin levels, specifically related to where their glucose is. But I think that another part of a continuous glucose monitor is the way it helps you Hawthorne affect yourself because you know that no matter what’s going on, you’re going to know what your sugar is, and that is gonna affect your physical activity levels. It may affect your dietary choices, just by virtue of knowing that when you pick up your phone, you’re gonna get a readout for what happened to your glucose over the last 10 minutes or 15 minutes.
Dr. Cary Blum: Yeah. I think that’s hugely motivating. Honestly, I have a lot of patients who just hate to see those numbers in the 200s, and having access to that information really can help change their lifestyle. I think this really sort of illustrates the principle that knowledge is power and knowing where you’re at is really the most important thing to attain control.
Dr. Greg Katz: One of the challenges with CGM in practice is it’s a pain in the butt to get for our patients because it is expensive and it’s often not covered, and it’s a little bit onerous to go through the paperwork of helping our patients obtain it. I would advocate that if we know that there’s a tool that’s better than what we currently have to date, we need to be trying to push the envelope so that our patients who need better ways of monitoring glucose have access to that. And I think that we’re the first people that it starts with. And so the onus is on us to make sure that we’re talking about this and mentioning it to our patients and going through the annoying motions of filling out those prior authorizations and having conversations with the annoying insurance people that we don’t actually want to talk to.
Dr. Cary Blum: Couldn’t agree more. And you know, like I actually cited that article in, in one of those prior authorizations. And lo and behold, my patient received her continuous glucose monitors. I’m not sure if it had anything to do with the citation, but it certainly helped her diabetes control.
Dr. Greg Katz: And when we’re thinking about the types of advocacy that we wanna do, making sure that our patients who are most in need have access to the tools that our wealthiest patients do is certainly something that, we should be putting our energy and our focus into emphasizing.
Dr. Cary Blum: Absolutely. I mean, a high value care often involves increasing prevention. If getting a CGM is gonna keep even one out of 10 diabetes patients from being out of the hospital, I think that’s an investment that, you know, people would be worth taking.
Dr. Greg Katz: Out of the hospital or avoiding retinopathy or neuropathy or any of the other -opathies that happen from chronically elevated glucose, you know. The evidence is pretty clear at this point that it’s better than the tools that we have now.
Dr. Greg Katz: Whenever we’re talking about measuring glucose, One of the elephants in the room is whether a glucose centric view of diabetes is actually the right way to be thinking about it. And the question that I have is whether we should be a little bit more insulin centric rather than just glucose centric. Because there’s two pathophysiologic processes that drive the problems in diabetes. One is high glucose, the other is high insulin and insulin resistance. Everyone’s heard multiple lectures talking about the difference between the microvascular complications of diabetes, where the risk is really reflected by what someone’s average glucose is over time, and the macrovascular complications of diabetes, which so many studies have found controlling the glucose better doesn’t actually have that much of an impact on, and probably to some extent it’s because the macrovascular complications of diabetes are driven by the effects of hyperinsulinemia and insulin resistance and the way that that drives dyslipidemia and accelerates atherosclerosis. And so I’m really always struck by the way that we spend so much time and we are so precise about the strengths and weaknesses of every single glucose measurement that we have, but we don’t really have a method of assessing the way that insulin resistance is playing a role here.
Dr. Cary Blum: Yeah, leave it to the cardiologist to bring it back to how none of this really matters. But no, seriously, actually, I agree with you completely. I think that’s the other half of the picture that’s missing. You know, everybody with type two diabetes by definition has insulin resistance before they even develop hyperglycemia. And so beginning to measure that and figuring out, you know, who would benefit from additional exercise, more sort of strict diet. And these days, you know, the GLP one agonists, which can help sensitize patients to insulin. I think that’s probably the future of where this is going.
Dr. Greg Katz: Yeah. Everyone has seen the lipid panel of a patient with diabetes, with the low HDL and the high triglycerides and the LDL that doesn’t seem like it’s really capturing what their cardiovascular risk is. And the reason that the lipid panel looks like that is at least partly because of the effects of hyperinsulinemia and insulin resistance. And so when we think about dyslipidemia in patients with diabetes, it’s a mistake to discount the role of insulin and the way that that impacts the abnormal lipid panel and the way that it accelerates atherosclerosis. And ultimately the way that it all causes the macrovascular complications of diabetes. And the reason that we care is because our patients with diabetes, most of them at least die of cardiovascular disease. And that side of the equation in diabetes, the macrovascular complications until very recently was never really impacted by any of the glucose lowering drugs that we have.
Dr. Cary Blum: And, you know, correct me if I’m wrong, Greg, but just drawing from previous episodes, I guess the other surrogate markers that we use to identify insulin resistance are abdominal girth, low HDL, for example, or high triglycerides may all be things that we’re looking at, even if we’re not directly measuring insulin levels.
Dr. Greg Katz: Yeah. Metabolic syndrome is insulin resistance and you know, you can draw a lot of specific distinctions between what one means and what the other may mean. But ultimately, when I hear metabolic syndrome, I think insulin resistance and that means that the patients who have insulin resistance are at increased risk of cardiovascular complications, increased risk of malignancy, increased risk of neurodegenerative diseases like Alzheimer’s. One of the proposed pathophysiologic mechanisms is the way that chronic hyperinsulinemia drives cell growth, which increases malignancy risk and the way that insulin resistance in the brain impacts the likelihood of somebody developing Alzheimer’s disease. And so this is the kind of thing where we don’t necessarily trend biomarkers to evaluate for how these things are how the risk of cancer or Alzheimer’s is impacted by diabetes. But it’s a real mistake to neglect the fact that our patients with diabetes are at higher risk for these other really serious illnesses. And so keeping that in mind, when you’re thinking about how do you manage a patient in my view, is really, really important and is not captured by all of these fancy tools that we have to evaluate somebody’s glucose.
Dr. Greg Katz: So you know, over the course of this episode, we talked about a lot. We talked about ways of measuring glucose and the positives and negatives of each of those methods to assess the control of our patient’s diabetes. We talked about A1C, which is gonna be influenced by anything that affects the lifespan of hemoglobin or the lifespan of a red blood cell. We talked about fructosamine, about glycated albumin, which are gonna be influenced by things that alter the lifespan of those proteins. And then we honestly talked about the future, which is continuous glucose monitoring for all. And continuous glucose monitoring we’re going to look back in five years or 10 years, or maybe a little bit longer, and we’re gonna wonder how barbaric it was that we lived in this age where we had to use all of these surrogates for glucose when we could just be measuring it directly. And you know, lastly, we sort of touched a little bit on the fact that diabetes has two major things that are going on pathophysiologically that cause problems. One is high glucose, which obviously is bad and causes every single -opathy that you can think of related to diabetes. And then the other is the sort of insidious effect of chronically elevated insulin levels and the way that that influences cardiovascular disease through dyslipidemia and accelerated atherosclerosis, and the way that that influences the risk of other chronic diseases related to diabetes, like cancer and neurodegenerative disease. And so glucose monitoring and glucose measurement only looks at the first one. And the second one is really something that isn’t ready for primetime in terms of how it applies to clinical care.
Dr. Greg Katz: All right, and that’s it for today’s episode. If you found this episode helpful, please share with your team and colleagues and give a rating on Apple Podcasts or whatever podcast app you used. It really does help people find us. Tweet us, leave us a comment on our website, Instagram or Facebook page.
Dr. Cary Blum: Thank you to Yichi Zhang for the audio editing and as always, we love hearing feedback, so email us at firstname.lastname@example.org. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.
Dr. Greg Katz: Listening to this podcast does not constitute the formation of a doctor-patient relationship, and nothing that you heard should be construed as personalized medical advice.
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Tags: CGM, Continuous Glucose Monitors, diabetes, endocrinology, Fructosamine, Glucose monitoring, Glycated albumin, Hemoglobin A1c, Hyperinsulinemia