February 3, 2015

Metabolic Theory of Cancer: Cancer Cells are Sugar Junkies

“One of the most common and profound phenotypes of cancer cells is their propensity to utilize and catabolize glucose at high rates.” (Mathupala et al, 1997)

“The higher the glucose levels, the faster the tumors grew. As glucose levels fall, tumor size and growth rate falls.” (Seyfried et al., 2012)

“Hyperglycemia was also directly linked to poor prognosis in humans with malignant brain cancer.” (Seyfried et al., 2012)

Cancer cells are sugar junkies.

If those five words, strung together in that order, are a surprise to you, then you haven’t been paying much attention so far. If you’ve been keeping up with the previous posts in this series on the metabolic origins of cancer, you will have seen this coming a mile away. (Or, rather, four or five blog posts away.)

Cancer cells love glucose. They need glucose. And they do everything in their power to suck up as much of it as they possibly can, even at the expense of healthy tissue elsewhere in the body. Short of actually taking control of the motor functions of your arms and hands in order to pour you a giant bowl of sugar-frosted breakfast cereal and cram it down your throat, cancer cells do everything they can to ensure they have access to a never-ending supply of glucose. 

In the past few posts, we’ve looked in detail at the main reason why cancer cells do this, and a few mechanisms for how they do it. I have been saying all along that cancer cells are wily little things, and they perform some stunningly impressive feats of metabolic Twister in order to accomplish the nefarious task of keeping themselves alive by gorging on glucose.

Since it’s been a while since the last post, let’s take a quick look back at what we’ve covered so far, regarding cancer cells’ dependence on glucose as their primary fuel.


Yes, that’s right, glucose is not their only fuel, just the primary fuel. Remember: cancer cells have mitochondria that are malfunctioning, reduced in number, or both. But that doesn’t mean 100% of their mitochondria are 100% useless. It just means that, compared to healthy cells, cancer cells require and metabolize more glucose, because even though some of their mitochondria can metabolize fats and ketones to some extent, relatively speaking, their mitochondrial capacity is severely compromised, and therefore, they fare much better using glucose. (Sorry if I’m stating the obvious here. I don’t want to harp on the details too much, but I do want to make sure we’re clear on what’s going on.) Cancer cells still metabolize small amounts of fats and ketones; they just don’t do it as effectively as non-cancerous cells that are replete with healthy mitochondria. (You can bet your sweet bottom we’ll come back to this when we talk about dietary strategies for managing cancer, but I wanted to make this point early on so that even here, you’ll start gaining some insight as to why ketogenic diets, by themselves, aren’t miracle cures for cancer.)  

We’ve gone to great lengths to explore the structure and function of mitochondria. We’ve also covered a few different things that can cause mitochondria to malfunction. Quoting from the researchers who’ve dedicated their careers to studying cancer as a metabolic abnormality, we’ve confirmed that, indeed, cancer cells do have mitochondria that are messed up (to use the official scientific term). Even before all that, we waded through some pretty gnarly biochemical weeds to learn about how cells generate energy (ATP). Recall from a while back that we looked at two main pathways for cellular energy generation: glycolysis (which subsequently leads to fermentation), and oxidative phosphorylation (OxPhos), via the Krebs cycle and electron transport chain.

Here’s the super-speedy version, in case anyone’s forgotten the major highlights: Compared to healthy cells of the same tissue type, cancer cells have fewer mitochondria, mitochondria that are malfunctioning, or both. Since mitochondria are where cells generate the vast majority of their ATP—from fats, ketones, and carbohydrates—if mitochondrial energy production is compromised, the cell must rely on some other way of producing energy—a way that doesn’t require mitochondria. This other way, you’ll recall, is glycolysis, which takes place in the cytoplasm, and which, like the good ol’ Energizer bunny, can keep going, and going, and going, no matter how “messed up” the mitochondria are. (And because fats and ketones can only be metabolized inside the mitochondria, the main fuel source for cells with compromised mitochondria must be a fuel that can be metabolized outside the mitochondria, via glycolysis—that is, glucose.) But you’ll also recall, from this post, that, compared to OxPhos inside the mitochondria, glycolysis is very inefficient. It generates far fewer ATP from the same amount of starting material—in this case, glucose molecules. Therefore, in order to generate the same amount of ATP as healthy cells, with healthy mitochondria, cancer cells need to consume far more glucose.

Hence, cancer cells are sugar junkies.

BUT…that doesn’t mean sugar causes cancer.

Before anyone starts getting ideas that I don’t mean to imply (at least, not yet), I am not suggesting that carbohydrate consumption causes or initiates cancer. (In a future post, we will revisit the notion of reactive oxygen species generated by excessive CHO consumption leading to damaged mitochondria [and therefore potentially to cancer], but certainly, this is only one of many things that might play a role in tumorigenesis.) What I am saying, and what this whole series—including the posts to come—supports, is that a glucose-rich environment provides cancer cells with the fuel type they use most readily and most effectively. So I don’t think we can say that consuming sugar (or, really, carbohydrate of any kind) causes cancer. But we can say that chronically elevated blood glucose allows and enables cancer to thrive. Of this there is no doubt.

  • “As the principal source of energy of cancer cells, elevated serum glucose in itself may fuel tumor progression.” (Champ et al., 2012)

Fires only continue to rage when something is fueling them, right? Curtains, books, carpet, clothing. Cancer continues to rage when it, too, has an abundant fuel supply to “burn through,” and most types of cancers’ favorite fuel is what again? Right, glucose. (Don’t ask me about the amino acid, glutamine. One thing at a time, kids.)

  • “The growth rate of the CT-2A experimental mouse astrocytoma was directly dependent on blood glucose levels. The higher the blood glucose levels, the faster the tumors grew. As glucose levels fall, tumor size and growth rate falls.” (Seyfried et al., 2015)
  • “Findings in animal models and in brain cancer patients indicate that tumor growth rate and prognosis is dependent to a significant extent on circulating glucose levels. Glucose is the prime fuel for glycolysis, which drives growth of most brain cancer. As long as circulating glucose levels remain elevated, tumor growth will be difficult to manage.”  (Seyfried et al., 2012)

Okay. We’re probably all on the same page now. Cancer cells need tons of glucose. They use tons of glucose. (Recall that we looked at that wickedly fascinating enzyme, hexokinase 2 [HK2], which allows cancer cells to burn through glucose at a much faster rate than healthy cells do. I swear, the details there still blow my mind, and, if page views are any indication, they blow your mind, too, because that post has over 300 more hits than the ones that came before and after it.)

As a reminder:
  • “In contrast, with type II hexokinase retaining the catalytic capacity in both domains, the isoform effectively retains the capacity to double the rate of formation of glucose-6-phosphate, relative to isoforms I and III. Therefore, it is not surprising that type II hexokinase is the isoform predominantly expressed in highly malignant tumors.” (Mathupala, Ko, Pederson, 2010.)
Remember how I explained that HK2 is like a two-car garage for glucose? It can handle twice as much at a time as the other forms of hexokinase. And remember also that the conversion of glucose to glucose-6-phosphate is the “rate-limiting step” of glycolysis. Once that occurs, the pathway is committed to happening. Once HK2 has converted glucose to glucose-6-phosphate, the rest of glycolysis will proceed, resulting in an inordinate amount of pyruvate, which will then get funneled toward fermentation.

The question we should be asking ourselves now is, how do cancer cells get all that extra glucose? See, as fascinating as that hexokinase stuff is, HK2 can only plow through all that glucose once it’s inside the cell, right? So something must first be facilitating the entry of abnormally large amounts of glucose into the cell.

Put on your galoshes. It’s time to do just a little more wading through the biochemical swamp, as we quickly explore mechanisms of glucose transport.


Glucose is a pretty important factor for human life. I am a loyal low-carber and a big proponent of low-carbohydrate and ketogenic diets for myriad health concerns, but I am not so ignorant of human physiology and biochemistry as to say that we can survive without glucose. We can’t. (This doesn’t mean we need to ingest it, pre-formed, as dietary carbohydrate, but if we don’t, then we need to get it some other way, typically by converting other fuel substrates into glucose. Sorry for the digression. This is just my way of making it clear that I am not some kind of low-carb “zealot,” and am absolutely not implying that glucose is “toxic.”)

Okay, so glucose = important. Because of this, our cells have many ways of getting it. One of the ways they get it is by using glucose transporters—abbreviated GLUT, which is not to be confused with glutes, which are the muscles that make your fanny look good in tight jeans (or out of them, hehheh…).

Just as there are different forms of hexokinase enzymes, there are different forms of glucose transporters. It seems there are upwards of 12 different kinds, but we typically only hear about 5 of them. Some of them require insulin to function effectively; some don’t. And even though they are called glucose transporters, some have a greater or lesser affinity for other monosaccharides. For example, GLUT5 is the main transporter for fructose.

The way GLUTs work is that they are synthesized inside the cell, and in order to help glucose get inside, they have to be “translocated” from the cytoplasm to the cell membrane. They need to span the cell membrane in order to snatch glucose out of the bloodstream and bring it into the cell. Different things stimulate the translocation of the GLUTs to the cell membrane. In some cases, this is spurred on by the blood glucose concentration itself. (The cell senses that there’s glucose to be had, so it moves the GLUTs to the membrane, in order for them to grab some of it.) GLUT forms 1 and 3 are both stimulated/upregulated by low glucose concentrations. That is, even when blood glucose is not high—in fact, especially when it’s not high, as long as we have GLUT1 & 3 being expressed, the cell will still be able to suck up glucose.

I’m not a huge fan of quoting from Wikipedia, but it can be useful sometimes:
  • GLUT1 is responsible for the low-level of basal glucose uptake required to sustain respiration in all cells. Expression levels of GLUT1 in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels.
  • GLUT3 has both a higher affinity for glucose and at least a fivefold greater transport capacity than GLUT1, GLUT2 and GLUT4…”

I’ll back this up with information from slightly more reputable sources in a sec, but first, let’s talk about GLUT4. GLUT4 is the main glucose transporter that is affected by insulin. When blood insulin levels rise (typically after CHO consumption, but also from protein), GLUT4s are translocated to cell membranes to suck up the glucose. It’s not surprising, then, that GLUT4s are predominantly expressed in skeletal muscles, cardiac muscles, and adipose tissue. (Skeletal and cardiac muscles work hard, and use a fair amount of glucose, and, of course, in a twisted way, GLUT4s do our bodies a favor by sequestering excess glucose as triglycerides [FAT] inside our adipose cells—rather than allowing it to accumulate endlessly in the bloodstream. This is likely one of the mechanisms of insulin resistance: after years of chronically, unrelentingly high insulin levels, eventually the GLUT4s “stop caring,” and they no longer respond by moving to the cell membrane to pull glucose from the blood. So blood glucose levels stay elevated. It’s like the Boy Who Cried Wolf—when the cells hear insulin calling again and again and again, eventually they stop listening.)

As an aside, I think this is part of why it’s not absolutely necessary to consume carbohydrate along with protein in a post-workout shake, meal, or other “recovery” strategy. After all, protein, all by itself, is insulinogenic. Not to the same degree as carbohydrate, but still a little bit—because, remember, insulin also helps amino acids get into cells. The reason your blood glucose doesn’t drop too low upon eating just protein (or protein & fat) is because protein also stimulates glucagon release, which counterbalances the hypoglycemic effect of insulin. Crazy, huh? It’s almost like a hormonally and metabolically healthy body just works.

Sorry for going off on all these tangents. Part of it is, I like thinking out loud. And another part of it is, I’m trying to convey just how complex this biochemical choreography is. Insulin and glucose tend to have bad reputations in the low-carb and ancestral health communities, but it’s really about context. Fire can be extremely destructive, or, when used appropriately, it can help make a damn tasty steak.  

Okay, now that we have some background about the GLUTs, the following lines will make sense:
  • “It has become increasingly clear that malignant cells compensate for this energy deficit by up-regulating the expression of key glycolytic enzymes as well as the glucose transporters GLUT1 and GLUT3, which have a high affinity for glucose and ensure high glycolytic flux even for low extracellular glucose concentrations.” (Klement, Kämmerer, 2011.)
  • “With regard to altered expression of transporters that have a higher affinity, of the currently recognized 12 isoforms of GLUT, it is the isoforms 3 and 4 that have the highest affinity for glucose. Not surprisingly, both have been shown to be over-expressed in most human cancers. However, GLUT1, ubiquitously expressed in all normal tissues, is one of the commonly observed over-expressed isoforms in tumors, along with GLUT3 and GLUT4. Thus, it may be that a partial GLUT isoform shift occurs during tumorigenesis, with the ‘normal’ form being maintained albeit at an elevated level in most tumors.” (Mathupala, Ko, Pederson, 2010.)

I was not about to pass out, 
I assure you.
So I’ll say it again:  Even when blood glucose is relatively low, these particular GLUT isoforms are champs at latching onto whatever little there is, and bringing it into cells. So whereas in a generally healthy population, blood glucose levels of 70-100mg/dl are pretty great, Dr. Seyfried’s research indicates that the most effective therapeutic window in the context of a ketogenic diet as cancer therapy is 55-65mg/dl. That, my friends, is quite low. It’s not unheard of, though, particularly for someone who is extremely well-adapted not just to elevated ketones, but perhaps even more so to elevated free fatty acids. (A few years back, after an unplanned 2-day fat fast [don't ask], I tested my blood glucose at 56 mg/dl, and I felt GREAT – felt fantastic, physically and cognitively. No hypoglycemic symptoms at all. So it can be done. I don’t have a ketone meter, so I can only assume my ketones were fairly high, but more than that, I was a major, major fatty acid-burning beast.)

Again, we will come back to these ideas in detail when we discuss ketogenic diets as adjunct therapy for cancer management. But I wanted to plant the seeds now, so that we’re all aware that “starving cancer” is not as simple as going on a low-carb or ketogenic diet. (If only it were!) Even when there are only small amounts of glucose in the blood, cancer cells are damn good at getting their grubby little paws on it.


Cancer cells’ affinity for glucose is not news. Doctors and researchers have known about cancer’s insatiable appetite for C6H12O6 for decades. I have mentioned the work of Peter Pedersen, PhD, in previous posts. A great deal of what we know about hexokinase 2 and these glucose issues came out of his laboratory. (If you started to learn about cancer as a metabolic disease after Robb Wolf started peppering podcasts and blog posts with the name of Thomas Seyfried, PhD, you can be excused for thinking Seyfried is the only guy with his finger on the pulse of this stuff. But in digging through the literature, Pedersen is everywhere, as are his colleagues and students. When it comes to HK2, Pedersen is a friggin’ rock star THE MAN.)

It wasn’t long after Pedersen’s discoveries about HK2 that doctors began employing positron emission tomography (PET) scans to diagnose cancer and monitor its progression. See, PET scans—at least, the ones they use for this purpose—use a radioactively labeled form of glucose, called 18F-fluoro-2-deoxyglucose (FDG). How it works is, a cancer patient gets injected with FDG, and because cancerous tumors are so good at sucking up glucose, the tumors act like a lightning rod for FDG. The FDG basically concentrates where there’s cancerous tissue, so doctors can see how much of it there is, and also where it may have spread to.
  •  “Work published as early as 1977 and 1981 by Bustamante and the author [Pedersen] on the important role of hexokinase in the ‘Warburg effect’ likely contributed to the development/use of PET imaging for cancer.” (Pedersen, 2007.)
  • “This characteristic is the basis for the wide-spread use of the functional imaging modality positron emission tomography (PET) with the glucose-analogue tracer 18F-fluoro-2-deoxyglucose. (Klement, Kämmerer, 2011.)
  • They now use “the high glucose influx of malignant tumors via mitochondrial-bound hexokinase as a tool to develop radio-labeled glucose analogs for in vivo imaging of tumors via PET, which has now become a universal mode of tumor detection and staging.” (Mathupala, Ko, Pedersen,2009.)

So, yeah, this isn’t news. The fact that cancer cells are sugar junkies is the basis for the current “universal mode of tumor detection.” Call me crazy, but shouldn’t that tell doctors and researchers something? Like, oh, I dunno…maybe sugar-loaded Ensure shakes aren’t really the best things to feed cancer patients? (Like this one, which has 51g of carbohydrate in just eight ounces. The first two ingredients are corn maltodextrin and sugar. Yes, this sounds like exactly what we should be feeding people who are incredibly ill -- particularly if their illness feeds on sugar. The fourth ingredient is canola oil, and corn oil is seventh. God bless America…)

Throughout this post, I have made an effort to emphasize that consumption of sugar and carbohydrates does not necessarily cause cancer. What I think it can do, and what research in animals and humans supports, is that once cancer has been initiated—by whatever is the actual cause—consuming large amounts of carbohydrates (and, Dr. Seyfried might argue, even small amounts) facilitates its sustained presence and growth:  

“Evidence exists that chronically elevated blood glucose, insulin and IGF1 levels facilitate tumorigenesis and worsen the outcome in cancer patients.” (Klement, Kämmerer, 2011.)

I’ve bolded the phrase “facilitate tumorigenesis.” These researchers aren’t saying that elevated blood glucose causes tumorigenesis, only that it facilitates it. We can think of it this way: all of us probably “have cancer” all the time. That is, we have cells that function abnormally, DNA that gets mutated, etc. But our immune systems and other self-regulatory mechanisms put the kibosh on these cells before things get out of hand: apoptosis, autophagy, etc. These cells get neutralized before they have a chance to grow like crazy and form tumors. Putting lots of glucose into the bloodstream simply makes it much more likely that these abnormal/pre-cancerous cells might bypass those regulatory mechanisms, morph into full-on cancer, and start hijacking the cellular machinery for their own purposes.

Speaking of mutated DNA, here’s what’s coming next time: Now that we’ve worked so hard to understand the metabolic origins of cancer, we’ll be able to pit the dueling cancer theories head-to-head: 

Is it mutations, or mitochondria? Hang onto your hats; it’s the cage match of the century!

*Continue to the next post: Mutations vs. Mitochondria



  1. Amy - I'm feeling disappointment when I reach the end of your blog. Keep the work coming. Very interesting!

  2. :) Thanks! I do have the next one ready to go, but I like to stay at least 1 or 2 ahead of myself, so I don't "write myself into a corner" and then have nothing to post for a couple of weeks. This stuff is really fun & fascinating to write about, but it does take a lot of time.

    1. I imagine it takes a lot of time and research. Just know that developing a better understanding of metabolism gives us the knowledge to make informed decisions on nutrition in developing a healthy way of eating. This is the reason I've become a regular reader of your blog. Many thanks.

  3. Oh thank goodness - I was starting to worry that you were dropping this series because not as many people were reading it as expected.

    1. :) No way. I actually love writing it, so I'm not going to abandon it before it's done, but yeah, I do wish more people were reading. Partly because I just think it's really important information, but also because, to be honest, knowing people are looking forward to it is really encouraging and motivates me to keep going. (But I know the few people who *are* following this are very into it, and that helps. Readership might be small, but it's dedicated.)

  4. Amy,
    Great series. I've been reading about the metabolic theory for months and still get insights from your explanation.
    Thank you!

  5. Really interesting, I've been following the series, reading and re-reading all of the posts to make sure I get the most out of it. Always looking forward for the next one.
    Keep up the good work!

  6. Thanks, Amy - another excellent article. I love this series!

  7. Ditto the low Glucose readings. I do 2/5 fasting with VLCHF. Thats 2 days of fasting/week the other days 23 hour fasts, i.e. 1 meal per day(tends to be a whopper). I see readings of 2.9 mmol/l (about 52 mg/dl for you Yanks) and 5 mmol/l for ketones at the end of the two days. I feel great also, so yes it is possible and surprisingly with no great effort, I never feel hungry. Question though and probably you answer this later but I'll put it now. Is this quantifiable? I.e. if I am at this level am I actually damaging the incipient cancer or will it eventually upregulate GLUT1 etc to compensate. Seyfried seems to think its sort of permanent, whats your take?

  8. Hi, Amy,

    The more I get into the cancer series, the more stunned I get at how little our modern doctors seem to know.