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My Wife Steered me to a New York Times Magazine Article that stirred thoughts of Glycolysis

Figure2a.pngThe late 19th / early 20th century was an interesting time to be alive. My wife and I have recently been reading about the lives of several people living at that time including, Elanor Roosevelt, Dietrich Bonhoeffer, and most recently for me, Nils Bohr. Reading about it naturally leads to talking about it and marveling at the way that this was a time of awakening across the world. Not quite the same as the Renaissance, but more with respect to the nations of the world becoming intertwined and the actions on one side of the globe had real repercussions on the other side. Others living at that time included Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883 – 1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917).There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few (not to forget the Kardashians and Paris Hilton).

It was a time of great artists and great scientists. Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883-1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917) could run into one another. Mark Twain could have taken Vincent Van Gogh for beer and an earful of clever conversation that acknowledged a crazy world, but didn’t fall into despair because of it.There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few -and lest we forget, we have the Kardashians and Paris Hilton to show us that, while the unexamined life may not be worth living, one populated with innumerable selfies is just HOT!

As there have been brilliant minds at all points in history, we too live in exciting times.  We live in times with scientists such as Richard Dawkins and Craig Venter who make it their duty not to just pursue science, but to share it with the rest of us; Computer makers Steve Jobs and Bill Gates revolutionized the amount of work on person or a small team can do; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell touch us and unite us with their music; and filmmaker John Lasseter brings life to the lifeless and makes cartoons parents can enjoy just as much as their children do. A.J. Abrams brought Star Wars back from the brink and reminded us why we fell in love with the franchise back before it was a franchise. to name a few (not to forget the Kardashians and Paris Hilton).

But, back to the article.

The  article she told me about that brought up the turn of the last century was part of an ongoing series about Cancer from the New York Times Magazine discussing the Warburg Effect, named for Otto Heinrich Warburg (1883 – 1970). Otto_Heinrich_Warburg_(cropped).jpg I knew of the effect, wherein tumor cells engage in aerobic glycolysis, primarily from the perspective of Craig Thompson’s work unravelling the link between Type II Diabetes and Cancer. That connection is based on Tumor cells’ overexpressing the glucose transporter, GLUT-4. The working model states that: given a sufficient supply of sugar and the ability to mop it up quickly via GLUT-4, the limiting factor in cell growth is not energy, but carbon.

It takes a lot of food to support rapidly growing cells (just look at teenagers). Much of that sugar goes to energy (not as readily apparent in teenagers), but a lot also goes to making the building blocks required for cellular proliferation. But to use the carbon in sugar for building rather than energy means that the sugar cannot be completely broken down to CO2 to be exhaled. Instead, cells break the sugar in half by glycolysis to make pyruvate for a net benefit of only 2ATP per glucose (as opposed to 36 possible). Then the intermediary molecules can be diverted to alternative synthesis pathways for those building blocks.

The basic reactions of Glycolysis are these:

glycolysis.png

However, the last enzyme in the pathway, Pyruvate Kinase can take two forms. The first is a tetrameric enzyme (M2-PK), which efficiently processes PEP into Pyruvate, which can either go on to be aerobically metabolized to generate more ATP or diverted to fermentation reactions.

An alternate, dimeric form, emerges when Pyruvate Kinase interacts with oncoproteins. This form (Tumor M2-PK) reduces the production of pyruvate to a trickle allowing for the buildup of metabolic intermediary molecules which may be diverted to alternate synthesis pathways for building materials.

An illustration comparing the pathway with either dimeric or tetrameric forms is shown here:

glycolysis2.png

[The figure above came from Sybille Mazurek and has been modified for emphasis. Thank you Sybille!]

All this is a much more mechanistic description than Warburg was able to offer in 1924. At that time, it was recognized that tumor cells were switching to glycolysis even with sufficient O2 available, but the best explanation was that perhaps the mitochondria, where the aerobic reactions of cell respiration occur, were broken. He also thought that this disruption was actually the cause of cancer rather than a consequence of other factors leading to cancer and the switch to aerobic glycolysis amongst the sequelae of more fundamental problems.

So, despite the details of his hypotheses proving to be incorrect, what he did get right was the recognition of an important shift in metabolism that occurs in tumor cells.

A lot of research has gone into understanding cancer and into understanding diabetes. An unexpected connection between type II diabetes and cancer led to an unexpected synergy between their research efforts. The connection arises as a result of individuals with  type II diabetes overexpressing insulin as a compensatory measure.

Recall the definition of diabetes and the difference between the type I and type II varieties…

Diabetes is an inability to properly regulate the amount of sugar in the blood. When you eat, insulin levels increase to tell cells to take up the elevated blood sugar that comes soon after.

Type I diabetes is a result of the body destroying the pancreatic islet cells that produce insulin early in life so that the insulin signal never happens and unhealthy amounts of sugar accumulate in the blood.

Type II diabetes (formerly called ‘adult onset’ diabetes before children started getting it) is a result of cells becoming unresponsive to insulin. The association with obesity roughly means that cell so often see insulin that they become accustomed to it and don’t respond appropriately. This is very much like an addiction response. To compensate, the pancreas makes more and more insulin until, eventually, cells are so unresponsive that they just don’t do their job any more and unhealthy amounts of sugar accumulate in the blood.

Two pathways; same outcome.

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and

nrc487381.fig2.jpg

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and resistant to death that they become a health hazard. (If you’re thinking this sounds like evolution on a cellular scale, you’re thinking the right thing.)

One thing that gives one cell an advantage over other ‘lawabiding’ cells in the body is being greedy when food comes around. this is another central problem with cancer. In healthy organisms, cells ‘recognize’ their place and are willing to sacrifice themselves for the good of the body. Cancer cells have reneged on that agreement and look out only for #1.

On a cellular level, this means that they put up receptors for energy-rich molecules like sugar and take it whenever available. One example receptor cancer cells often use for this is GLUT-4. The very same receptor that we saw providing sugar for energy and carbon for building above. It turns out that Insulin binding to insulin receptors triggers the mobility of GLUT-4 receptors from intracellular vesicles to the cell surface. The environment that makes this all possible for tumor cells to do so well is one in which there is excess insulin – like in the circulation of someone who has type II diabetes and has been producing more and more insulin to try to coax cells to take glucose out of the blood.

The take home message:

  • Type II diabetics have very high levels of circulating insulin.
  • Cancer cells can use insulin signals to upregulate glucose-capturing receptors.
  • Cancer cells begin to favor dimeric form of pyruvate kinase.
  • Cancer cells can also perform aerobic glycolysis, the Warburg effect, to get both energy and biological building blocks from this sugar.
  • The cells that do it best have the most (cellular) progeny.

Therefore:   Obesity –> Type II Diabetes –> Cancer

 

 
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Posted by on May 30, 2016 in Uncategorized

 

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Diabetes and Kidney Failure

I wish my parents played Mozart when I was asleep because half the time I don't even know what the heck anyone's talking about!

I wish my parents played Mozart when I was asleep because half the time I don’t even know what the heck anyone’s talking about!

I don’t really think I’m that thick a guy (despite plenty of evidence to the contrary), but I do often encounter these blocks where I just don’t know what’s going on.

Most recently, it was in preparing to discuss the digestive system and how the pancreas participates in both the production of enzymes to digest food (Pancreatic Juice contains trypsin, chymotrypsin, elastase, etc) as well as hormones to aid the body in dealing with the coming wave of nutrients in the blood (i.e. how insulin and glucagon mediate blood glucose homeostasis).

The next unit we were getting into was the renal system – and in having our introductory discussion about the kidneys and their functions, the topic of kidney failure came up. That quickly led to a segue into diabetes (recalling the digestive system) and how many diabetics end up requiring dialysis due to chronic kidney failure.

‘So what’s the connection? Why do diabetics get kidney disease so often?’

I thought I knew – then, as my mouth started to open – I realized that I didn’t. I closed my mouth.

I think I asked my students to look into it, but … I couldn’t wait. So I jumped in.

diabetesFirst, a confirmation. A report from the 2007 US Department of Health and Human Services confirmed that not only is diabetes a common cause of kidney failure, it is the most common cause of kidney failure by a rather large margin.

Then, a quick reminder or the function of the kidney and the structure of its functional unit, the nephron – or which each kidney contains millions.

Briefly, the function of the kidney is to filter blood.

Peanut Gallery: ‘I thought the spleen did that!’

-well, the spleen does do that. But for an entirely different purpose. The spleen filters the blood for foreign particles, etc. as a function of the immune system. Lymph nodes filter the lymph for any foreign material brought back to the circulatory system as ‘run-off’, the spleen filters blood as it circulates through the body.

The Kidney also filters blood, but it does so in order to remove waste products that will otherwise build up and become toxic to the person / animal.

The way it does this filtration is by using a glomerulus. The glomerulus is a knot of capillaries with porous epithelia. The pores are large enough to permit the passage of water and other small molecules (urea), but small enough so that larger proteins and cells won’t leave the blood. Whatever material does filter through then either moves along and becomes urine, or is selectively reabsorbed into the blood.

[Image Removed as Requested by Artist]

The glomerulus looks a lot like this: (or at least it would if life were as cool as some people’s artistic impressions)

This is where blood comes in, at relatively high pressure, and the small molecules and water are pushed through fenestrations (windows) in the capillaries so they can drain into the renal tubule. The combination of capillary epithelial cells, basement membrane, and podocytes (cells that sit upon the capillaries) altogether called the Glomerular Filtration Barrier.This is the place where kidney function can really take a hit if there’s a problem – and if this breaks, the whole thing is broken.

Not surprisingly, it’s the glomerulus that fails in diabetes. The question is, ‘why?’

One prevailing theory has been that diabetics have generally higher amounts of glucose in their blood and it is known that glucose levels too high and too low are both dangerous. So, it’s not too much of a stretch to suspect that this is somehow to blame. The resulting injury is therefore called diabetic nephropathy.

However, more recently, the podocytes have been investigated as possible culprits. Rather than glucose itself, work published in 2010 suggested that it was insulin signaling – not glucose- that was involved in the damage to cells. Podocytes do have an insulin receptor that is engaged when glucose levels are high enabling the cell to restructure its cytoskeleton in a way that helps the cells to withstand the increased glomerular pressure that comes with filtering post-meal blood (incidentally, high blood pressure is another cause of kidney failure).

‘Knockout’ mice which specifically lack this insulin receptor on these podocytes (but otherwise express insulin receptors appropriately) were shown to suffer kidney damage very similar to that seen in diabetic nephropathy. Importantly, this damage occurred despite animals being otherwise normal (i.e. no abnormally high level of glucose in the blood). To be clear, without the insulin receptor, podocytes were unable to remodel cytoskeleton following meals, this lack of remodeling led to damage to the structure.

These results are also consistent with other animal models of diabetes (type I and type II) that exhibit a failure in glomerular insulin signaling early on in kidney disease.

Because these podocytes are terminally differentiated cells, they do not renew following damage meaning that kidney disease of this sort does not improve, but only progressively worsens.

This gives us a model that looks something like this

(ps – if anyone with deeper knowledge of this field reads this, I would certainly appreciate corrections)

Model

 
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Posted by on March 25, 2015 in Uncategorized

 

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Obesity, Diabetes and Gastric Bypass Surgery

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             Glucose

Several semesters ago, I was teaching a course called ‘Human Biology’ as an adjunct. As opposed to my normal class in General Biology, this one contained an anatomy and physiology component. My own history in the lab is one of a molecular and cellular biologist. The only system that I know reasonably well from personal experience is the immune system, so I was learning a lot by teaching this class and doing the reading to remind myself of what I learned many years ago.

I particularly enjoy making class a discussion about specific topics that my students are interested in (even if I cannot always answer such varied questions) and one day a student asked why it was that gastric bypass surgery immediately cured diabetes.  

As I said, I’m something of a novice in these areas of systems biology, and given what I knew I could not come up with a reasonable explanation. In fact, I doubted that this could happen and the weekend digging for any publications describing the effect. To my surprise, it was well known. Unfortunately, no one else had a very good explanation for it either. However, as asserted in the associated Perspective article, “gastric bypass surgery pImageatients can stop taking diabetes medications before substantial weight loss has occurred” –  a surprising feature of the intervention also seen by my student (who had this surgery himself). This suggests that the surgery itself must trigger a hormonal change in patients, rather that weight loss simply reversing the condition over time.

Happily, the most recent edition of Science caught my eye with an article titled, ‘Reprogramming of Intestinal Glucose Metabolism and Glycemic Control in Rats After Gastric Bypass,’ by Saeidi et al that examined the effect in a rodent model. As Hans-Rudolf Berthoud explains in his review of the work, 

“glucose preferably enters the pentose phosphate and other glycolytic pathways that provide substrates for nucleotide and protein synthesis, consistent with accelerated tissue growth. Most important, and as an “unintended” by-product of increased glucose uptake by the expanding gut tissue, systemic glucose concentrations are reduced and the diabetic state is reversed.”

As satisfying as this finding may be, it remains a mystery why this effect would persist long term after the new gut has completed its transformation. An alternate, or perhaps complementary explanation for this effect in humans may lie in the extreme calorie restriction patients are required to adopt post-surgery. “When control subjects were given the same low amounts of food eaten by surgical patients, the same rapid improvements in glycemic control were observed,” providing evidence for a non-surgical pathway to the same endpoint. 

——-

One last point…

This article immediately reminded me of work done by Craig Thompson and others on the relationship between obesity, diabetes and cancer, summarized in a review article in a 2009 issue of Science. This article described how it is that obese individuals suffer higher rates of cancer than non-obese persons. Among the links they described was how obesity leads to type 2 diabetes resulting in higher blood sugar concentrations, a condition favorable to oncogenesis.

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                    Explaining the Warburg Effect

The same article went on to add that cancer cells often use glucose in a way that that is surprisingly inefficient in terms of the energy it captures (known as the Warburg Effect). This paradox of rapidly dividing cells apparently underutilizing glucose was resolved once it was observed that cancer cells get not only energy from glucose metabolism, but building materials to keep up with the unusually high demand that rapid grown imposes.

Altogether, these articles do much to clarify how the body utilizes fuel, regulates blood glucose and the what the overall health affects of these regulations.

 
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Posted by on July 27, 2013 in Uncategorized

 

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