SREBP1

Hey, everyone!  I hope everything's going okay over on your end.  Over here, I'm just in pain from all the karate classes and hiking I've been doing (but it's okay, it's a good pain).

We're going to get into a topic that has been one of my biggest interests since we learned about it last year in biology.  It's an emerging field in the realm of genetics called "epigenetics," and it's just a fascinating subject to me.

Rewind back to the days of Charles Darwin, who documented and published a work called On the Origin of Species, which discussed his findings in the Galapagos Islands.  He noticed that different islands had species of birds with differently shaped beaks, and formed the earliest theory of evolution.

That one on the top left has seen things.

Skip forward a bit to Gregor Mendel.  He grew a lot of pea plants.  Like, a lot of pea plants.

This many.

After breeding plants with different traits together, he noticed certain patterns in the generations that proceeded the parent generations.

These variations.

This paved the route for a lot of our modern understanding of genetics--that our genes are set, and there's nothing we can do to change them.

OR CAN WE?

*dun dun dunnnnn*

That's where epigenetics comes in.  Basically, epigenetics says that, while you can't change your genes themselves, you can change how the genes are expressed.

DNA is wrapped around a molecule called a histone, like this:

Like a little spring!

This is mostly done to save space, since DNA is so long.  A lot of DNA doesn't code for anything, so it stays coiled up in histone groups that are methylated (which just means a methyl group is attached).  When it's time for DNA to be transcribed to make stuff, the histones become phosphorylated, which uncoils the DNA.

Epigenetics controls the coiling and uncoiling of the DNA wrapped around these histones.

Awesome!

Let's bring this back to what I've been studying.  There's a section of DNA that codes for the creation of Acetyl-CoA Carboxylase, which creates Malonyl-CoA (which inhibits fat mobilization into the mitochondria).  This gene starts transcription from the promoter gene SREBP1, which is actually called "sterol regulatory element-binding transcription factor 1," a name that I hope to never type ever again.

SREBP1 is turned on in the presence of insulin and glucose, which are in high supply in a person with diabetes.  Therefore, the cell keeps making Acetyl-CoA Carboxylase, which keeps making Malonyl-CoA, which is kind of causing the problem in the first place!

Fun fact: if you eat sugar, in about a minute, SREBP1 gets turned on, which inhibits the mobilization and use for fuel of fatty acids.

So, not eating a ton of sugar really affects things not only at a cellular level, but at a genetic level as well.  And if that's not cool, I don't know what is.

The Charlie Foundation

Today's Super Special Fun-Time Extraordinary Playtime Post is mostly going to be a plug for a website.  But it's a cool one, so I'm sure you can find it in your heart to forgive me.

Don't you?  Don't you?  Why are you ignoring me?!

 It's called the Charlie Foundation, and it actually has nothing to do with diabetes.

The Charlie Foundation was created because of a young boy named Charlie who suffered from epilepsy.  He was having multiple seizures a day for years until his doctors put him on a highly restrictive ketogenic diet.  His condition improved to the point where he was mostly seizure free, and the foundation was founded "to provide information about diet therapies for people with epilepsy, other neurological disorders and tumorous cancers."

While a lot of anecdotal evidence exists to verify this diet's treatment of epilepsy and other neurological disorders, no one is really sure why ketogenic diets work.  This is partly due to the fact that there are actually very few scientific studies that show what ketones actually do.

We know that they exist and do something.

There is a pretty good chance that ketones have a preservative (and possibly even regenerative) effect on brain tissue because of the success of ketogenic diets in managing epilepsy, as well as Alzheimer's and Parkinsons'.  The problem is that the body can only produce them by burning long chain fatty acids in the mitochondria, which can only get in if CPT1 is open.  CPT1 is closed in the presence of Malonyl-CoA, a byproduct of a glucose-heavy diet, aka a normal diet.  So, the body can't get ketones unless it burns its own fat.

OR CAN IT?

*cue dramatic music*

 Medium chain fatty acids, unlike long chain fatty acids, don't need to enter the mitochondria through CPT1, and can take a figurative back door in.  The oxidation of medium chain fatty acids still produces ketones, with the added bonus of not having to completely swear off sugar.  Medium chain fatty acids are found in things like coconut oil.

The source of all of life's joy.

Thanks for reading!

HbA1c

Hello, readers!  Today we're going to talk about how people are actually diagnosed with type 2 diabetes.

As I mentioned in my last post, one of the defining factors for being diagnosed with diabetes is not insulin resistance but a number called HbA1c (which stands for "glycated hemoglobin").  If it's above 6.5, you can be medically diagnosed with type 2 diabetes--if it's only a little bit lower, you are what we can call "prediabetic," or, on your way to developing diabetes if things continue the way they are going now.  Either that, or you're diagnosed with "metabolic syndrome," which is just as vague as it sounds.

There's something wrong with you metabolically, but we don't know what to classify it as!

Metabolic syndrome includes symptoms like high blood pressure, obesity, LDL problems, and, shockingly, insulin resistance.  That's...a pretty wide range of symptoms, there.

Anyway, returning to HbA1c.  If you have diabetes, your blood sugar is perpetually high because your body can't produce enough insulin to lower it again because you're insulin resistant.  All this glucose floats around in your bloodstream for a while, just taking up space.

Like this rebellious teenager.

The thing about glucose is that it's really, really sticky.  This causes problems in a bunch of the parts of the body, mostly in nervous tissue, as glucose sticks to nerves and makes them slow down a lot, which can cause blindness and other health problems.  This also makes wounds harder to treat in the hospital, because all the glucose hanging out in the tissue slows down the healing process tremendously.

One of the things glucose sticks to is the hemoglobin in red blood cells--the longer a person is hyperglycemic, the more glucose sticks itself to the hemoglobin molecules.  And, since glucose is so sticky, it stays that way for the duration of the life of the red blood cell.  Since red blood cells last for about 2 weeks, this provides a long-term test for finding the amount of glucose stuck to red blood cells, an indicator for type 2 diabetes.

The shark is the hemoglobin, and the remoras are glucose molecules.

As long as HbA1c is above 6.5, that is.  If you're stuck at 6.4, you can't be diagnosed and/or treated for diabetes, so you can't be given insulin to offset the resistance you've built up.

The thing is though, if you treat insulin resistance using, say, a lifestyle change that dramatically reduces the daily intake of glucose molecules, you'll have less glucose floating around in your bloodstream, and thus less to attach to hemoglobin molecules in red blood cells, and thus a lower HbA1c.  Just putting that out there.

Isogenic Diets

Hello, everyone!  For this entry I'll be comparing a low-carb diet (or "ketogenic" diet, if you want to show off in front of your friends) with something called an "isogenic" diet.

First of all, let's define what, exactly, a ketogenic diet is (again, because repetition helps to remember things).  A ketogenic diet creatively uses the term "ketogenic" because it involves the creation of ketone bodies.  These ketone bodies come from the oxidation of fat in the liver; the body is able to metabolize fat because there is a shortage of glucose.  The main form of glucose that humans eat come from carbohydrates, which include breads and sugars.

I have to admit something, though: the term "low-carb" is actually a bit of a lie.  Carbohydrates consist of several different materials.  Most people associate the term with grains and sugar only, but in actuality substances like cellulose are carbohydrates as well.

Pictured: carbohydrates.

Pictured: also carbohydrates.

The main thing about cellulose is that humans can't digest it.  So, even though foods like celery are pretty much pure carbohydrate,

Green, fibrous, cellulose.

since they're made of cellulose, you can eat as much of them as you want without getting the sugar from them.

So, calling a ketogenic diet "low-carb" is not really accurate.  A more truthful definition of a ketogenic diet is a high-carb, low-glucose diet with moderate protein intake.

Isogenic diets have gained a lot of popularity in recent years with society's growing focus on all-natural, healthy lifestyle changes (gluten-free, anyone?).

Basically, the main selling point of an isogenic diet is "nutritional cleansing."  People who go on this diet swear that by eating certain foods (and not eating others), they can flush out toxins in their digestive system.

Pun totally intended.

These people say that by cleaning out toxins from the colon, people can lose weight, since, apparently, the digestive tract can hold up to 25 pounds of extra body weight.

That's as much as a really fat cat!  Probably not this one, though.  He's really fat.

By replacing meals with supplements and protein shakes, the body can purge itself of toxins while still remaining fully functional and nutritionally satisfied.  Unfortunately, this diet has no scientific proof of actually working, as well as no promise of long-term weight loss after initial possible weight loss.

But is there any merit to these isogenic diets?  Let's look at the claim that the body can carry a large amount of excess weight in the digestive tract.  This sounds an awful lot like something called visceral fat.

Aka the beer belly.

It is true that the body can carry extra fat in the abdominal cavity.  But, as I've gone over in a previous post, visceral body fat doesn't cause insulin resistance or other metabolic problems, since the fat is contained in adipocytes and is therefore metabolically inactive.  So, if you're starting an isogenic diet to fix your insulin problems because it gets rid of visceral body fat (supposedly), it's not going to help much.

The protein shake part is more interesting.  A major part of ketogenic diets is their relatively high amount of protein compared to other diets, which is used in gluconeogenesis (the creation of new glucose molecules from protein) in order to keep a person's blood sugar from dropping too low.  So, is that what isogenic diets do?  Is it really just a ketogenic diet wearing a different hat?

"I'm so confused about which diet I'm following!"

Well, if we look at the major supplier for isogenic diets, Isagenix, we can see that this isn't quite the case.  Their chocolate protein shake has these nutrition facts:

So many numbers!

It has 24g of protein, which is pretty good.  However, in a ketogenic diet, you should really eat around 120g of protein a day, so this is only one fifth of the daily amount of protein in a ketogenic diet.  And then there's the amount of carbohydrates.  The total amount is 24g, but we can subtract the amount of dietary fiber, giving us 16g of sugars and other digestible carbs.  This isn't so great--since I can eat a max of 50g a day, I have a little leeway when it comes to smaller numbers like this, but people on stricter ketogenic diets (like those who start in order to prevent seizures) can't have this many carbs a day.

In shorter words, the shakes are pretty low-protein in comparison to ketogenic standards, and the amount of carbs is pretty high for most people in ketogenic standards.

Plus there's the whole issue of isogenic diets possibly not working in the first place, so there's that.

Thanks for reading!

A Return to Some Biochemistry: Part 2

Hello, readers, and thanks for tuning in to this weeks stunning conclusion: What All That Stuff I Was Talking About Last Time Actually Means!

This entry will be pretty short, because there's only so much blabbering about lab tests that I can actually do in one sitting before I start repeating myself.

Let's review what I talked about in my last post.  Your body uses molecules called lipoproteins (which vary in size based on the amount of cholesterol and lipids inside the molecule).  LDL (low-density lipoprotein) extract triglycerides and cholesterol from fat cells, and HDL (high-density lipoprotein) takes fat and cholesterol into the target cell.

Vacuum cleaners were involved.

HDL and LDL will look and act differently in a healthy person than a person with insulin resistance/metabolic syndrome.  To see this, we can use lab tests to see a bunch of different variables that could indicated that someone is insulin resistant.  Dr. Walker uses lab results from a company called the Health Diagnostic Laboratory (it may or may not be a coincidence that this spells out "HDL"), which provides a huge amount of data regarding metabolic processes, along with some treatment algorithms based on the lab's findings.  One of the things tested for is the size of HDL and LDL particles.

As HDL and LDL travel through the bloodstream carrying cholesterol and fatty acids, they tend to grow in size.  While this is only by a few nanometers, physicians can detect these small changes.  When a healthy person has a lot of fat being oxidized (as I went through in my last post), their HDL and LDL are relatively large.  Dr. Walker likes to call this "big and fluffy."

Pictured: actual HDL and LDL.

When a person suffers from insulin resistance, they cannot burn fat easily, since the body continues to make Malonyl-CoA in the presence of insulin, shutting down the CPT1 gate long chain fatty acids take into the mitochondria.  Therefore, a person will not transport much fatty acid, meaning the sizes of HDL and LDL are relatively small.

Not so big and fluffy.

Let's put in some numbers here.  In this instance, the patient is unquestionably insulin resistant.  While they are not considered a type 2 diabetic (since their HbA1c, which I'll talk about later, was less than 6.5), they scored a perfect 100 out of 100 on the sliding scale of insulin resistance.  So, while not considered a diabetic, this person was certainly considered pre-diabetic, and was extremely insulin resistant.

This person's first test results showed an LDL size of 20.4 nm (at around the 25th percentile and within a high-risk range), and an HDL size of 8.5 nm (below the 25th percentile and well within a high-risk range).  Healthy individuals have LDL and HDL sizes of larger than 21.2 nm and 9.6 nm, respectively. For those of you whose eyes just glazed over, these numbers are really small, which means that the patient has a high risk of developing diabetes, as well as eventual cardiovascular disease and other metabolic problems.

After a few months on a low-carb diet, the numbers have changed significantly.  The size of the LDL particles has grown from 20.4 nm to 21.1 nm, which is almost to the 75th percentile and is considered at a low risk for cardiovascular disease.  HDL size has grown from 8.5 nm to 9.1 nm, which, while only almost at the 50th percentile, is a much better number, and a marked decrease in risk for developing cardiovascular disease.  Sweet!

Go science!

Even better--the insulin resistance score has decreased from a huge 100 to a low 25, well below the 25 percentile and in optimal range to prevent cardiovascular disease and the development of type 2 diabetes.

The patient's HbA1c (a number used primarily to diagnose diabetes) has also decreased significantly as well.  Originally a 6.1 (0.4 away from being considered diabetes), the number has dropped to 5.2, well beneath the threshold of diabetes and pre-diabetes.  This indicates that diabetes really shouldn't be considered a chronic disease any more--problems with insulin resistance, HDL, HDL, and other metabolic processes can be regulated by using medications and good, old-fashioned understanding of scientific principles, and possibly even cured completely.

And if that isn't a good way to end, I don't know what is.  Thanks for reading!

A Return to Some Biochemistry: Part 1

Hey, everyone!  I hope you've been keeping busy.  My family is actually at a Lynyrd Skynyrd concert at the moment (my friend's little brother is one of the opening acts, how cool!), so what better way to spend time than writing about biochemistry.  I can't think of anywhere I would rather be at all!

Anyway, I'm going to return to some biochemistry!  I'll actually split this up into two separate posts--this one will be about the function and purpose of certain molecules, and the next one will be about how a low-glucose diet can change them and make them healthier.

This post is going to be about fat oxidation.  Exciting!

But let's review a little first.  Remember that with an excess of glucose, the body produces Malonyl-CoA, which shuts down the oxidation of fat in the mitochondria.

Excess of glucose.

Inhibition of CPT-1, which long chain fatty acids use to get into the mitochondria.

When you don't eat sugar, Malonyl-CoA isn't produced, so the CPT1 gate is opened, which means long chain fatty acids (what's making up triglycerides, for the most part) can be burned as fuel.  Yay!

So, how do the triglycerides get to the mitochondria, anyway?  A healthy person doesn't have any ectopic fat immediately available, so there's no fat in the muscle tissue.  A person on a low-carb diet can't get fat from the liver, either, since they would have burned through all of that already, too.  Well, the obvious answer is from regular fat cells.

From your booty.

Basically, when your body needs to transport fat from one place to another, it produces molecules called lipoproteins.  These lipoproteins act like vacuum cleaners--some suck long chain fatty acids out of fat cells, and some suck these fatty acids into metabolizing cells.

First, let's look at low-density lipoproteins (LDL for short).

As modeled by this fetching vacuum cleaner.

When the body needs to move fat from a fat cell, it sends over some LDL.

This is what Photoshop was made for.

Then the LDL sucks triglycerides from the fat cell,

Fun fact: it actually looks exactly like this.

meaning the LDL is now carrying around long chain fatty acids.

This looks really silly.

The LDL then takes the long chain fatty acids to where they're needed.  Let's say it's a muscle cell.

I'm starting to regret using vacuums.

A different lipoprotein, called high-density lipoprotein (HDL for short) takes over from there.  It takes the long chain fatty acids brought to the cell by LDL and takes it into the cell.

A challenger appears!

What am I doing with my life?

Once the long chain fatty acids are inside the cell, they can enter the mitochondria through the CPT1 gate and be burned for fuel.

We're done with this madness.

And now, with this silly vacuum cleaner nonsense done with, I can end this here for now.  Tune in next time for the thrilling conclusion: what does all this actually mean in terms of health?  Thanks for reading!