Another Success Story - long but hopefully worth it.

[Guest guest]

I guess the old saying: " It's the exception that proves the rule " is right, and

I'm the exception. ;-)

When I told back in October that I intended to stay on Iodoral while

doing my T3 therapy, she said she'd be very interested to know if it worked

because she hasn't seen many people for whom that is true. Well, it worked, so

she can now add me to the shortlist. I've continued to take a single 12.5 mg

tab every morning. No HC or Isocort or Iron supplements either. Nothing but T3,

and not all that much required for success. I never took over 75mcg and that was

only for a few days. And my ferritin is only 47.

Here are the stats from my latest labs:

Began 's protocol on November 5, 2009

After ten days, reached 75mcg per day on November 15 -- became hyper, with 99+

temps and sweats, pulse in the 90's -- cycled down to zero in a week and then

began again on November 23 using a modified protocol. Modified in this case

means I began with 6.25 mcg and added more T3 very slowly, as Val recommends,

and also that unlike 's recommendation did not take compounded

time-release T3 but Cynomel.

BLOOD TEST on Dec 4th:

TC and LDL dropped 100 points!

Triglycerides dropped from 67 to 42

HDL rose from 88 to 97

A1c dropped a bit to 5.0

APO B/APO a-1 = .56 -- HALF the *lowest* risk for CHD!

FT3 = 404 (up from 291)

RT3 = 10 (down from 25).

Ratio = 40.4!!! (up from 11.64)

T4 Total = 3.7 (4.5-12.5)

FT4 = 1.0 (1.4-3.8)

Sodium = 143 (128-145)

Potassium = 4.9 (3.6-5.1)

Ferritn = 47 (20-288)

Iron = 67 (40-160)

I reached a dose of 50mcg on 12/16. My temps reached 98.6 steady two days after

that. By 12/25 my temps were 99.9 so I reduced my dose to 37.5 and have been

there every since. My temps have been rock solid at 98.6 all day, every day for

the last 3 weeks. No hypo symptoms at all, and it's clear from my blood tests,

lack of symptoms and high energy that my T3 is reaching my cells. I've lost 2

inches from my waist and abs in this time -- mostly due to the excess

cholesterol dump I think, since it binds to fatty acids and is excreted.

Even more importantly, I've been doing deep, deep medical research these last

two months and believe I have found the cause of my RT3 problem to begin with:

Leptin Resistance. My blood test for that revealed that I am severely leptin

resistant even though I'm no longer insulin resistant to any degree! I've

decided to write about it here in the hopes that it will ring some bells for

other members and perhaps help them as well.

Leptin is the King of all the hormones. It manages and gives orders to them all,

including, tellingly, insulin -- yet it takes orders from no hormones. It reigns

supreme. It is created from your adipose fat cells, so the more stored fat you

have, the more leptin you will produce.

When you begin to eat, your leptin travels up through the bloodstream to the

blood-brain barrier, where with the help of a protein gets folded into a

three-dimensional shape that lets it slip through a precisely shaped keyhole to

reach the hypothalamus. The leptin gives your brain a lot of information that

will be used to determine how to *handle* your ingested energy: burn or store.

And the brain has many tools at its disposal to make your metabolism do exactly

what it wants, from making cells insulin resistant (thus storing more fat) to

signaling T4 to stop converting into T3 and start converting to RT3. Or, to

conversely, to have it make more T3 and 'turn up the heat' to burn more energy.

YOU don't control this. Leptin and your brain does.

But leptin does more. It signals the brain about how much energy *this* meal

contains versus how much stored fat (the brain only sees 'energy' or 'not

energy') you have. If the brain thinks it has sufficient energy it raises

another hormone to send the signal for you to stop eating. That's when you get

that " Can't eat another bite " feeling and you put down the fork, no matter how

delicious the food. Doggy bags were created to deal with this hormone. And

how it works is important, because that signal makes glucagon (which controls

insulin rise) decrease via a hormone called amylin.

And leptin does still more. It acts like an A1c test for fat, telling the brain

not only about the meal you're eating now, but about how much energy you've

eaten over the last several days. [Which explains why we see weight gains on the

scale not the day after a binge, but 72 hours later]. This is the crucial

information, because the brain doesn't like to make sudden changes. It gathers

the leptin info over the course of a few days and only then decides what

hormones to use to either burn off excess energy or RETAIN energy by changing

your metabolism via your hormones and liver.

Amazingly, leptin was only discovered in 1994! And it set off a true Gold Rush

among Big Pharma because of how it was discovered: mice bred to be fat (no

matter how little they ate) were discovered to have low levels of this hormone,

yet when it was synthesized and injected into the mice, they overcame their fat

genes and became skinny. Oh! Big Pharma thought -- the Holy Grail! We'll

synthesize leptin, patent it, and have the Mother of all Blockbuster Drugs to

sell, one that will reverse obesity with a single pill.

They poured millions and millions into R & D, but when the first human trials were

done, disaster loomed. Yes, the obese people injected with it did lose weight.

For the first two weeks. Then they stopped losing, gained it all back, and put

on a bit more for good measure. And this was true for all study subjects.

Turns out, when they actually examined fat people, they had four to five times

MORE leptin than thin people. WTF???

At this point, all R & D stopped, and some companies sold their leptin divisions.

One company -- Amylin -- bought out the biggest, and more about them later.

So, by 2000, what researchers knew is that obese people are not only often

insulin resistant (which begins in the liver), and not only often thyroid

resistant (which begins in the liver), but are almost all leptin resistant --

and in all three cases, the result is the same: the correct hormone is produced,

but is blocked from reaching the cells, which in turn means that the correct

signaling cannot get through. The actual process for this is that the leptin

cannot be folded into the proper shape and thus cannot cross the blood-brain

barrier.

With little or no leptin reaching it, the brain believes the body is in danger

of starvation regardless of actual calories consumed, and takes immediate steps

to slow down the metabolism. So you get fat, which creates more pooled leptin

and you become ever more leptin resistant. It's a vicious circle because for

hormones, the ability to reach the cells with the right signal is everything.

This was why, for instance, my cholesterol kept rising until it was sky-high: T3

carries the signal the liver needs to know there is sufficient cholesterol in

the blood, but RT3 lacks that signal. As soon as cytomel allowed T3 to once

again reach my cells, the correct signal reached the liver, which immediately

dumped excess cholesterol out of my body.

When leptin doesn't reach the brain, it's much, much worse. What it means, in

essence, is that while I see a still-overweight woman when *I* look in the

mirror, what my *brain* sees is a very thin woman on the edge of starvation. And

it will do everything in its considerable power to conserve as much ingested and

stored energy as possible.

What this usually means is:

1: During a meal, the leptin that normally would go to the brain saying 'lots of

energy here, boss' doesn't get through. So the brain never sends the hormonal

system of 'you're full you idiot, so stop eating!' Thus, leptin resistant people

are usually always hungry and always eating.

2: In order to conserve as much energy as possible in the easiest to store form

(fat), the brain sends out a specific hormone that not only tells us to eat, but

to eat lots and lots of carbs, particularly sweets. That's because the brain

knows this will ultimately create insulin resistance, which means more

triglycerides made in the liver, which means more stored fat. This is why most

leptin resistant people say they 'crave' sweets. They do, but only because they

are being ordered by the brain to crave them.

But what happens when the brain is stored in a body that eats high fat, low

carb, and is thus not only satisfied with less food, but with almost no sweets?

I'll tell you what happens: the thwarted brain simply pulls another tool from

the box for conserving energy: the thyroid hormones. By creating a RT3

imbalance, energy and fat are stored not burned, and the metabolism is slowed to

such a state that no amount of exercise, no eating this or not eating that, no

calorie reduction will overcome it. In fact, the more you do to lose weight, the

more the leptin-deprived brain conserves energy. This finally explains the

mystery of how morbidly obese patients can be locked into a hospital metabolic

ward, fed 500 calories a day -- and gain weight. Mysterious no more.

But what to do about it, that's the question. And for that, someone needed to

show exactly how people become leptin resistant (and diabetic, too!). And

finally, someone has. In a major study done at Boston Children's Hospital

Research Center in 2008 and published in the January 2009 issue of " Cell

Metabolism " as: " Endoplasmic Reticulum Stress Plays a Central Role in

Development of Leptin Resistance " this mechanism was revealed. From the article:

" The endoplasmic reticulum (ER) is a sophisticated luminal network in which

protein synthesis, maturation, folding, and transport take place. Perturbation

of these processes in several different pathological states creates a condition

defined as ER stress and leads to activation of a complex signaling network

termed the unfolded protein response

(UPR). Previous studies have demonstrated that ER stress and activation of UPR

signaling pathways play a dominant role in the development of

obesity-induced insulin resistance and type 2 diabetes. Furthermore, reversal of

ER stress with chemical chaperones—agents that have the ability to increase ER

folding machinery—increases insulin sensitivity and reverses type 2 diabetes in

obese mice.

SUMMARY

Leptin has not evolved as a therapeutic modality for the treatment of obesity

due to the prevalence of leptin resistance in a majority of the obese

population. Nevertheless, the molecular mechanisms of leptin resistance remain

poorly understood. Here, we show that increased endoplasmic reticulum (ER)

stress and activation of the unfolded protein response (UPR) in the hypothalamus

of obese mice inhibits leptin receptor signaling. The genetic imposition of

reduced ER capacity in mice results in severe leptin resistance and leads to a

significant augmentation of obesity. Moreover, we show that chemical chaperones,

4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have

the ability to decrease ER stress, act as leptin-sensitizing agents. Taken

together, our results may provide the basis for a novel treatment of obesity. "

To summarize the summary: the study proved that when something/s (still unknown

but I believe was right about outside stress, like major surgery in my

case, which is when my weight loss stopped after losing 65 pounds but 20 pounds

from goal) stresses the ER in the brain, leptin resistance begins. The ER then

activates the UPR (unfolded protein response), which means the leptin can no

longer get through. And then all metabolic hell ensues.

What is stunning about the study though, is that the researchers went further.

Once they'd proved the faulty mechanism, they decided to test whether or not

sending along a 'chaperone molecule' with the leptin would undo the UPR and let

the leptin through. And they not only did it, they did it with two non-toxic

drugs already approved by the FDA for treating other diseases!

When they gave obese mice a ten-day 'pre-treatment' of 4-PBA the mice didn't

lose weight or fat, but once leptin was added to the injections, those mice grew

thin and *lean* with lots of lost body fat. And the mice stayed lean. When their

hypothalamus' were harvested, it showed that indeed leptin signaling (leptin

sensitivity) had been restored.

The real eye-opener was with TUDCA though. Just treatment with it alone caused

major weight and fat loss. And when leptin was added, just a fraction of the

amount used with the 4-PBA was needed for even more drastic weight loss. Which

was also stable.

TUDCA is biologically identical to UDCA (sold as Actigall in this country),

which is used to treat liver diseases. TUDCA was used by the researchers because

it's an inject-able liquid, whereas the UDCA is taken orally. Isn't it amazing

how everything metabolic somehow leads back to the brain's connection with the

liver? And the 'U' in UDCA stands for 'urso' -- Bear in Latin -- because it

comes from bear bile. The liver. And it's been used by Native Americans for

centuries to treat illness. It is such an incredible substance that there are

now clinical trials all over the world using TUDCA to treat Huntington's

Disease, Cystic Fibrosis, and Altzheimer's. Researchers believe they are on the

verge of major breakthrough's for all three, thanks to this simple substance.

So, armed with this knowledge (and the fact that I had diagnosed my own RT3 and

Cholesterol problem, and treated them both of them myself successfully), I met

with my Endo. I was there for two hours. She did most of the question-asking,

and I provided most of the answers.

When we were done, she agreed that it was indeed likely that my RT3 problem was

originally caused by my leptin resistance, and also with my hypothesis that if I

did not treat and cure the original problem (LP), my brain would continue to be

leptin-deprived, continue to think I'm skinny, and would only pull another

metabolic trick out of its hat to retain my weight and fat. I believe this alone

can explain why some people on T3 can lower RT3 and get T3 back into the cells

but not lose weight. And why for many, RT3 and/or hypo symptoms return when they

return to dessicated thyroid.

She agreed to support my being an experiment of one, with help from the Doctor

who is leading the UDCA Cystic Fibrosis study at the University of Michigan,

whom I contacted and spoke to at length.

Starting this week I will begin a 'pre-treatment' of Symlin (pramlintide

acetate) injections with the two sample 'pens' my Endo gave me. Symlin is a

synthetic form of Amylin, a sister hormone of leptin that plays a huge role in

proper insulin use in the body as mentioned above, by signaling the liver to

decrease production of glucagon. Type 1 Diabetics no longer make Amylin, and it

is either low or missing or not working properly in Type 2's -- which is not

surprising given that I believe this is their form of leptin resistance.

How it works:

" Symlin, by acting as an amylinomimetic agent, has the following effects: 1)

modulation of gastric emptying; 2) prevention of the postprandial rise in plasma

glucagon; and 3) satiety leading to decreased caloric intake and potential

weight loss. "

For me, the most important point is reduction of glucagon, which does not work

properly in leptin resistant people.

Symlin is made by the company Amylin, which was the company I mentioned earlier,

that purchased the R & D and rights to patent leptin back in 2000. In fact, Symlin

has been shown to cause rapid weight and fat loss in type 1 and type 2 diabetics

who take it with their insulin (because I believe based on my research that it

too restores leptin signaling; see the Holtof site for more info) -- and the

company is currently in trials to convince the FDA to let them market it for

weight loss. Followed, no doubt in my mind, by a form of leptin they are working

to produce.

If my hypothesis is correct, in two months Symlin will fully restore my

amylin/leptin connection, after which I will begin supplementing with

UDCA/Actigall. I fully expect to have my letpin resistance restored, my T3

problem permanently fixed, and my metabolism completely healed. I also expect to

lose the 20 pounds I couldn't before, as well as the 10 I added back when my RT3

began to rise. And I fully expect my insulin sensitivity to grow even better,

and my A1c to continue to fall.

Knowing now what I know about the brilliance of our intricate hormonal and

metabolic systems, and the ability of our brain to rule them *absolutely*

despite any of our intentions or actions, I find the advice " To lose weight

simply eat less and exercise more " akin to saying " To lose weight bury a chicken

bone in the backyard at the full moon and say the following incantation. " Both

will be equal in their efficacy. Same thing for " cut out dairy, don't eat

grains, count calories, don't count them, eat this, don't eat that, " etc. etc.

etc.

A person with a perfectly healthy and functioning metabolism will not store

excess energy (fat) in the first place. If they feast a day or so they might

gain a pound or two, but a week of eating as usual will see that gone without

them having to do anything, or eat anything, or not eat anything special. That's

how we evolved, and that's how we're still built. Our ancestors never had to

'diet' and neither should we.

Abuse or stress my make that metabolism non-functioning, but to cure it requires

science, not anecdote or one food over another. My heart aches as I read the

same posts over and over on all the various forums dealing with obesity, from

calorie-counting forums to low-carb forums. Everywhere is anecdote and useless

advice, and science nowhere to be found. I've written this very long post hoping

that here at least, with Val and Nick, science will have a place and that their

readers will now have a test -- leptin serum level -- to begin, and some

solutions to follow.

To a Happy and Healthy New Year for us all...