The Big Picture: Short Chain Fatty Acid dehydrogenase, Metformin, Pancreatic Beta cells, NADPH, riboflavin and thyroid.

So how does Metformin work?  Metformin raises the AMPK which RAISES insulin.  Here it states that the CBP (CREB binding protein) which tells the Pancreatic beta cells to release insulin. 

To test their hypothesis, researchers induced insulin resistance in mice by feeding them a high-fat diet over several months. Mice on high-fat diets developed insulin resistance, and their high blood glucose levels did not drop to normal after eating. Once treated with metformin, however, CBP was activated to the levels of nondiabetic mice, and their blood glucose levels returned to normal. However, when given to diabetic mice with defective copies of CBP, metformin had no effect on blood glucose levels, a proof that metformin works through CBP.
Researchers further were able to determine that metformin worked on one particular section of CBP by studying the drug's effects in mice with normal CBP and in mice missing this section of their CBP. The mice with normal CBP responded to metformin with a drop in their fasting blood glucose -- much like diabetes patients do -- while the mice missing that section in their CBP had no decrease in their blood sugar.
Because CBP is involved in growth and development and a variety of metabolic processes in other organs, this newly discovered pathway may hold therapeutic promise for conditions like growth retardation, cancer and infertility, investigators say.

Another important finding in the study: investigators have discovered a biomarker that can predict how well a person will respond to treatment with metformin and help doctors determine the optimal therapeutic dose, which can vary widely from person to person. The Hopkins team has found that in mice, metformin changes CBP in white bloods cells -- just as it does in liver cells -- creating a molecular marker that is easily measured via a standard blood test.

http://diabetes.diabetesjournals.org/content/55/11/3193.full

 Backtrack a little bit.  The researchers said that cAMP from glucagon slows down the metabolism.  This is not entirely true until you actually read through the cascade of events.  Glucagon releases cAMP that tells the body that it's in a negative energy balance and to hydrolyze the triglycerides to release energy from the fat/adipose stores for fuel.

cAMP triggers PKA which triggers CREB that actually tells the body to slow down metabolism.

So all Metformin is really doing is slowing down metabolism to trigger insulin spikes.

Since PCOS is affiliated with insulin (because it is caused by TOO MUCH INSULIN)- we have to reevaluate type 2 diabetes to see where PCOS comes in.

The Pancreatic alpha cells release glucagon. The body needs ZINC in order for this to happen.

The Pancreatic Beta cells not only release insulin, it releases other things like HADHSC which encodes the RIBOFLAVIN based short chained fatty acid dehydrogenase.  Which literally breaks down short chained fatty acids.

Backtrack a little more, short chained fatty acids increase the MCT that tells the pancreatic Beta cells to release insulin.   If you didn't already know, many babies in the US are born with disorders of fatty
acid metabolism and come down with very severe bouts of hypoglycemia.  They have long chain, mid chain and short chain fatty acid dehydrogenase.  This can be triggered or amplified with very weak thyroid activity and a lack of riboflavin.   IT can also be affected by inflammation which is what I'm thinking. 

TGF-b1 blocks TSH.  Leptin releases B-Cells from the lymphnodes? 
Speaking of leptin, the mesenchymal stem cells need leptin to tell it to make stuff other than adipose tissue.  This is where C/EBP and CBP slows down the metabolism.  Which makes it easy to gain weight because it triggers too much insulin.

By the way, FAT OXIDATION IS BLOCKED BY INSULIN!!!  INSULIN BLOCKS THE HYDROLYSIS OF TRIGLYCERIDES TO RELEASE ENERGY.  

INSULIN BLOCKS FAT LOSS.

Pyruvate can upregulate MCT1 to tell Pancreatic Beta cells to release insulin too. 

The thymus T-cells have insulin receptors!  Gnrh increases t-cells and that triggers more insulin which results in higher FSH/LH which results in ... um... cysts on those ovaries.

Back to adults now.  The "experts" assume that all people in the world are type 2 diabetics and in need of insulin instead of tackling inflammation, weak thyroid, hyperinsulinemia/hypoglycemia/weight gain.

This is a very dangerous assumption because the human body need a balance set of signals to straighten itself out.  Anything that messes up the balance the body creates for itself is infact dangerous. http://diabetes.diabetesjournals.org/content/55/11/3193.full
 
 If you've seen pictures of starving babies in Ethiopia, they are very skinny with swollen bellies.  They're the kwashikor babies.  The bellies are swollen from some inflammatory response to starvation.  Their bodies can no longer metabolize the short chained fatty acids because their weak thyroid disables riboflavin to be converted into the necessary enzymes that create short chained fatty acid dehydrogenase.  These short chained fatty acids, including the overhyped butyrate, acetate, etc.
WILL RELEASE INSULIN.  :)  Which increases ornathine, without thyroid activity the ornathine dehydrogenase cannot be formed so we get arginine and lots of nitric oxide.

Who else has really slow metabolism and a lot of nitric oxide?

Women with PCOS!
 
The dumb idiot shills are screaming that we should throw Omega 3's at them.  Without a healthy thyroid response, how are their bodies going to manage the probiotics and SCFA's in the first place?

Others say "protein".  Which protein?  Tyrosine?  Proline?  Proline is already bioavailable.
Leucine increases weight and blood cholesterol if you are already hypoglycemic/hyperinsulinemic because leucine triggers..........  ... insulin spikes!

These incomplete story telling vague blanket statement "scientists" say that short chain and mid chained fatty acids are better for you than long chained fatty acids.  They don't include the fact that leptin is the source of the mid chained fatty acid dehydrogenases or else that mid chained fatty acids combine with Acyl Coa to create GHRELIN. You  know, that hunger peptide with all too real psychological effects. CART and NPY-y5R (the peptides affiliated with cocaine addiction) are upregulated with ghrelin.



Guess who has a BIOAVAILABLE level of mid chained fatty acids?  ANOREXICS!   Anorexics dont' eat coconut oils.  AS a matter of fact, they don't eat anything at all!   Thats' why they're anorexics.
Bulemia is triggered by ghrelin.  This is the sticky wicket with eating disorders. 

Also, healthy thyroid/riboflavin levels are required for the HADHSC to create short chained fatty acid dehydrogenase. http://link.springer.com/article/10.1007%2FBF01800662#page-1

If not, you get lots and lots of insulin response to glucose/fat intake.  Yes FATS INCREASE INSULIN BY RELEASING GLP-1.

NOW.

Add Gnrh from Kraft dairy products to your system and you have xeno-estrogens and other steroids that activate the T-cells and trigger high insulin levels. High fasting insulin levels.

Think of what the nitric oxide is doing.  Increasing more harmful metabolic perameters that are not necessary anti-inflammatory.  SREBP-1.  HIGH CHOLESTEROL.

Plasma membrane cholesterol accumulation has been implicated in cellular insulin resistance. Given the role of the hexosamine biosynthesis pathway (HBP) as a sensor of nutrient excess, coupled to its involvement in the development of insulin resistance, we delineated whether excess glucose flux through this pathway provokes a cholesterolgenic response induced by hyperinsulinemia.

Exposing 3T3-L1 adipocytes to physiologically relevant doses of HYPERINSULINEMIA (250pM-5000pM) induced a dose-dependent gain in the mRNA/protein levels of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR). These elevations were associated with elevated plasma membrane cholesterol.
Mechanistically, hyperinsulinemia increased glucose flux through the HBP and O-linked β-N-acetylglucosamine (O-GlcNAc) modification of specificity protein 1 (Sp1), known to activate cholesterolgenic gene products such as the sterol response element-binding protein (SREBP1) and HMGR. Chromatin immunoprecipitation demonstrated that increased O-GlcNAc modification of Sp1 resulted in a higher binding affinity of Sp1 to the promoter regions of SREBP1 and HMGR. 

Luciferase assays confirmed that HMGR promoter activity was elevated under these conditions and that inhibition of the HBP with 6-diazo-5-oxo-l-norleucine (DON) prevented hyperinsulinemia-induced activation of the HMGR promoter. 

In addition, both DON and the Sp1 DNA-binding inhibitor mithramycin prevented the hyperinsulinemia-induced increases in HMGR mRNA/protein and plasma membrane cholesterol. In these mithramycin-treated cells, both cortical filamentous actin structure and insulin-stimulated glucose transport were restored. Together, these data suggest a novel mechanism whereby increased HBP activity increases Sp1 transcriptional activation of a cholesterolgenic program, thereby elevating plasma membrane cholesterol and compromising cytoskeletal structure essential for insulin action.http://www.ncbi.nlm.nih.gov/pubmed/23315940

Vitamin B3 is NADPH, which is required as a lipid raft for iodotyrosine deiodinase that breaks down thyroid T3 and T4 in the liver to complete the thyroid feedback loop.  If there's' too much t3, the thyroid will not release any more which can slow down your metabolism. 

Thiols convert T4 to T3.
http://www.biochemj.org/bj/157/bj1570479.htm

"Plasma iodide is partly replenished by that lost from the thyroid into the blood and by iodide liberated through deiodination of iodothyronines in peripheral tissues"https://www.inkling.com/read/williams-textbook-of-endocrinology-melmed-polonsky-larsen-kronenberg-12th/chapter-11/iodine-and-the-synthesis-and

Iron and copper are good for the thyroid as is iodine, selenium, zinc and tyrosine.
http://perfecthealthdiet.com/2010/12/micronutrient-deficiencies-an-underappreciated-cause-of-hypothyroidism/

What is overlooked is the PHOSPHATE part of the equation.

ATP (Adenosine Tri-Phosphate) is the energy currency in all living creatures.
ADP (Adenosine Di-Phosphate) is the "engine"?  This is Adenosine Tri-phosphate minus a phosphate.

IGF-1 is upregulated with ADP which leads to platelet aggrigation and proliferation.  Many inflammatory markers trigger apoptsis.  Apoptsis slows down metabolism, this we need to be careful about since the science should only be using apoptsis to correct problems since metabolism is supposed to keep everything else in check.

AMP (Adenosine Mono-Phosphate) happens during energy metabolism and it's used to tell the body that it's in a negative energy balance.  cAMP from glucagon stores tells the body to release energy from adipose tissues.  MAPK releases muscarenic receptors from acetylcholine that tells the body to release bile salts to block the brush border membrane that blocks the binding of adenosine A1 receptor to adenosine which upregulates leptin and calcitonin (it competes with cAMP? I'm not sure about which part of the cascade it interrupts).  It could possibly explain why the body doesn't absorb necessary B vitamins required for a healthy metabolism.  AMPK releases insulin.   AMPK competes with xanthine dehydrogenase which upregulates leptin, leptin which increases thyroid activity.

In a nutshell, this picture shows how glucose metabolism works and the enzymes involved featuring ATP and ADP.  Citrate is a product of ornathine and arginine.  Pyruvate upregulates Malonyl CoA that blocks Carnitine PalmitoylTransferase 1 (cpt1) that pulls long chained fatty acids into the mitochondria to be oxidized for fuel.  Carnitine PalmitoylTransferase 2 (cpt2) pulls the long chained fatty acid into the cell for oxidation, it's blocked by odd chained fatty acids and when this happens the person gets a bad case of rhabdo.  But anyways, Carnitine is created from lysine and methionine at the request from the thyroid (t3).




http://www.bio.miami.edu/tom/courses/bil255/bil255goods/07_glycolysis.html




When Malonyl Coa blocks CPT-1 induced beta oxidation of fat cells, your body goes into some kind of anaerobic metabolism and releases lactate.  It releases carbon dioxide when it's in aerobic metabolism because carbon binds the fat cells together.

But anyways, you see how insulin is released during glucose metabolism and how you get pyruvate from this.  MCT-1 transporters turn and keep the pancreatic beta cells releasing insulin which blocks hydrolysis of triglycerides to use fat as fuel.   So if you're trying to lose weight, this is a road block you have to get past but this elaborates on how insulin works to store ATP. 

Increased ATP/ADP ratio triggers insulin response. 
Adiponectin/Leptin ratio increases insulin response.  (AMPK increases adiponectin)
Acetylacetone/Beta-hydroxybutyrate increases insulin response. 

Increased ATP/ADP in the cytosol is correlated with increased thyroid activity (T3) The NADPH plays a part in this since likes to sit in the cortisol. 

Decreased ADP/O = a drop in thyroid activity because during a negative energy balance, the ADP loses one phosphate and becomes AMP.


Studies show that phosphate supplementation prevents a drop in thyroid levels when women were dieting.  http://www.drdebe.com/articles/reviving-your-thyroid

During periods of phosphate supplementation, the resting metabolic rate (RMR) increased by approx. 12% (p < 0.05) in group 1 and 19% (p < 0.05) in group 2. Phosphate supplementation ameliorated also a decrease in plasma triiodothyronine level and a decrease in thyroxine to triiodothyronine ratio. There were no differences between groups in the plasma insulin, catecholamine, growth hormone, cortisol and testosterone levels. Phosphate supplementation did not affect plasma lipids or blood glucose concentration. It is concluded that phosphate supplementation in obese patients on a low-energy diet enhances RMR irrespectively of the rate of weight loss. This effect seems to be, at least partly, due to an influence of phosphates on peripheral metabolism of thyroid hormones.http://www.ncbi.nlm.nih.gov/pubmed/8807564

NADPH is a reducing agent.  It's blocked by Acetyl Coa Carboxylase (ACC) and appears to be perfectly proportional to good metabolism. NADPH loses that one phosphate to bind with something else.

Again, Vitamin B3 or Niacin is NADPH.

And to conclude, you can easily see a direct correlation between parathyroid and thyroid activity.
The feedback look is really fascinating.  Leptin is directly proportional to calcitonin release (from Adenosine A1 Receptors in the brush border membrane).  Calcitonin is released from the Parafollicular C cells from the thyroid to reduce the levels of Calcium.  The Calcium receptor Ca2+ calmodulin dependant kinaise beta increases AMPK. 

Calcitonin is converted to bioavailable Vitamin D which results in IGF-1 which blocks acetyl coa carboxylase (ACC).

ACC increases malonyl Coa and increases ATP/fat storage.

http://en.wikipedia.org/wiki/Acetyl-CoA_carboxylase















So in a nutshell, you could say that IGF-1 blocks fat storage.

Now notice the positive correlation between thyroid secretion of calcitonin from the C-cells and thyroxin.

Here's how the calcium feedback loop works.  If the Parathyroid gets the message that the blood calcium is low, it will release calcium in the blood and tell the thyroid not to release the calcitonin.
Sometimes the parathyroid gets the message to release Calcium at a seriously high level and a very high parathyroid hormone level in the system is an indicator of either cancer or metabolic troubles.  People who work out too hard, ie. Cross Fit?  Get rhabdo which is caused by high PTH levels. 

I get rhabdo.

Even without rhabdo, a heightened release of calcium comes from the bones and will cause osteoporosis.

So taking Calcium supplements prevents a fall in calcium levels read by the Ca2+ Calmodulin dependant Kinase beta so it will release Calcitonin.

Calcium is affiliated with inflammation when it's released by the metabolism of glucose. 
Calcium is a key signal for naive T-cells in the thymus (which can result in an increase in insulin).
http://www.ncbi.nlm.nih.gov/pubmed/11244045

Then guess what happens?  The T-cells release NITRIC OXIDE that BLOCKS Th17 cells.

T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation.

http://www.ncbi.nlm.nih.gov/pubmed/23797094 

Th17 comes from IL-17 which comes from CD4+ which is upregulated by our metabolism and thyroid stimulator LEPTIN. Th17 is a T-cell.  Leptin triggers the release of B-cells.http://www.immunityageing.com/content/10/1/3
http://sciencescape.org/paper/23199324#301
Leptin is upregulated with adipose tissue.  It's not always correlated with obesity and sometimes obesity is caused by leptin resistance or a low level of leptin. 

C/EBP blocks leptin's signal to mesenchymal stem cells and tells it to create fat cells instead of cartilage, muscle, bone or hemoglobin.  CBP is the C/EBP binding protein.   TGF-beta 1 is a t-cell that tells the thymus to lower T-cell production.  TGF beta 1 blocks leptin.

 Now you get the gist.  Everything is connected and now you know why it's very important to eat your antioxidants.

AND THE BEAT GOES ON...