Insulin Degrading Enzyme

What is it?:  Insulin Degrading Enzyme is a thiol zinc-metalloendopeptidase located on the cell surface and is responsible for insulin catabolism and degrading amyloid β-protein. Many of its functions and processes remain unknown.



Most Likely:
1) IDE can hinder the onset of Alzheimer's disease (1) (2) (3)



Maybe:
1) IDE can hinder the onset of type 2 diabetes (3) 




Theory:
1) High levels of free fatty acids in the blood can inhibit production of insulin-degrading enzyme (4) ... (of course this seems obvious because in healthy people FFAs increase when blood glucose decreases, leading to less insulin needed by the body)






Studies that contributed:
1) Insulin-degrading Enzyme Rapidly Removes the β-Amyloid Precursor Protein Intracellular Domain (AICD)
http://www.jbc.org/content/277/16/13389.full

2) Degradation of Alzheimer's B-Amyloid Protein by Human and Rat Brain Peptidases: Involvement of Insulin-Degrading Enzyme

http://www.springerlink.com/content/u1nq74521582520m/

3) Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis

http://www.sciencedirect.com/science/article/pii/S0197458005000199

4) In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters

http://endo.endojournals.org/content/144/6/2404.full.pdf

Studies that didn't contribute (but still worth reading):
--Insulin-degrading enzyme
http://cat.inist.fr/?aModele=afficheN&cpsidt=3107042

--Alzheimer's β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme
http://www.sciencedirect.com/science/article/pii/0014579394003874

--Insulin-degrading enzyme is differentially expressed and developmentally regulated in various rat tissues

http://endo.endojournals.org/content/132/2/604.short

--Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats

http://hmg.oxfordjournals.org/content/9/14/2149.full

--Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

http://neuro.cjb.net/content/24/49/11120.full

--Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

http://www.nature.com/nature/journal/v443/n7113/abs/nature05143.html

--Degradation of Soluble Amyloid b-Peptides 1-40, 1-42, and the Dutch Variant 1-40Q by Insulin Degrading Enzyme from Alzheimer Disease and Control Brain

http://www.springerlink.com/content/wj38321812010422/

--Neurons Regulate Extracellular Levels of Amyloid β-Protein via Proteolysis by Insulin-Degrading Enzyme

http://neuro.cjb.net/content/20/5/1657.full

--Insulin-degrading Enzyme Regulates Extracellular Levels of Amyloid β-Protein by Degradation

http://www.jbc.org/content/273/49/32730.full

--Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC153065/

Advanced Glycation End-Products

What is it?: Advanced glycation end-products are the final result of glycation reactions, which is an uncontrolled (no enzyme) reaction where a sugar molecule covalently binds to a protein or lipid molecule.

Most Likely:
1) Increasing consumption of glucose (I would suspect any sugar) increases AGE formation within the body (1) (3) (10)
2) A constant state of hyperglycemia increases AGE formation within the body (1) (3) (10)
3) AGEs are pro-inflammatory (7) (8) (11)
4) AGEs play a role in development of diabetes (5) (9) (11)

Maybe: 

1) Higher levels of AGEs are an accurate biomarker for cancer (2) (8)
2) AGEs accelerate diabetic damage and complications, especially vascular complications (3) (12)

Theory:
1) Oxidative stress increases AGE formation (3)

2) AGEs play an active role in the biology of the lung (4)
3) Shorter cooking times, at lower temperatures, with lots of water decrease AGE formation in food (I suspect this to be true based on my limited chemistry knowledge) (6)
4) Only 10-15% of AGEs from food make it into the bloodstream




Contributing Studies: 

 
1) Hyperglycemia-Induced Reactive Oxygen Species Increase Expression of the Receptor for Advanced Glycation End Products (RAGE) and RAGE Ligands http://diabetes.diabetesjournals.org/content/59/1/249.full

2) Receptor for advanced glycation end products (RAGE) soluble form (sRAGE): a new biomarker for lung cancer
http://www.elis.sk/download_file.phpproduct_id=1669&session_id=8rhr5sub8bg8ug1km661r4tif4

3) Advanced glycation end products and the kidney http://ajprenal.physiology.org/content/289/4/F645.full

4) The Receptor for Advanced Glycation End Products (RAGE) and the Lung
http://www.hindawi.com/journals/jbb/2010/917108/

5) Advanced glycation end-products: Implications for diabetic and non-diabetic nephropathies http://www.sciencedirect.com/science/article/pii/S1262363609001931#sec6

6) Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet
http://marshfieldceliac.weebly.com/uploads/2/5/5/7/2557865/ada_ages_in_food_reduction1.pdf

7) Expression of High-Mobility Group Box 1 and of Receptor for Advanced Glycation End products in COP
http://ajrccm.atsjournals.org/cgi/reprint/200903-0340OCv1

8) RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666642/

9) Smooth muscle cell pathophysiology and advanced glycation end products (AGEs). http://www.ncbi.nlm.nih.gov/pubmed/20412043

10) Biologic Variability in Plasma Glucose, Hemoglobin A1c, and Advanced Glycation End Products Associated with Diabetes Complications
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769979/?tool=pubmed

11) Advanced glycation end products, oxidative stress and diabetic nephropathy
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952094/?tool=pubmed

12) Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes
http://www.sciencedirect.com/science/article/pii/S0304416511000638

Studies that didn't contributed: (still good to read)

--Homodimerization Is Essential for the Receptor for Advanced Glycation End Products (RAGE)-mediated Signal Transduction
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906307/?tool=pubmed

--AGE, RAGE, and ROS in diabetic nephropathy
http://www.ncbi.nlm.nih.gov/pubmed/17418682

--Advanced glycation end products and receptor-oxidative stress system in diabetic vascular complications
http://www.ncbi.nlm.nih.gov/pubmed/19954478

--Therapeutic uses of drug-carrier systems for imidazole-containing dipeptide compounds that act as pharmacological chaperones and have significant impact on the treatment of chronic diseases associated with increased oxidative stress and the formation of advanced glycation end products
http://www.ncbi.nlm.nih.gov/pubmed/20486899

--Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: A role for Nrf2 in vascular protection in diabetes
http://www.sciencedirect.com/science/article/pii/S0939475309003172

--Deletion of the Receptor for Advanced Glycation End Products Reduces Glomerulosclerosis and Preserves Renal Function in the Diabetic OVE26 Mouse
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911065/?tool=pubmed

Saturated Fat

 The villainization of saturated fat is an appalling one that marks (in my opinion) the ultimate failure in nutrition as a science, and is a main marker of how nutrition is no longer a science (if it ever was) but a game of politics and money. It is stupid at best and dangerous at worst. I've tried rationalizing how saturated fat became the victim and I've figured it out...

How Saturated Fat Became The Enemy In One Act:

Some guy: "I wonder what people should less of/more of to stay healthy?"

Ancel Keys: "I've wondered the same thing but my data from my recent study is rather inconclusive."

Some guy: "Well that's a bummer..."

Ancel Keys: "Hey I know! Let's close our eyes and point at a list of suspects and whatever we point at will be the one that is detrimental to health and  I'll spin my analysis, review, data set, and conclusion to show this."

Some guy: "OK!!"

Ancel closes his eyes and plummets his finder down. It lands right in between saturated fat and sugar.

Ancel Keys: "Hmmmm..."

Enter John Yudkin. Audience applauds

John Yudkin: "Well the answer is obvious isn't it Ancel? It is sugar. All prior evidence shows this and your study also shows this if we look at all countries that you have data for."

Ancel Keys: "Yeah... but it can't be sugar, I mean veggies and fruit have sugar and they are the healthiest thing for you... besides saturated fat looks nasty."

John Yudkin: "Is fruit really that good for you though?"

Ancel Keys: "HERETIC!!! SPAWN OF SATAN!!! GET OUT OF HERE THIS INSTANT!!! I'LL BE SURE TO RUIN YOU FOR THAT!!!

John Yudkin is escorted out.

Ancel Keys: "Well it's settled eat less saturated fat and you will live longer, be thinner, and have less heart problems."

Some guy: "Alright!!"

Flash forward 10 years... Some guy is now 57 years old and having a heart attack because all his arteries are clogged. His final thought was how could this happen... I never at saturated fat. 

What is it?: Saturated fat is fat in which the triglycerides contain only saturated fatty acids, which are fatty acids that have no double bonds between the carbon atoms of the fatty acid chains (hence the name). The carbon chain of the fatty acid is fully saturated with hydrogen atoms. The difference between the many kinds of saturated fatty acids is the number of carbon atoms, which can range from just a few to over 30.


Most Likely:
1) Saturated fat is relatively benign when it comes to heart disease (1) (6) (7)
2) An increase of saturated fat increases LDL (mostly the large, puffy one) and HDL (2) (6) (8)
3) Replacing saturated fat with polyunsaturated fat, monounsaturated fat, and carbohydrates lowers total cholesterol, LDL, and HDL. Replacing with carbohydrates also increases fasting triglycerides. (3) (4) (5) (8) (9) (10)


Maybe:
1) Increasing saturated fat lowers V-LDL cholesterol (11) (12) 


Theory:
1) Increased saturated fat may increase heart disease in women (13)
2) Increasing consumption of lauric acid boosts HDL (14)
3) If suffering from heart disease lower saturated fat intake can prolong life (15)
4) Replacing saturated fat with polyunsaturated fat allows HDL to carry out its anti-inflammatory properties more effectively. (16)







Studies that contributed:


1) Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease
http://www.ajcn.org/content/early/2010/01/13/ajcn.2009.27725.full.pdf

2) Lowering Dietary Saturated Fat and Total Fat Reduces the Oxidative Susceptibility of LDL in Healthy Men and Women
http://jn.nutrition.org/content/130/9/2228.full

3) Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials
http://www.ajcn.org/content/77/5/1146.full

4) Dietary Fat and Risk of Coronary Heart Disease: Possible Effect Modification by Gender and Age
http://aje.oxfordjournals.org/content/160/2/141.full

5) Dietary fat intake and risk of coronary heart disease: the Strong Heart Study
http://www.ajcn.org/content/84/4/894.full.pdf

6) Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory
responses of adults with moderate hypercholesterolemia
http://www.jlr.org/content/43/3/445.full

7) Plasma C-reactive protein concentration is not affected by isocaloric dietary fat reduction
http://www.sciencedirect.com/science/article/pii/S0899900705003102

8) Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease
http://www.sciencedirect.com/science/article/pii/S0002934301009871

9) Are refined carbohydrates worse than saturated fat?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869506/

10) The effect of replacing dietary saturated fat with polyunsaturated or monounsaturated fat on plasma lipids in free-living young adults
http://www.nature.com/ejcn/journal/v55/n10/abs/1601234a.html

11) Dietary Carbohydrate Modifies the Inverse Association Between Saturated Fat Intake and Cholesterol on Very Low-Density Lipoproteins
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170517/

12) Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory
responses of adults with moderate hypercholesterolemia
http://www.jlr.org/content/43/3/445.full

13) Dietary fats and 16-year coronary heart disease mortality in a cohort of men and women in Great Britain
http://www.nature.com/ejcn/journal/v56/n8/full/1601509a.html#tbl3

14) Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials
http://www.ajcn.org/content/77/5/1146.full

15) Dietary fat intake and risk of coronary heart disease: the Strong Heart Study
http://www.ajcn.org/content/84/4/894.full.pdf

16) Consumption of Saturated Fat Impairs the Anti-Inflammatory Properties of High-Density Lipoproteins and Endothelial Function
http://www.sciencedirect.com/science/article/pii/S0735109706013386


Studies that didn't contribute (but are still good to read):

--Saturated fat–rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1177997/?tool=pubmed

--Effect of dietary cholesterol, trans and saturated fatty acids on serum lipoproteins in non-human primate
http://apjcn.nhri.org.tw/server/apjcn/Volume11/vol11sup5/S408.pdf

--Coconut oil as a protective carrier of dietary vitamin A fed to ruminants
http://www.ncbi.nlm.nih.gov/pubmed/9433672

--Dietary Saturated Fatty Acids Down-Regulate Cyclooxygenase-2 and Tumor Necrosis Factor Alfa and Reverse Fibrosis in Alcohol-Induced Liver Disease in the Rat
http://onlinelibrary.wiley.com/doi/10.1002/hep.510260622/pdf

Start Here

I figure the best place to start is the beginning (duh...) and in this case the beginning is the motivation for this blog.

I am the worst speaker ever.

Whether it be commenting on blogs, talking to someone face-to-face, on the phone, etc... I suck at conveying ideas in a compelling manner. Perhaps its the fact that I have two lazy eyes and never make eye contact... probably. So you may ask why is someone who can't talk blogging? The reason is rather simple: I may suck at talking but I'm very good at showing and doing... and that's what this blog is about.

This blog is going to show the studies available on various nutrition topics and based on evaluation of the studies draw conclusions on what we actually know and what is pseudo-science, bro-science, and just straight crap (Seven-Countries Study?).

The drawn conclusions will be broken up into three categories:

1) Likely True: This is the high honor, where there are at least three randomized, controlled, HUMAN trials, performed in a way that minimizes confused and incorrect results.

2) Maybe: Where there are one or two decent-good studies done in the area, but really needs more research before incorporating it into your daily life.

3) Theory: There is only one good study and some surveys/animal studies that back the idea, definitely needs more research before going long term on the idea.

So what is a good study?

A good study is a human study of a large population that is randomized and preferably double-blind, only looks at one variable, uses an unbiased statistical analysis when interpreting the results, and uses all data that is available. That is my definition, if you don't like it start your own blog and use your definition.

The best study...n=1...

These conclusions are designed to show you what has the best chance of working for the general population and should give you a good starting point. Everyone is different though, so minor to major tweaking will most likely be required for your personal needs/goals/health. I would suggest trying to incorporate the ideas listed under "most likely" in whatever topic you are interested in and then if unsatisfied with the result or just want to try something else monkey around with the "maybe" ideas and see what happens.

Final thought: I am not a super human who can weed through 1x10^10 studies per day so if you find that a topic is lacking a study(s) by all means send me the name of it and a link if there is one. I don't want to be getting flamed because I missed this one study that is the end-all-be-all in that particular topic, so be nice and just let me know and I will add it and edit the conclusions. Also if there is a topic you don't see let me know and I'll start poking around that area.