#CAC and The Widowmaker Movie 2015 - teaser time...! #cardiovascular #LCHF

The Widowmaker Movie 2015 fascinatingly reveals how big business puts money ahead of saving lives. But you don't need to be fooled by the shenanigans of the money-grubbers. Find out about the supreme technology to reveal true extent of heart disease in your body - and take action before it's too late....!

Teaser here:  

Full movie at Vimeo - click image below:

For more details visit http://www.IHDA.ie

FIT-CEO Conference in Ireland on 30th Nov - still time to sign up! #performance

Just returning from Low Carb Universe Mallorca today, and time to gear up for the next event. This next one is being led by Jim Kirwan and will have a focus on strategic well-being and personal performance in your career and life. I will be covering the core science which enables longevity and vitality, while the other excellent speakers will cover a range of crucial enablers for your performance and productivity.

Most of the people seeing this post will be from outside Ireland - so make sure to send this link to your people "back in the old country"!

https://ynlm.ie/product/irelands-1st-strategic-wellbeing-conference/

As a bonus, anyone who signs up to the conference will get a signed copy of myself and Dr. Gerber's new book when it launches in the US (early February 2018). This has been three years in the writing, and will have all the science and strategies you need for health and longevity. It is backed up by Dr. Gerber's decades of success in his family medicine practice, and has nearly 400 citations and references for those who wish to research further:

 http://www.simonandschuster.com/books/Eat-Rich-Live-Long/Ivor-Cummins/9781628602739

So if you're in Ireland and want to propel your performance...what are you waiting for?

Fat Emperor live and unhinged on Ketogeek's podcast ;-) #LCHF #Keto #CAC #Longevity

...just taking a moment to blog on my recent podcast with Fahad from Ketogeeks. Covered a ton of stuff, but I've timestamped this link to my favorite 15 minute segment:

Note I've used the Youtube version to enable time-stamping - full podcast options here:

https://ketogeek.com/blogs/news/episode-13-ivor-cummins

Don't forget to subscribe for free at:  http://www.thefatemperor.com/subscribe !

And see the fascinating Widowmaker Movie 2015 feature film on Vimeo here for a mere $1 ! :  https://vimeo.com/201445705

Full contents as laid out by Fahad in his post:

Time Stamps: 

4:58 – Paradigm shift in cardiology

6:36 – How do practitioners respond to latest research in cardiology?

7:46 – How do regular people and cardiologists find reliable science?

9:25 – What are the challenges for physicians & cardiologists going low carb?

10:28 – What brought Ivor to the low carb lifestyle?

13:25 – What is the relevance of Cholesterol, Ferritin & GGT for heart disease?

15:57 – Why Ivor decided to go against the doctor’s advice

17:17 – Relevance of particle sizes of cholesterol?

18:43 – Various ratios and how they represent insulin sensitivity

20:23 – HOMA index and the 2-hour insulin test

23:00 – The role of blood pressure in heart conditions

25:23 – Role of insulin resistance & hyperinsulinemia in heart disease

28:44 – High fat vs. High carb in the context of insulin resistance

32:45 – Calcification test, inflammation & buildup in arteries

36:42 – How is a calcification test conducted?

38:00 – How can you have the Calcification test done?

40:31 – Mechanism and concerns with Statin drugs

43:26 – Steps to take if you have heart disease and the “Ten Commandments”

47:26 – How to fast and keep it simple?

51:40 – Can everyone become insulinemic and insulin resistant?

54:56 – Role of genetics vs. environment in driving chronic conditions & insulin

57:47 – Can chasing low insulin go too far?

1:01:36 – Type 3, Type 4 & Type 5 Diabetes XD

1:05:10 – What is IGF-1 or Insulin-like Growth Factor 1?

1:06:46 – How do vegetable oils drive inflammation in the body?

1:11:36 – American Heart Association & their BS science.

1:14:23 – How fat storage and insulin resistance works in both overweight and seemingly thin people

1:19:09 – Can an overweight but insulin sensitive person be at risk of chronic diseases?

1:23:55 – Appetite & low carb or Keto diet

1:25:49 – What kind of study would Ivor conduct in humans?

1:29:15 – How do you make sense out of anecdotes?

1:33:45 – Magical claims about keto and exogenous ketone products

1:37:00 – Final Notes & Plug 

 

Back on Vinnie Tortorich's Super Podcast - enjoy the Riff...! #NSNG #Cholesterol

Vinnie needs no introduction - we had another great chat on all that matters, and a little clarification on all that don't. Callouts for Drs Mike Eades, Jeff Gerber and Ted Naiman - and Dr. Shawn Baker too... :-) 

https://vinnietortorich.com/2017/10/10-things-that-will-transform-your-health-with-ivor-cummins-episode-924/

Tip: just click the "Play Podcast" icon below the Splashscreen, especially if you don't have iTunes:

Important Talk by Nick Mailer at #AHS17 - A Crucial #Breastfeeding Narrative.

Myself and my wife Eilis have always felt very strongly about breastfeeding's important role in developing infants. All of our five children were thus fed, until 1 year and beyond. Now Nick Mailer has filled in the gaps with a fascinating history of this fundamental human function.

The history and facts around breastfeeding have been twisted beyond recognition during the past century - as rampant profiteering messed up the pitch. Enjoy this erudite discussion on a linchpin of ancestral health...it will bring you up to date for sure:

Summary:  "Until the arrival of forceps and the “male midwife”, men in traditional societies had little role in the birth and early feeding of infants. Women used traditional models of co-nursing, peer-support and matriarchal custom to help establish breastfeeding. From the 19th century, men inserted themselves insistently into the birthing process. Some interventions saved lives; others damaged early mother-child bonding. In the 20th century, men (largely) promoted formula as “scientific” and superior to breastfeeding. When this was revealed as profoundly inaccurate, cynical exploitation of the “New Man” as a model of nurturing masculinity - from dad in the birthing room to his “heroically” doing the night feeds - ironically undermined further the important physiological role of women in feeding infants. This talk examines how to resolve this mismatch between ancestral expectations and the laudable desire for gender equality, and discusses helpful roles men can undertake in an infant’s crucial early months."

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Aseem Malhotra in Ireland - TV3 AM Interview ! #cholesterol #PHCUK

Had a great meal last night with Aseem, who was in Ireland for a TV interview organised by Maev Creaven (Aseem will be among the great speakers at Maev's upcoming Irish event:   https://fmcireland.com/home ). 

http://IHDA.ie's David Bobbett hosted the dinner; we had an vibrant discussion on the power of calcium scanning (CAC) and the nutritional root causes of chronic disease. Sadly David had to rush off and missed the photo! :

in http://www.peploes.com/ restaurant Stephen's Green Dublin

in http://www.peploes.com/ restaurant Stephen's Green Dublin

Here's Aseem's great performance on Ireland's major morning TV show - keeping it clear and simple, keeping it real - his book with Donal O'Neill details how to leverage the science for optimal health https://www.amazon.com/Pioppi-Diet-21-Day-Lifestyle-Plan/dp/1405932635 :

We also discussed PHC UK (www.PHCuk.org), the upcoming PHC Ireland, and the plans afoot for affiliated PHC organisations all around the world - watch this space !

Please subscribe for free at:   http://thefatemperor.com/subscribe

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Dr. David Unwin - resolving Diabetes and Obesity - with Science ! BACPR2017

Do you want to know the cheapest, simplest method for resolving Type 2 Diabetes and Obesity? A method which empowers and motivates the patient to save themselves - without being pickled with pharmaceuticals?
Well then you need to listen to the doctor who figured it out some years back, and is saving people left, right and centre. And these people love him for it - as well they should.
Humble and elegant, possessed of an enormous technical ability that can deploy new scientific understandings...to push back the tsunami of diabetes, obesity and CVD in our society.
He rather reminds me of Professor John Yudkin. But Yudkin was beaten back through no fault of his own. Whereas David will prevail.

Because David is supported by an army. A fighting force which will win this battle against disease-breeding foods for once and for all: 

"Call us legion...for we are many."

Please support ongoing work by subscribing at http://www.thefatemperor.com/subscribe - free and will always be free !

and learn about the most powerful diagnostics for Heart Disease at http://www.IHDA.ie

Direct YOUTUBE Link:

https://www.youtube.com/watch?v=RFd_O42J_JM

If you want to know a little more of the technical detail, and the crucial nature of liver function and GGT - you can enjoy this chat with David in London last year:

Ivor Cummins Talk at Cardiology Conference BACPR 2017 London #LCHF

It was an honour and a privilege to speak yesterday at the British Association for Cardiovascular Prevention and Rehabilitation (BACPR) annual conference.
A huge thanks to President-elect Dr. Scott Murray, President Dr. Joe Mills, Executive Director Sally Hinton and Scientific Officer Dr. Aynsley Cowie - for affording me the opportunity to share an alternative technical view of the root causes and primary markers for CVD.
No-one has all the answers, no-one has a monopoly on the truth. It is by discussing and debating the science that we will progress against the enormous disease burden our society faces.

I was proud to join all the other excellent speakers who are striving to make a difference in this great challenge we need to face in the coming decades.

My talk is somewhat uncompromising, and may even appear dogmatic. The content and messages are however driven by the hardest of science and the most decisive data available. I hope you enjoy the talk...and not least - the controversial conclusions that I reach.

Ivor Cummins BE(Chem) CEng MIEI PMP©

Please see http://www.IHDA.ie for information on the most accurate diagnostic for heart disease

And subscribe to http://www.thefatemperor.com/subscribe - for more FREE science-based health information !

DIRECT YOUTUBE LINK:  https://youtu.be/5Nqg2ahW5sQ

With Professor Scott Murray at The Hilton, Paddington.

With Professor Scott Murray at The Hilton, Paddington.

The times they are a changin' - #GLUCOSE #SPIKE Awareness !!!

Well here's a must-watch. No proper discussion of #insulin, hyperinsulinemia and insulin resistance - but significant progress towards root-cause nonetheless. Of course hyperinsulinemia underpins the whole shootin' match, but we need to wait for everyone to catch up with that. Also they are dangerously obfuscating with their "too thin" warning - being thin is perfectly healthy on a low-carb diet, as you become a superb fat-burner. But lacking bodyfat on a high-carb diet can be dangerous indeed. The nuances matter - they matter a LOT.  Also very misleading is the guy around 35min - he had meat and fish as a major portion of his calories compared to the rice - but of course they have to give credit to vegetables before the other. Not that this is untrue - but should not be the first thing mentioned ideally. And why did he need the rice at all - it is after all just GLUCOSE in the first place! Right. Also, the skipping breakfast data is misleading too - because the experiments were conducted using high-carb SUGAR-BURNER guys. Pity no-one can pull it all together properly. But watch this space...

See: https://www.youtube.com/watch?v=wiVFtRlObZk

Thanks to Andy Lopez for link :-)

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Fat Emperor, with some home truths on Chronic Disease - and Root Cause Fix !

Okay the great Keto Dudes (Carl and Richard) have released my recent talk at Ketofest 2017 (Connecticut). 

I didn't pull punches here - hope you feel my passion for the outrageous lack of understanding that exists in orthodox preventative medicine. We aim to help fix that situation - with #LCHF of course, and many other science-based interventions.

I hope you enjoy this talk - I know I enjoyed giving it.

Please share, and not just with your friends and family. Share it with your doctor. It should help them immensely. 

Supported by http://www.IHDA.ie

- please subscribe to http://www.thefatemperor.com/subscribe

And please do see the Widowmaker Movie for a mere dollar at:

at https://vimeo.com/ondemand/thewidowmakermovie2015

With #LCHF and root cause solutions applied - it could save your life !

A case history of high #GGT and #SIBO, with Gut-based root cause - interesting !

Quick post today on interesting case of something that can drive up GGT. With potentially huge increases in liver-related complications later in life. It is based on an email conversation with a person who was struggling to deal with chronically elevated GGT. I'm guessing Dr. Guðmundur F. Jóhannsson will enjoy this one. And it may be important for many people out there who have elevated GGT. As far as I know there is no published literature around this. So this may be a first. Share with anyone who is smart enough to be measuring and monitoring their GGT number. Note also that although not a key factor in Joe's case, a healthy #LCHF regime will hugely assist in improving SIBO for myriad people! Here's a tip from Gabor Erdosi however:  "LCHF with lots of plants is insufficient against SIBO/SIFO, you need to go as far as dairy free zero carb!"

The conversation verbatim below:

JOE (April 2017): I understand you had an issue with elevated GGT and did a lot of research around that problem. I have the same problem. Would you be so kind and share your insights with me? What are the risks if it stays high? How can I lower it? Did you manage to control it? How? Maybe you can point me to the key scientific papers that I should study. Many thanks for your help

IVOR (April 2017):  Two things commonly drive up GGT - Alcohol and Carbohydrate excess. I and other cases had values over 100, whacked down promptly with low carbohydrate (I drink plenty of red wine – but this still ok with low carb regime). The following is a good resource, but they won't mention low carb: http://www.healtheiron.com/ggt-science-library

As can be seen in the above link the risks are for cardiac disease, liver and other cancers, and all-cause mortality. I would aim to be below 30. Serum Ferritin synergistically links to GGT risk - again the way to lower this (and eliminate metabolic syndrome inflammation that drives it) is low carb healthy living. A good site for low carb:  http://www.dietdoctor.com . Attached my metrics driven good by low carb living; excessive sugar and carb drives inflammation and the liver / physiology suffers....

my GGT tumbled in approximately 8 weeks only - this biomarker should respond quickly (e.g. it is often used to verify if alcoholics are staying dry. Their GGT levels drop fairly promptly when off the drink. But due to unknown biological changes that years of drinking have caused in their liver and organs - their GGT rockets up when they drink again. Even a couple of days drinking will do it. The GGT goes up way faster than a non-alcoholic's would when exposed to similar short bursts of alcohol. Amusing that Robert Lustig equates alcohol with sugar as a hepatic poison - he's on the ball…!

There is a director of the Iron Disorders Institute who I traded emails with a couple of years ago; I gave her my hypothesis and she agreed 100% - said she had discovered same link of high carb to high GGT, and was actually writing a book on it; I must get back to her and see if she ever finished !

JOE (Aug 2017): Hi Ivor, I just wanted to close the loop on this: In my case, low carb and low A1c didn't help much. While my TG and HDL improved, my GGT remained in the 150-250 region (where it has been for almost 20 years!). But what did help was the following: it turns out I must have had SIBO and SIFO for most of my life. After a cure with rifaximin and neomycin followed by nystatin, my GGT is now down to 40. Amazing! Bacterial Endotoxins and Mycotoxins must have poisoned my liver. Just wanted to let you know, because I didn't find much written about SIBO/SIFO and GGT. Many thanks again for your help!

Best

Joe

http://www.thefatemperor.com/subscribe for more case histories from my massive email backlog...!

Professor Matthew J. Budoff pt 2: Primary Care Physicians and CAC

Dr. Jeff Gerber asks most of the questions in part two of our interview with Professor Matthew J. Budoff. He wrote the atlas of CT technology, and has unparalleled knowledge in this sphere: http://www.springer.com/gp/book/97815...

We focus here mainly on the imperative for primary care physicians to become educated in the power of the CAC score from the Coronary Calcification Scan. The incredible predictive power is summarized here in one of Matthew's countless peer-reviewed published papers:  https://www.hindawi.com/journals/scie...

 

First and main interview below - covers all the requisite details on CAC ! :

Did you know that 40% of heart attacks occur in the 10% of people with highest CAC Score? Or that ~60% of 'Framingham Middle Risk' people are reclassified after a CAC - into LOW or HIGH risk groups? Or that people with a yearly rising CAC score - have 6 to 8 TIMES the heart attack rate compared to those with stable CAC? That's right - the Calcium Scan is cheap, fast and unparalleled - and it is grossly underutilized.

The CAC is now recommended in the 2013 European and American Cardiology guidelines. But the majority of doctors have no idea about it. To find out more go to http://www.IHDA.ie for great information. And watch David Bobbett's 'The Widowmaker Movie' (2015) with Gillian Anderson and Larry King:

LINK BELOW ALSO AS ABOVE SOMETIMES PROBLEMATIC:

https://vimeo.com/ondemand/thewidowmakermovie2015


Millions of lives over the past 30 years have been lost due to ignorance of the scan's power (and no small amount of politics and profiteering).

Time to fix the situation.

www.thefatemperor.com/subscribe

Calcification and CAC with the expert: Professor Matthew J. Budoff, MD, FAAC

Dr. Jeff Gerber and myself finally caught up with Professor Matthew J. Budoff in California. He was a pivotal figure in recognizing the power of the CT Scan of the Heart - and decades ago to boot. He has led extensive cardiac research efforts over the past decades, publishing an enormous number of papers on calcification scanning and many other areas of cardiac research. Here is just one example - an excellent summary of CAC's power:

 https://www.hindawi.com/journals/scientifica/2012/812046/

He also wrote the atlas of CT technology:  http://www.springer.com/gp/book/9781573402675

Did you know that 40% of heart attacks occur in the 10% of people with highest CAC Score? Or that ~60% of 'Framingham Middle Risk' people are reclassified after a CAC - into LOW or HIGH risk groups? Or that people with a yearly rising CAC score - have 6 to 8 TIMES the heart attack rate compared to those with stable CAC? That's right - the Calcium Scan is cheap, fast and unparalleled - and it is grossly underutilized. Learn the key points in this interview, in less than 20 minutes:

Second part of interview below - focus on the primary care physician imperative:

The CAC is now recommended in the 2013 European and American Cardiology guidelines. But the majority of doctors have no idea about it. To find out more go to www.IHDA.ie for great information. And watch 'The Widowmaker Movie' (2015) with Gillian Anderson and Larry King (best dollar you'll ever spend!). David Bobbett founded www.IHDA.ie and funded this excellent movie to awaken the people - link below:  

Also direct link below:

https://vimeo.com/ondemand/thewidowmakermovie2015

Millions of lives over the past 30 years have been lost due to ignorance of the scan's power (and no small amount of politics and profiteering).

Time to fix the situation.

www.thefatemperor.com/subscribe

London Calling ! BACPR #Cardiovascular Event this October 5th #LCHF

A most interesting event will be taking place in London later in October It is being run by the British Association for Cardiovascular Prevention and Rehabilitation (BACPR). Welcome will be cardiologists, doctors, nurses, nutritionists - and interested members of the public. 

The 2017 conference sessions will include many fantastic speakers. Oh, and me too :-). Link below has the current schedule, which includes Dr. Aseem Malhotra and Dr. David Unwin:

http://www.bacpr.com/resources/BACPR_conference_2017_.pdf

Hope to see you there...register at:  http://www.bacpr.com/pages/news_box.asp?NewsID=19495696 !

Also for cardiovascular prevention strategies, don't forget to subscribe for free at WWW.THEFATEMPEROR.COM/SUBSCRIBE

Supported by www.IHDA.ie - the Irish source for crucial information...on identifying Heart Disease early enough to prevent Heart Attacks

Just back from #PHCManc2017. Time to progress #PHCIreland...!

Jason, Jeff and I had a fantastic weekend at the www.phcuk.org conference in Manchester. We enjoyed giving our talks, but more importantly mixing with so many exceptional and dedicated people. The event was packed with nutritionally-astute GP's. It was really quite extraordinary - and has the makings of a revolution: www.phcuk.org/conference

Something's also been brewing in the auld emerald isle. You guessed it - the embryonic www.phcireland.org is in gestation. We suspect that a Canadian entity will be coming to term by 2018... ;-)

We had the honour of hosting Dr. Jason Fung, his wife Mina and Dr. Jeff Gerber on Tuesday night (in Shanahan's on the Green). See Jason's fantastic resource at https://intensivedietarymanagement.com/

 David Bobbett and www.IHDA.ie brought us all together for an excellent discussion. Strategy will be imperative in tackling our epidemic of chronic disease - there are so many headwinds. The use of excellent diagnostic technology like the CAC scan will also be required, to identify those with severe but hidden disease. The latter folks will require well-formulated #LCHF as a minimum intervention.

Thanks to Dr. Gearoid O'Laoi for the photos:

We will start off with just MD's and consultants until we are ready to expand. The structure will be extended in late 2017 / early 2018. In the initial grouping we have some seasoned #LCHF GP's and surgeons, a pathologist and a psychiatrist. This is the first time we have all met in one place. The group will grow. In the past day or two we have been approached by a highly experienced #LCHF endocrinologist - and a hugely accomplished vascular surgeon. We expect many more from the medical community to come forth.

We will defer to the excellent leadership of Sam Feltham and the PHCUK organisation. But we will create an affiliate in Ireland to focus the effort that will be required. Recruitment to the group will continue over the next six months until we are ready to open for members.

The talking heads currently blame the victims. We blame the bad nutritional science that has been foisted on the people. Ireland is on a collision course for diabesity Armageddon. Someone has to do something about it: http://www.ipcra.org/ireland-leads-the-obesity-epidemic-in-europe 

Note: we apologize to Jason and Mina for such a sudden exposure to the fiery passion of the Irish crew (just like for the drug trials, they perhaps should have been afforded a "run in period"... :-)

Diabetes Unpacked - support The Noakes Foundation and help all with #Diabetes

Jeff and I had the privilege of writing a chapter for the new book on diabetes from the Noakes Foundation. It is packed with valuable information on the science of diabetes - our modern health epidemic. Most importantly it elucidates on how this epidemic can be halted through understanding its root causes. Appropriately it is dedicated to all diabetics - those who have suffered through the bad science of the past decades. The bad, bad science which underpins their condition.

The book is available at http://diabetesunpacked.com/ - all proceeds go to The Noakes Foundation. Please show your support for the hundreds of millions of diabetics in our world today - and buy a copy to help save them from quasi-exploitation.

Dr. Gerber has finally made it to Ireland and sits here on my deck in Dublin - "warming his arse" as we say... :-)

Denver's Diet Doctor gets published - #Insulin and #CRP Revelations !

Well lookie here, what have we got? Looks like the inflammatory marker of CRP is intimately related to elevated Insulin. Can't say I'm surprised - but super job to Dr. June S Yang and Dr. Jeffry Gerber to extract the reality from the data. But what about the amazing LDL? Surely it too correlated with CRP? Given the enormous focus on LDL for several decades?

Eh, no. As usual when you look closely...LDL sneaks away in shame.

This is a very well-written and accessible paper, with very significant implications indeed. Please share it far and wide ! Link to full paper below:

http://bmjopensem.bmj.com/content/3/1/e000236

 

Fasting Insulin and CRP below - impressive OR's :

LDL and CRP below - big fat nothing :

And of course Trig/HDL and CRP below - impressive OR's again:

...and don't forget to go to www.thefatemperor.com/subscribe for free updates supporting the science !

Gut MIcrobiome, Dysbiosis - and the pandemic of Insulin Resistance...

Hi all - I've been becoming more and more interested in the linkages between the gut microbiome / dysbiosis and the disease-driving curse of Insulin Resistance. Bad nutritional inputs directly lead to gut issues and potential permeability. These problems in turn have been shown to drive insulin resistance and through inflammatory pathways. To compound things, the bad nutritional inputs also directly drive insulin dysregulation through yet more pathways. The adipose tissue occupies a central mechanistic place in the disaster. Do you see a perfect storm forming here? Yep - right. Let's take a closer look:

Drew Duglan has done a lovely piece of study tying together some of the threads in this complex web of interaction. I've reproduced this below with his permission - enjoy !

(Don't forget to subscribe for free at www.thefatemperor.com/subscribe ! )

Drew Duglan May 17th 2017

(Drew is a post-doctoral researcher at The Scripps Research Institute, currently working in the areas of metabolism and circadian rhythms.) 

Insulin resistance and the (mal)adaptive immune system

A convincing case has been made that the development of type 2 diabetes has its origins in adipose tissue dysfunction, leading to uncontrolled lipolysis and the precipitation of full blown systemic insulin resistance (IR). As many intelligent folks here have pointed out (Gabor, Ivor and others), individuals that have the capacity to store excess nutrients by making new adipocytes (hyperplasia) can remain insulin sensitive and are metabolically healthy in their obesity (1). It is instead the enlargement of existing adipocytes (hypertrophy) which is the red flag; under these conditions there is a greater propensity for adipocyte cell death, stimulating the infiltration of immune cells that can induce a damaging pro-inflammatory cascade (2). An initial trigger for much of this may be a process called endoplasmic reticulum (ER) stress. The ER is an intracellular organelle which is critical for things like nutrient metabolism, calcium storage and protein folding. With an imbalance between protein load of the ER and its folding capacity, misfolded/unfolded proteins accumulate, leading to a stress response. Perhaps unsurprisingly, some of the major initiators of ER stress are nutrient overload (or deficiency), hyperglycemia and dyslipidemia; some of the major consequences are oxidative stress, insulin resistance and the activation of the adaptive immune system (3).

T-cells run wild

Obesity-related insulin resistance in both animals and humans demonstrates an influx of adaptive immune cells into adipose tissue, particularly in the visceral fat regions, usually located around the abdomen. Key players in this process are T-cells, and more specifically, certain subsets: cytotoxic T-cells, T-Helper type 1 (TH1) and type 17 (TH17). These effector cells release different cytokines such as IFN-γ and IL-17, which both directly disrupt insulin signaling in the adipocyte and invite other innate immune cells to the inflammatory house party (4, 5). Macrophages (but also neutrophils) readily accept the invitation and become differentiated into their pro-inflammatory state (M­1), secreting their own cytokines in the process. These chemical factors, such as TNF-α and IL-6, further impair glucose uptake, reduce normal lipid storage and only reinforce the inflammatory positive feedback loop. The negative arm of this process would normally include T-Helper type 2 (TH2) cells and the regulatory T cells (­Tregs), which are anti-inflammatory and help dampen the hostility of the immune system, in an effort to avoid potential autoimmune responses. However, during IR these immune buffering tactics are compromised; the adipose tissue shows reduced populations of these modulatory cells and the careful balance shifts towards the pro-inflammatory state (6).

Adipocytes increase demand but choke normal supply

At the same time, adipose tissue inflammation may also suppress the function of different lymphoid tissues elsewhere. Metabolic syndrome is associated with increased ectopic fat deposition in the bone marrow and thymus, areas that are critical for the generation and maturation of adaptive immune cells. This results in a less diverse population of T-cells, effectively restricting the range of invading pathogens to which our immune system can respond (7). So while the adipose tissue summons increasing numbers of pro-inflammatory leukocytes, it limits resources elsewhere, impairing normal immune surveillance. This may go some way to explaining why obesity and insulin resistant folks suffer more from common infections and respond less successfully to vaccinations (8). The hormone and lipid profile typical of IR will only make this situation worse: diminished responsiveness to insulin prevents the differentiation of anti-inflammatory T-helper cells (9); HDL is decreased, which normally neutralizes bacterial lipopolysaccharide; while elevated leptin and reduced adiponectin prevents appropriate modulation of the immune system (10, 11).

A self-reinforcing loop towards autoimmunity?

Aside from a hypervigilant immune system, autoimmunity is normally also characterized by autoantibodies directed at self-antigens i.e. elements of our own tissues. Not only do B lymphocytes directly activate pro-inflammatory T cells during IR, they can indeed produce pathogenic antibodies to certain host cell proteins. Screening of obese subjects has shown that IR is associated with a distinct circulating autoantibody profile, with some of the most abundant antigen targets being proteins in the Golgi apparatus or glial fibrillary proteins (12). It’s concerning that the bulk of these targets are intracellular proteins ubiquitously expressed in all manner of tissues, such as the nervous system, pancreas, liver, muscle and fat. It seems plausible that adipocyte cell death could initially release antigenic proteins that not only trigger an autoimmune response at the site of the adipose tissue, but also prime the adaptive immune system to eventually recognize those same proteins in other organs. Alternatively, these antigens may simply already be present due to other tissue inflammation and cell death, potentially in response to hyperglycemia or ectopic lipid deposition. Some of the most frequently detected autoantibodies in type 2 diabetic subjects are those directed at the pancreatic beta cells, which may be predictive of future beta cell burnout (13). These cells seem to be particularly vulnerable to hyperinsulinemia, lipotoxicity and inflammation, which is often occurring long before a standard diagnosis of type 2 diabetes (based on blood glucose) is ever made.

Inflammation inside and out

Admittedly, the chronic inflammation is being viewed here from an “inside-out” perspective, i.e. insulin resistance within the adipose tissue that then triggers metabolic and immune dysregulation in the periphery. It’s worth noting, however, that this downward spiral of IR may be sparked and/or perpetuated by more of an “outside-in” process, namely gut dysbiosis. The presence of intestinal permeability and altered gut microbiota can be observed in obese subjects, which opens the door to foreign particles that can induce an immune response and contribute directly to adipose tissue inflammation (14, 15, 16). For those folks who are metabolically very sick, it’s quite possible that both these mechanisms are at play. This 1-2 punch would see over-filled adipose stores switching on insulin resistance and heavily recruiting innate and adaptive immune cells, only to be joined by antigenic material that breaches a leaky gut during the continued ingestion of an inflammatory diet.

References

(1)    Heinonen et al. Adipocyte morphology and implications for metabolic derangements in acquired obesity. Int J Obes (Lond). 2014 Nov;38(11):1423-31.

(2)    Klӧting et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E506-15.

(3)    Tripathi et al. Obesity and endoplasmic reticulum stress. Front Immunol. 2012; 3: 240.

(4)    Nishimura et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009 Aug;15(8):914-20.

(5)    McLaughlin et al. T-Cell Profile in Adipose Tissue is Associated with Insulin Resistance and Systemic Inflammation in Humans. Arterioscler Thromb Vasc Biol. 2014 Dec; 34(12): 2637–2643.

(6)    Feuerer et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009 Aug;15(8):930-9. doi: 10.1038/nm.2002.

(7)    Andersen et al. Impact of Obesity and Metabolic Syndrome on Immunity. Adv Nutr. 2016 Jan 15;7(1):66-75.

(8)    Painter et al. The weight of obesity on the human immune response to vaccination. Vaccine. 2015 Aug 26; 33(36): 4422–4429.

(9)    Viardot et al. Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology. 2007 Jan;148(1):346-53.

(10) Loffreda et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998 Jan;12(1):57-65.

(11) Tsang et al. Novel immunomodulatory effects of adiponectin on dendritic cell functions. Int Immunopharmacol. 2011 May;11(5):604-9.

(12) Winer et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011 May;17(5):610-7.

(13) Turner et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet. 1997 Nov 1;350(9087):1288-93.

(14) Veilleux et al. Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis. BMC Gastroenterol. 2015 Sep 16;15:119.

(15) Sato et al. Gut Dysbiosis and Detection of “Live Gut Bacteria” in Blood of Japanese Patients With Type 2 Diabetes. Diabetes Care. 2014 Aug;37(8):2343-50.

(16) Tsai et al. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes 2015 Jun;64(6):1886-97.