Tuesday, December 06, 2016

Dunnigan-type Familial Partial Lipodystrophy

Ivor posted a link to this paper on FB:

Premature atherosclerosis associated with monogenic insulin resistance

Obviously the role of hyperinsulinaemia as a driver for CVD was his main point, reiterated from the paper. Which I think it would be rather hard to disagree with.

But what got me really interested was that here we have a monogenic form of insulin resistance. One (rare) gene defect and all the rest of insulin resistance follows, with early inset CVD etc. So what does this single gene do, which results in the failure of insulin signalling? Well, it seems to have nothing to do with insulin signalling per se, oddly enough.

The affected gene codes for a laminin, one of a family of important structural proteins essential for normal nuclear function, mitosis and important in the control of apoptosis. The particular mis-sense mutation found in the folks detailed in the paper appears to target adipocytes. The gene causes Dunnigan-type familial partial lipodystrophy. Children are born normal and stay pretty well normal until puberty. At that time they lose peripheral fat, maintain central fat and become IGT/diabetic. They lose adipocytes, ie they lose the ability to effectively store fatty acids.

As you lose your sump for fatty acid storage the ability of insulin to inhibit lipolysis in the remaining, overly distended adipocytes, fails so serum free fatty acids rise.

Now, I would be the last person to suggest free fatty acids per se inhibit insulin's action (any more than intracellular accumulated triglycerides do), but a metabolite of fatty acids almost certainly does. Be that acyl-carnitine or acyl-CoA, be that at the redCoQ-complex III docking site or elsewhere, be that via free radicals or not, elevated free fatty acids are a precursor for a molecule which generates insulin resistance. This is quite separate from my ideas on the Protons thread where it is the oxidation of fatty acids which acts as the switch for insulin signalling.

So, does Dunnigan-type partial lipodystrophy cause elevated fatty acids to levels which might be potentially facilitative for insulin resistance? Well, the Hegele paper doesn't report FFA levels. He is to be commended for his perception that insulin per se might have something to do with CVD but he, and most of the rest of the researchers on lipodystrophies, focuses on the elevated triglyceride and related lipoproteins. As they would.

But anyway, I found one paper which delivered the goods on free fatty acids:

Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (LMNA) With Partial Lipodystrophy

Free fatty acids in affected people: 0.66±0.05mmol/l.

In unaffected people: 0.43±0.03mmol/l, p less than 0.0001.

Makes sense to me, like a mild, late onset version of Berardinelli-Seip lipodystrophy and compatible with the concept that getting fat is fine until you can't gain more weight, so leak FFAs from adipocytes when you really shouldn't. Berardinelli-Seip folks are born emaciated, with no fatty acid storage capability... And yes, they are very diabetic.

Now, there are other many other issues based around elevated free fatty acids and many of them give some interesting insights. I'm not sure which I want to go to next. I'll have a think about it.



Galina L. said...

Thank you for your post, Peter. As a person who likes to speculate(silently)about the people I observe, I have been wondering for a while about the phenomenon of some naturally thin people who stay very thin regardless of their diet. I have noticed they age quite fast and are very, very emotional, two of such individuals I know are prone to panic attacks. I grew up in a fast-food-free society, we didn't have an obesity epidemic then, and I had a chance to notice that thin people often didn't live to an old age, unlike plump ones. May be now we don't have an obesity epidemic, but overfeeding epidemic,some lucky individuals have an easy growing fat tissue which removes extra nutritions from circulation, while others sustain more damage. I am only half serious. I do understand the picture is more complex.

Peter said...

Yes Galina, I'm thinking that there may be people in whom fructose (or alcohol) penetrates past the liver in significant quantities and induces insulin resistance in adipocytes while they are still small. So you can have metabolic syndrome, including the behavioural issues (JK's Pasture type people???) without obesity, especially on a high carbohydrate, low fat diet. There are other snippets which support this idea...


Galina L. said...

Peter, may be the current obesity epidemic is just the mass-adaptation to the recent overeating during last 50 years? Our LPL does a better job nowadays. Also,probably, the thin people of the past ate enough fat to stay thin, but too much bread for that amount of fat to avoid cardiovascular deceases?
I also decided to find the old Stan't post about a better cardiovascular health now compare to 60 years ago http://stan-heretic.blogspot.com/2012/12/9-times-less-atherosclerosis-now-than.html. We all had an interesting conversation than.

Peter said...

Back in 2012 I was just thinking about linoleic acid and increased insulin sensitivity of adipocytes leading to allow weight gain. I noticed recently that trans fatty acids increase lipolysis and markedly blunt insulin's ability to suppress lipolysis. So actually we could still have decreasing incident CVD (not checked this recently, I believe the drop may have halted) due to switching from hard to soft margarines. You still have to ask why PUFA increases CVD deaths in the Syndey and Minestota excavated studies. But these are interesting ideas to explore.... Might be working at the prostaglandin level here rather than adipocyte insulin sensitivity?

johnnyv said...

It would be mmol/l not mol/l for free fatty acid concentrations surely?

Peter said...

Copy paste from table 2! Corrected.


ItsTheWooo said...

Excellent posts Peter, pleasure to read.

Inflammation from WAT distention/resistance to insulin, FFA induced IR via cyclical pathology of hyperinsulinemia-> WAT growth -> genetically max distention and inability to inhibit lipolysis/suppress FFA any longer is the real mechanism of diseases of obesity. We can see that in these rare examples of adiopcyte pathologies mimicking maximum growth to failure to respond to insulin, but the pt is emaciated physically.

I also think there is a CNS interaction in the middle of all this, where insulin induced transient crushed FFA oxidation , is perceived by the brain, drives the hunger of "reactive hypoglycemia. Glucose numbers widely reported as normal during patients with "reactive hypoglycemia", although subjective hunger/weakness of the pt. What is not seen is a mitochondrial energy drop from abrupt insulin surges interfering with FFA oxidation and likely swift suppression of available FFA. I gained insight into a likely FFA driven mechanism of "reactive hypoglycemia" when I had it occur to me eating MCTs (cocohnut) while low carb. My glucose numbers shifted only slightly, my ketones ROSE, but likely what my meters could not tell me is the insulin produced from exogenous ketones inhibited FFA level/fat oxidation to produce the hallmark weakness/hunger of "hypoglycemia" as known by patients. As a leptin insufficient weight reduced person with very sensitive WAT tissue, trivial insulin elevations can suppress my FFA and induce hunger , which typically require far more egregious insulin elevations in normal individuals. FYI, using metformin (which enhances FFA oxidation by the same mechanism leptin normally does) has TOTALLY corrected my fragile insulin sensitivity, I can now eat coconut ad lib and never experience this "hypoglycemia" like event. My WAT is more resistant from the greater FFA oxidation induced by this medication.

Also, i think there is a more direct role in the brain where insulin induces hyperphagia by preventing leptin depolarization of the POMC, the two receptors are colocalized with opposing actions. So, if hyperinsulienmic, from a brain standpoint with regard to appetite and other POMC functions, its as if you are leptin insufficient.

Anyway, sorry for rambling. As always, great food for thought , sparks of insight.

ItsTheWooo said...

Sorry, i should have clarified, there is a CNS interaction, in that the actual HUNGER and energy weakness that drives the progressive food consumption. FFA stability shifts (at lower levels of insulin resistance -> "Hypoglycemia" a misnomer for what is fat burning instability from overshoots of insulin to control glucose) combined with likely antagonistic effects of excessive insulin levels on key aspects of leptin signalling int he brain, explain why this is a positive feedback loop vs terminating naturally with greater FFA leakage from increasing IR + obesity. It, the fat gain, *does* eventually terminate, but that varies differently based on genetic makeup, how adipocytes behave, brain leptin sensitivity vs insulin and so on.

Peter said...

Hi Woo,

Good. I’d assumed there would be a CNS insulin/leptin interaction but as you know this is not really an area which I’ve looked at much. But on the FFA level and hunger/reactive hypo front, do you remember the Spanish kiddies, given 40g of mixed carb/protein and suppressed their FFAs for something like four hours? Third figure down in http://high-fat-nutrition.blogspot.co.uk/2010/03/butter-insulin-and-dr-davis.html. That’s a healthy volunteer group. No hypoglycaemia but I'll bet they were hungry!

But eventually, I’m looking to tie together the changes in mitochondrial function detailed by Tucker and Karl in to something resembling the development of glucose intolerance with age, at whatever chronological age that age presents at… Dunno, might be possible. I never know where these threads are heading!


ItsTheWooo said...

Yes, my own experiences suggest a more CNS interaction not just adipocyte level. I responded very well to leptin therapy for example, but my response to the therapy was still contingent upon adherence to a carbohydrate restricted diet - if insulin were elevated from eating carbohydrate the hormone replacement therapy did not work as well WRT hyperphagia/energy . There is also the fact if leptin were irrelevant, fasting/starving would be a superior energy/satiety condition than eating food, which is clearly false. Type 1 diabetic children are massively hyperphagic in spite of no insulin and unimpeded lipolysis/ketogenesis, insulin corrects this - because insulin synthesizes leptin and corrects the balance in the brain. Type 1 diabetics also respond just as well to leptin injections alone, sans insulin, which is not widely known. Leptin controls liver glucose, leptin controls satiety and contentment with food, leptin hotwires the POMC and sympathetic stimulation of adipocytes to burn fat effectively; insulins satiety effects largely depend on downstream effects like, synthesizing 5ht (5ht2c->POMC) and largely by synthesizing leptin.

But that's rambling.

Fabulous blog entry Peter. Too bad no one evaluates subjective hunger or energy ratings, i bet that would be illuminating.

"Hypoglycemia" is an unfortunate misnomer, this applies to two things: absolute hypoglycemia usually related to insulin therapy/drugs where blood sugar is below normal. It also refers to the widely experienced phenomenon usually in overweight, mildly insulin resistant people where postprandially one feels impulsively hungry/weak during the peak of postprandial insulin release approximately 1-1.5 hours. In the latter type of hypoglycemia, pts usually never actually experience hypoglycemia, its merely culturally it was believed these symptoms are caused by a low blood glucose level, similar to how varicella was called chicken pox as it was originally believed to be caused by chickens.

As a result of "debunking" hypoglycemics actually experience hypoglycemia (the second type), the obesity research conclusion is that we are insane malingerers who are hysterically addicted to food. This makes as much sense as debunking the chicken origin of the fluid filled vesicles of varicella, therefore concluding the entire syndrome is psychiatric. Golf clap. But thats modern obesity research for you.

I'm pretty certain its a FFA/fat oxidation depression effect of critical insulin (or in my case, trivial insulin, given baseline WAT supersensitivity from weight loss). I was able to robustly elicit the syndrome using only MCTs which generate rather trivial insulin, although I am supersensitive to it and normal individuals do not get hunger or this syndrome from using the products. My glucose shifted from 80->75 only, ketones from 0.8->3, but i was ravenous and weak. I knew then there is no way it is induced by glucose, and it's very real, likely depression of FFAs and disruptions of beta oxidation is the real cause of this syndrome.

Again in your typical obese, mildly IR patient it requires big postprandial insulin to do this as they are rather IR at baseline, their biggest pathology is hypersecretion of insulin that wonks up CNS leptin and adipocyte fat burning. The hypersecretion is caused by the insulin resistance, to control their hefty glucose intakes, it requires an insulin level that destroys fat burning dynamics and opposes brain leptin excessively.
In my case, before medication, almost any insulin at all would do this. My baseline fasting is 2, so probably, anything greater than that haha.

Metformin, great med ;) WAT lipolysis/fat burning support for weight reduced patients.

Sorry for yet more rambling, your ideas and writing are very thought provoking.

Adam Rinde said...

How do we follow your blog? is there a follow button?

Peter said...

Adam, it's at the bottom of the page of posts looking like

"Subscribe to: Posts (Atom)"

Wooo, I've just gotten the whole mouse intermittent hypoxia paper and none of it makes any sense, plus it gives out basic data on a "need to know" basis. I need to find a more plausible paper! Some of the things they mention simply don't make sense. Bummer.


NY said...

So if you tend to gain weight easily, it means things are not too bad as yet and there is considerable "room" for improvement. Keep getting fat is the price to pay for not getting diabetic on junk diet.

Peter said...




Peter said...

Though it might be better to phrase it as "a junk food diet causes a loss of calories in to adipocytes". While ever there is room, you're OK. Once they're full, you're diabetic...


Peter said...

These folks (from the abstract) seem to have some sort of an idea....



karl said...

If you want a fat mouse - feed them LA(linoleic acid) and carbs. But there are quite a few overweight people that don't get CAD.

The latest narrative goes something like this - cholesterol is a normal part of the healing process - the accumulation is not what is starts the damage. The initial damage happens in the fairly deep intima - a thickening - likely caused by growth factors. Insulin + others?.

So - imagine someone that eats T2D inducing LA (via HNE) - their body responds by making more insulin. Higher insulin damages the arteries - the body responds with an inflammatory response including moving lipids.

If the above narrative is correct - it would explain why statins don't do much for people without advanced CAD - only when it has progressed to the point that the repair process is actually starting to swell the artery walls.

One further bit - eating large amounts of LA increases oxLDL - which the macrophages in the artery walls mis-identify as a dead or dying bacteria and respond by engulfing the particles - until we start calling the macrophages foam cells.

I think there are four negative effects of by LA(not a human food in large quantities) that can do damage

- Inappropriate insulin sensitivity in adipose tissue - producing weight gain.
- Increase in production of protacyclin and thromboxane (what fish oil is supposed to block)
- Production of HNE causing insulin resistance.
- Increases oxLDL

Is the above narrative correct? Really hard to say for sure. It does seem more correct than the discredited cholesterol mantra. Let's not make it dogma - but instead check it against objective observations.

In the mean time, eating bunches of LA - a food substitute seems a like a bad idea to me. Concentrated seed oils just aren't human food - a really cheap food substitute?


Betsy said...

Does this mean diabetes starts as an inability of the mitochondria to utilize fats and ends up as the inability of the mitochondria to use glucose?

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