Sunday, February 19, 2023

How can insulin resistance cause weight gain? (1) ALDH2

Mea culpa. Sorry all for neglected comments else where on the blog and IRL. Blame Tucker for this link in here... Here's the next post.

There are three studies which have profoundly shaped my thinking about weight gain. First is this one

Insulin resistance is protective against future weight gain (but not metabolic syndrome!)

Second is this one

in which formerly obese women (ie at high risk of weight regain) are much more insulin sensitive than closely matched control women:

And finally this one:

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

in which normal weight, young people with a marked predisposition to obesity are more insulin sensitive than a matched control group:

So, when Tucker presents us with this paper looking at mice engineered to mimic people with reduced ability to detoxify the known generator of insulin resistance, 4-HNE (amongst other molecules)

then I have to think about this graph:

which is very exciting from the Protons perspective. 4-HNE augmentation causes insulin resistance *and* causes obesity. Yet obesity is the result of excessive insulin *sensitivity*, and is clearly visible (in this study) between weeks four and 16, as weights diverge:

Obviously by week 28 both groups of mice are going to be solidly insulin resistant so will gain minimal extra weight. It's weeks 4-16 we're interested in. You don't get fat without storing fat. We use insulin signalling to store fat. Resisting insulin signalling resists fat storage. A paradox, sent to provide insight.  That's worth a post in its own right.

Fascinating stuff. Lots to dig in to.



  1. Cliffhangers now Peter? Please get cracking on that next post!

  2. I must know more!

    This is a subject of intense interest to me, as I come from a family with at least four generations of diabetics... most of whom don't get fat until *after* they get diabetic. Plus we all have exactly the same trollish body-type. Chiseled muscular calves. No butt. Weight gain all around the middle-- my cousins joke that at the family reunion we all look like barrels tottering around on stick legs. Just recently discovered familial partial lipodystrophy and have been pondering that-- it's supposed to be super-rare, so it's probably not that, but still... the pictures look like all my old aunties. And then what about MODY? (I think even autosomal dominant inheritance is not enough to account for the sheer number of diabetics in the family-- that should only be ~50%, but I think it's way higher than that). My great-grandma and her sister were the first in the family diagnosed T2D, born in the 1890s, and never got fat at all.

    It's clearly not as simple as insulin resistance = weight gain = diabetes.

    Everybody tells you the diabetes happened because of eating too much sugar or gaining too much weight, but... I was a skinny teenager with blood sugars randomly dipping into the 30s. Underweight with gestational diabetes in my first pregnancy... but hey if you just exercise and lose weight it'll all come right, yeah? I do have 20 pounds to lose *now* after 3 kids, but the metabolic derangement and PCOS (which I understand is insulin resistance of some sort) definitely came first. Weight gain happened downstream. I keep pulling at threads trying to figure out where it *started*, because it seems like that's the way to figure out what's best to do about it now. Losing weight is great, but the weight isn't the cause, so... what is?

  3. Just Peachy, how do you react to alcohol? Bad hangovers?

    I am/was the overweight version of what you're describing otherwise. Gt gt grandma diagnosed (dead of) DM in the 1880s approx when it was a new thing to diagnose and at least one family member known in each generation since plus some obvious preDMs two generations after mine. My sister is all skin and bones but not DM.

  4. Hi JustPeachy,

    I have certain viewpoints. One is that T2 diabetes is the inability to suppress FFAs on a carbohydrate/insulin based diet. Adipocyte diameter is one cause, high levels of 4-HNE, systemic fructose acting on adipocytes, ethanol acting on adipocytes, trans isomer of oleic acid are others. If you release FFAs in the presence of insulin you will become insulin resistant and have to store those FFAs somewhere. After conversion to triglycerides in the liver they will be stored in the most insulin sensitive adipose tissue available, ie the mesenteric and omental depots. "Correct" your diet after diagnosis -> increased LA -> obesity as this allows easier expansion of all adipocytes.

    Just my view


  5. @Passthecream
    I stay away from alcohol. Have indulged in a glass of wine or a beer maybe 4-5 times ever, but dislike the way it makes me feel-- confused and disoriented. Dunno about hangover, not sure I've ever drunk enough to get one, or if I could tell it apart from an ordinary migraine. My family history of DM is completely nuts. Great GM *and* her sister had it, the sister lost 4-5 babies on that account and didn't live to be old. Great GM was allergic to pig insulin, controlled with strict diet, lived into her 70s and had 11 kids. Of those 11, at least 10 were eventually dxed with DM (including my GM, who also controlled with diet, lived to 70s, and was never on insulin), and among my mother's 30 first-cousins most had a DM diagnosis by age 50, one of them T1 in childhood. Mom and both her siblings T2-- my mother by age 40. I'm one of four siblings, and *so far* I'm the only diabetic among us, at fortyish.


    What do you mean when you say "correct" here? Have been low-carbing for so long that my default assumptions here may not be accurate.

  6. @Peter

    So... different body tissues have different sensitivity to insulin, and this leads to uneven fat deposition patterns, which would go a long way toward explaining why everybody in my family has a bloated toad gut paired with the trim ankles and sculpted legs of a hammer-throwing enthusiast.

    Bookmarking this page so I can read up on adipocyte diameter, 4-HNE, etc. Always appreciate leads to follow.

  7. My bad JustPeachy,

    "correct" means "doing as your saturophobic endocrinologist says".

    NB there are models which suggest visceral fat is the most insulin *resistant*. Model dependent and the researchers with these models are not ones I respect. Could just be bias speaking there.

    Of course exogenous insulin has its own issues re insulin-induced insulin resistance, also ROS induced. T1 diabetics always develop T2 diabetes this way, in addition to the stupid dietary advice from endocrinologists


  8. Yes, I have done a lot of reading on exogenous insulin as well as observing it with my mother who is insulin-dependent. I am doing my utmost to stay off of the stuff for as long as possible, though lately have been frustrated to see my fasting glucose creep up to just over 100 (I want it to be at 85 like it used to be!) even on a low-carb diet :(

    I badly want the "just LC and exercise and you won't be diabetic anymore!" paradigm to be right, because that would make it solvable. But it appears to be more complex than that.

    Even with fasting BG elevated, I've lost several pounds over the last couple of weeks (wasn't trying to). That's never happened before. I've always had to get fasting glucose under tight control before I could lose weight. The only thing that changed was adding a biotin supplement to see if it'd help with a bit of skin trouble. Now here we go back into the literature to see if/how that might or might not cause weight loss without lowering glucose (??). The other option-- that the biotin is unrelated and I've just started dropping weight in spite of elevated glucose-- seems scarier.

    Time to break out the notebook again and go down a few more obsessive-reading rabbit holes.

  9. Peter I think you had dm1 and dm2 transposed there.

    JustPeachy I suffered unjust hangovers from any type of alcohol in my student days but continued drinking nonetheless. It rouses my curiousity to hear aldh/2 being discussed in these other contexts.

    To paint a disturbing picture I'm built like a saddlemaker with a wide frame but pear-shaped tendency of top half, minimal gluteus and legs that would look good under a kilt. That part similar to your description, and the strong family history in my direct line and many other dm relatives I suspect, died early or unwell but not always their siblings, some appeared anorectic. What genetic inheritance pattern is that?

    I am a lipophiliac but I gain weight so easily even if I have too much fat in my diet. I have settled back to Lutz proportions ( "life without bread", 70 -100g carb), rigorously avoiding pufa and sugar/fructose. Many who tread the hflc path report blood sugars trending higher over time. If this is not developing DM1 I think it is gluconeogenesis unleashed and it might be problematic.

    But I dunno.

    I'm trying to understand the many implications of Peter's current creative burst!

  10. @Passthecream: "JustPeachy I suffered unjust hangovers from any type of alcohol in my student days but continued drinking nonetheless. It rouses my curiousity to hear aldh/2 being discussed in these other contexts."

    ALDH2*2: "Within each population, alleles at one or more of these three loci are protective against alcoholism..."

    Of course it also makes you more susceptible to seed oil toxicity. If you're eating rice that's a problem, so you would probably want to eliminate the n-6 fats from the rice, which are mostly in the bran. Hence: white rice.

  11. Passthecream "Many who tread the hflc path report blood sugars trending higher over time. If this is not developing DM1 I think it is gluconeogenesis unleashed and it might be problematic."

    I've been curious about this also. My blood sugar has always hovered around 100, despite virtuous HFLC habits for ~12 years.

    Of course one might also revisit the idea that this level of blood glucose is 'bad'. Question assumptions!

  12. This comment has been removed by the author.

  13. Tucker, that is one of those amazing truths hidden in plain view!

    CN yes. Is it harmfull?

    Otoh after first losing approx 30kg on an enthusiastic hflc style over the last 10? years I've lost another 5kg since december by cutting back the added fats a little. I might have been overdoing it.

  14. @Passthecream

    We're in good company then! As you say-- we'd all look great in kilts. But it's devilish trying to find jeans to fit when the waist needs a 10 and the legs want a 6-- anything that can be buttoned sags like the skin of an anorexic elephant. I've become a skirt person in middle age.

    Have been doing LC in some form or other for about 15 years (and yeah, also avoiding veg oil). It works, but my threshold for keeping glucose numbers in check seems to be under 20g carb/day, which is difficult to maintain so it ends up being a a long-term slow wobble between getting my numbers right, and slacking off and realizing they're creeping up again, getting a 165+ reading after eating something questionable. Like a carrot, or a chicken salad at a potluck that turns out to have apple chunks in it, or nuts. Then we climb back on the wagon because even the most monotonous diet is still better than going on insulin.

  15. JustPeachy --- stretch denim slim leg jeans! Much better for instance than trying to climb a ladder when not wearing braces in regular jeans. With all respect to tartan addicts, kilts as we know them were invented by a quaker steel mill owner as a practical item of clothing for his highland forestry workers who were cutting wood for charcoal. They are by nature very functional.

    This is high level rather than fine-grained (pun?) but my instincts about carbs vs lipids tell me that the combinations can be tricky and if you have even a small amount of simple carbs you should reduce the lipids by quite a lot more than equal calorie amounts even as much as 1:1 w/w. Like fuel to the fire, if we have so much insulin already sloshing around as to drive too-easy weight gain via the more sensitive adipocytes accompanied by significant ffa and insulin driven insulin resistance, then adding extra insulin resistance via food choices on top of that might be sub-optimal.

    Isn't there an idea in the Optimal Diet that if you want to lose weight by burning off some fat, the fat you burn obviously shouldn't be much from what you eat but rather what you already contain. The weight to lose is a countable part of your diet. This makes sense but generates a paradox --- to promote fat burning you should avoid insulin stimulating foods ie carbs, certain proteins.

    Little fat, no carbs, no milk or beef, so what's for dinner???

  16. JustPeachy in line with my understandings about overpopulation, we have so many people because we just have too much 'high quality' food. Hyperinsulaemia is a feature of modern industrial agriculture rather than a bug. Too much addictively rich food sloshing about , too easily acquired.

    Weight stability is my primary diagnostic indicator. Unless my weight suddenly falls away without obvious causes which I would interpret as beta cell weakness, I aim to keep slowly losing and keeping it off.

    DKA versus ketosis - I have heard of other people who find plain ketosis a stinky business. Heaven knows what's stored in our adipocytes after years of gourmet eating or what the different enzymes are doing, or not doing. Is there an ald/h/2 connection? You probably need to measure sugars and ketones, insulin if possible, to understand what is going on there. I have never been able to hit high ketone numbers on the meter so ??? Everyone is different.

  17. @Passthecream

    I want that theory of DM to be true *so badly*. And perhaps it is, to a large degree in the broader culture. I've just never been able to square it with the family history, beginning with great-gma who came from a poor rural family. That clearly didn't happen because of too much rich food-- and the same for her children, who gardened, raised hogs and chickens, gigged frogs, fished, hunted, and stewed the occasional opossum to keep food on the table all through the 1920s and 1930s. Food was scarce enough that they all joked about it as adults-- the boys had made an artform of saying unsavory things at dinner, to see if they could get their sisters to abandon food on their plates, so they could eat it themselves, because they were always hungry. They avoided malnutrition, but only just. Meanwhile, dad's side of the family was prosperous and well-fed all those years... and none of them are diabetic.

    So in aggregate, perhaps it's industrial ag making the largest contribution. But that picture is incomplete. There's more to it than that. I don't know what it is (and wish I did). Genetics? Chemical exposure? Mitochondrial inheritance?

  18. JP, yep. It is different in my heredity because the DM(x) tend to be heavier. It is through my father's side - his mother, grandfather, gt grandmother etc. And a much older sister but he grew up poor and skinny through the great depression and WW2 and was impossibly thin until his later prosperous years when he had multiple health problems. It is very difficult to find a theory to run with however the shape and weight problem seems common so must provide clues.

  19. @Passthecream

    Yeah, I think it's the same problem you run into with quite a lot of things-- autism and depression come to mind-- where there are likely multiple causes/contributing factors, and possibly it's a label that encompasses multiple distinct pathologies with similar symptoms.

    My great gma was diabetic, but was never overweight. Of her 11 children, 1 was (maybe) not DM. The other ten-- none were obese, five became plump in middle age, and five remained thin all their lives, but they were all diagnosed with T2D, eventually. My mother's generation was a bit fatter, but the most common pattern was to become diabetic first, and then the weight gain set in. My mother and her sister are very typical examples of this: rail thin until their late 30s, and then starting to put on weight, but never became grossly obese-- I do wonder if maybe we're just deficient in number of fat cells somehow, so when we do the same things that make other people grossly fat, we run out of "space" sooner, and get adipocyte distension and leakage at a lower weight than average. It's that or the IR just sets in long before weight gain.

    From what I've read, this is not typical for T2D, and if you develop diabetes while still thin, long-term outcomes tend to be worse (discouraging!). So I'm keen on finding out whether, as a family, we may actually be dealing with something like MODY or FPL, which might make more sense than just "yeah, every one of you ate your way into this". The fried chicken and banana pudding at the family reunion are not a good thing, and a poor diet high in industrial crapola is exacerbating the problem for sure. But it's hard to see it as a root cause.

  20. @Passthecream: it's on my to-do list. The trick is finding a doc who's ever even heard of those things, and convincing them to order the test. I got my mother to ask her endocrinologist about genetic testing for MODY a few weeks ago, and they had no idea what she was talking about :/

    I prefer to stay away from doctors, but for this, maybe it's worth making some calls and harassing some telephone-answerers to see if anybody's willing to run the test, and how much it would cost.

  21. Just FWIW, with 23AndMe you can download your raw data, assuming you know what to look for. I've done that for at least one thing.

    I don't trust their "reports" about various conditions much, being all epidemiological and sketchy.

  22. CN I heard that wrt the raw testing data you can get hold of third party database/lookups which will decrypt it for you. BTW do you still run a site or blog related to the tremor problems? I have lost the link.

  23. @Passthecream, thanks. I'll see if I can find that database.

    After 12 years, I recently let the forum expire and evaporate. Facebook took up most of the slack for my little orphan neuropathy. It's on the wayback machine, latest version

  24. @CN, passthecream: I'll look into that. So far the only test I can find a price for, just for monogenic diabetes, costs $1500 (yikes!), so if you could get the same info with a commercial genome sequence and somebody's 3rd party decoder ring... that could be significantly cheaper!

  25. It was a long time ago that I heard about it and I believe it was an open source arrangement but I guess that the doors might be tightening on that since it is big business nowadays. 1500$ = probably 50$ for the test and 1450$ for the medical overlay. I presume you're talking Imperial US$. Ouch. When I booked a test for the hla b27 genetics here it cost approx 85 kangaroo$.

  26. Im not sure if this is genuinely free or not. It seems to be but????

  27. I think it is key to remember a couple of of Petro's factoids:
    The liver becomes insulin resistant first, muscles second, adipocytes last.
    Insulin levels in the obese remain about 10 times those of a normal person even under complete starvation.

    If we have PUFA producing inappropriate insulin sensitivity in adipose tissue - the lipids will first go to fat-tissue.

  28. Karl "Insulin levels in the obese remain about 10 times those of a normal person even under complete starvation."

    But for how long, the important question.

    Lose enough weight, detox the pufa and get those ffa down by shrinking the lipid droplets in the adipocytes and ( I hope) things might get more normal.

    Also perhaps a circular question, which comes first, the insulin or the obesity?

  29. Btw I think it was Tucker who pointed out recently that if you don't have enough pufa overload to do the job , an excess of fructose/sucrose can still do it. Or words to that effect. Too much food floating around of an innapropriate mixture - it still has to go somewhere, as the various ratios, preconditions and total quantities dictate.

    I think the simple metric of blood glucose levels vs weight loss/gain/maintenance can tell you most of what you need to know. Include ffa with that if you can measure it easily.

  30. Top link, third illustration down, has multiple “fasting” insulins from one obese person fasting. Second has Hall’s healthy subjects fasting/fed/post absorptive. Obese person’s fasting insulin on obesogenic food is way above a normal person’s. By 4 days it’s comparable to a Hall volunteer. So both are correct, it’s a matter of what we mean by “fasting”.