Insulin resistance and obesity

Some people believe insulin resistance (IR) causes obesity, and they are not pleased when I say this is actually a controversial topic in the field…

“Bill isn’t toeing the company line.  Again.”

So I asked a simple question: if IR causes obesity, how?



The Common Response: 1) IR -> 2) hyperinsulinemia -> 3) more insulin = more fat mass.

However, this is flawed.

Easiest rebuttal (somewhat of a strawman, but whatevs): Barbara Corkey and her group has done a lot of work showing that insulin hypersecretion (caused by dietary additives, preservatives, weird chemicals, etc.) may actually precede & causes IR… not enough insulin hypersecretion to induce hypoglycemia, just enough to induce IR.

So that basically breaks the 1st step in the Common Response, but doesn’t really disprove the possibility that IR still causes obesity (or can cause obesity).

In any case, check out Corkey’s 2011 Banting Lecture.  Highly recommended, a lot of food for thought.



More nuances:

Theoretically, gaining fat mass is helped, not hindered, by insulin sensitive adipose.  It’s thought that once adipose resists insulin, the accumulation of fat mass in adipose slows ,and the development of ectopic fat and diabetes accelerates.  Admittedly, this is somewhat of a cop-out because IR, in this #context, generally refers to glucose intolerance which largely reflects hepatic and skeletal muscle insulin sensitivity.  Adipose tissue insulin sensitivity is different (ie, it reflects lipid metabolism as opposed to glucose metabolism).

But still, there are lean people with IR who do not go on to develop obesity and insulin sensitive obese people.


Black Swan



In other words, IR is neither necessary nor sufficient to induce obesity.  Insulin, probably, but not IR.

Insulin is there to grow fat tissue for the obesity epidemic, not replenish glycogen after yoga.”

Furthermore, adipose doesn’t require hyperinsulinemia or insulin hypersecretion to grow.  Not even close!  Fertilizing fat mass is insulin’s forte.   Read this post!

And if IR caused obesity, it’d be reasonably safe to assume obese people should have IR (unless it magically resolves upon achievement of obesity) (unlikely).

Two key exceptions: 1) not all obese are IR; and 2) exercise reduces IR in obesity, but don’t cause fatt loss (in many cases).

But the point of this post is really about the “how.”

Of course, nine times out of ten, I’m the first to say there are as many pathways to obesity as there are distinct obesity phenotypes.  Just like the existence of isolated IGT, isolated IFG, and combined IGT/IFG.  Ie, it’s not a singular continuum of IGT -> IFG -> diabetes (or IFG -> IGT -> diabetes).

Some researchers even think: increasing fat mass -> inflammation -> insulin resistance… which puts IR after weight gain… really hard to say something is causal if it happens after the fact.



Can insulin resistance precede obesity?  Yes, and I bet it does in many cases.  But that doesn’t make it causal.  IR and obesity may just share an underlying cause…

Maybe it’s a combination of things, initiated by epigenetics and/or environmental factors and/or processed junk foods.  This would include Corkey’s hypothesis, which states [roughly]: certain dietary compounds increase insulin secretion just a little bit.  Not enough to cause hypoglycemia or even come close to qualify as hyperinsulinemia (even according to Kraft!).  It would also include the inflammation hypothesis because many of these very same food compounds contribute to inflammation.

And what sets the stage, the ‘permissive’ factor if you will?  you guessed it, circadian arrhythmia hahaha

I strongly believe circadian arrhythmia is one, if not the, common underlying factor which causes IR, IGT, IFG, obesity, etc., depending on which other factors are present.

Adipose tissue even exhibits daily circadian fluctuations in insulin sensitivity: more resistant in the morning, more sensitive in the evening. It is known. Eg, see Part 3 of this post.


that’s all, for now

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  • Marty Kendall

    how about metabolic dysfunction -> IR / metabolic inflexibility / high insulin -> inability to access fat stores for fuel -> increased appetite / drive to eat more regularly / inability to fast -> excess calories -> fat gain -> obesity?

    • rs711

      sounds plausible. however we still need to explain how metabolism changed from ‘functional’ to ‘dysfunctional’. The more we know about how metabolic homeostasis is maintained then the easier it is to figure what needs to be pushed/pulled to lose that balance.

      • Marty Kendall

        could a lack of metabolic hormesis play a part?

        • rs711

          id bet it does. but that a descriptive answer, not an explanatory one.

    • Tl;dr: an unsimplified version of “the common response”

  • Martin

    It’s genetics. Some people won’t get obese even if heavily IR. But it does not mean they are fine or that IR is harmless. IR is considered an element of the so called metabolic syndrome, which is implicated in many chronic diseases and obesity is just one common side effect which some people are lucky not to develop. Even is some people won’t get obese eating sugar and starches and developing IR it does not mean they won’t ruin their health mid to long term.

    • “It’s genetics. Some people won’t get obese even if heavily IR.”

      …because IR may not cause obesity

      • Martin

        Sure, obesity is just a side effect of the broken metabolism, one of many and not the worst one. Which again does not mean that IR is fine or eating lots of carbs is fine as long as you don’t get obese. You will suffer from other problems down the road.

        • Jack Kruse

          Today’s scientific research problems will not solved by experimental apparatus; they will be solved in a man’s head by extraordinary thinking. The problem is right now mankind’s head is up his own ass believing his delusions of grandeur. There is no biochemical facts on obesity, only interpretations. The natural truth is always simpler. You must seek your answer, in your lit environment.
          The problem is not to find the answer, it’s to face the answer we get. Why is our group using light via the eye and radial artery to help obesity? We want to give modern humans a “emulated third eye” literally to assimilate light via their eye clock in the RPE that connects to the SCN. We want the RPE mitochondria ATPase to spin faster to make more melatonin dopamine, norepinephrine and melanin. Why? It reverses circadian illness fastest. Today the lighting in virtually all research laboratories is still the responsibility of the janitor and is classified as ordinary building maintenance instead of being part of experimental design. This is why the research in nutrition and biochemistry is worthless, in my opinion. When you add in the fact that they usually study mice and rats who are nocturnal, they completely miss all the good data generated because humans have photopic eyes and skin. Why does this matter? Your human photopic eyes means that your eyes and biochemistry are not designed around scotopic eating of food or light. It is built around a different set of variables no one controls for. This is a simple quantum idea that rules Mother Nature’s mitochondrial design. Mice and rats retina’s is scotopic folks. Knowing about biochemistry and not connecting it to anything else in a cell like solar light radiations, is akin to buying a guitar that Prince once owned and then expecting that you could play Purple Rain as Prince did in life…………

    • rs711

      the “it’s genetics” answer just pushes the answer back.

      How does Genetic Profile A tend to obesity more than Genetic Profile B?

  • I actually went on a mornin’ twitter rant about this a few days ago and you describe many of the points i made. I agree with a lot of this. Obesity and IR are not always related and when they are its probably genetic fat storage potential is maxed out leading to inflammatory (i.e. fat gain resistant) WAT tissue -> IR.

    Another thing that needs to be noted and never is, is that insulin resistance is not this homogenous entity. It varries by tissues and attending outcome is radically different. Someone with insulin sensitive muscle and liver, and relatively IR fat tissue from high fat metabolism, is called a lean energetic healthy person.
    OTOH, a person might be IR muscle and liver with relative insulin sensitivity of fat, and they are an IGT flabby sarcopenic IGT sick person.

    The behavior of the adipose and how it responds to insulin is definitely hierarchically controlled, by the brain, by the nervous system… but i would say for the majority of people frank insulin excess acting on adipocytes is a primary driver of obesity. Look at our diets. We can *measure* the hyperinsulinemia of obese americans and it is visible as acanthosis of the skin, a growth marker for chronic hyperinsulinemia.

    IMO, at the end of the day? Obesity, the majority of western obese people, are eating too many hypercaloric meals with carbohydrate (fat + carb) and teh result is severe insulin excess and obesity.
    Which is why the low carb diet works as well as it does – as long as it is followed. If rare genetic brain disorders mutliating how leptin works in the hypothalamus to make the white fat cells grow even under low insulin levels were the real cause of our obesity, LC wouldnt be the duh solution that it is.
    The diet WORKS, without starvation, without deprivaiotn and hunger, because it corrects the endocrine level cause of the fat storage and energy dysregulation…as long as it is followed.

    Ok, thats my 2 or 3 cents 😉

  • rs711

    Couldn’t IR be necessary but not sufficient to cause obesity?

    The Common Response you describe is illogical because it puts the effect before its cause (the ‘insulin resistance’ is placed before the ‘insulin stimulus’). Resistance requires 2 things:

    1) a signal or stimulus [in this case insulin] 2) an adaptive mechanism to change the magnitude of response to said stimulus [in this case insulin receptor &/or intracellular pathways downregulation]

    It’s the same for antibiotic resistance. Resistance occurs only if there is sufficient evolutionary pressure (aka amount/frequency of antibiotic agent) acting on an adaptive mechanism (the natural selection of random mutations on antibacterial molecules)

    • Seeing as there are examples of obesity w/o IR , then IR is not necessary as Bill originally said (I agree).

      There are a lot of obesity syndromes, and some involve insulin sensitivity (rare).

      You seem to assume resistance to insulin requires insulin overexposure like antibiotic resistance but that is false. It is entirely possible for insulin resistance to occur independently w/o being a reaction to prior insulin exposure.

      This goes back to my point before. People view “insulin resistance” as this homogeneous entity that is equal throughout the body, with one common driving route (conventionally believed to be insulin excess). This really is so far from true IMO.

      • rs711

        “entirely possible for insulin resistance to occur independently w/o being a reaction to prior insulin exposure” ==> ok, good to know because im not aware of other mechanisms to be honest. so if it’s not analogous to antibiotic resistance, do we know how IR occurs otherwise? have their been interesting mechanisms proposed?

        Just to be clear, I don’t see IR as a homogeneous entity. In fact, after reading your interesting ‘twitter rant’ the other morning i jumped in pointing to 3 factors suggesting IR doesn’t present monolithically:

        1) tissue specificity 2) circadian pulsatility 3) mitochondrial heteroplasmy

        Im still skeptical about there being (truly) non-IR obese. ==>
        I dont think it’s a bad theory, i think it’s qutie reasonable. But I do see the following problems with how this hypothesis has been supported so far:
        1) Studies supposedly supporting this, like Pittas ’05 for example, divided patients into IS & IR groups which is not representative of IR/IS being a spectrum. The cut-offs are somewhat arbitrary & loose in my opinion.
        2) Still in Pittas ’05 & with Gardner ’15, there never has (yet) been statistically significant results being Group x Diet. Maybe this will change with Gardner ’16 follow-up?
        3) As far as I know, the criteria for IR (via IGT measures) is quite flimsy compared to the much more stringent Kraft criteria. The more stringent the criteria the more unlikely it seems there are to be non-IR obese.

        I think how tissue levels of IR/IS differ is possibly more important than an overall IR/IS status as measured by a 2hr OGTT + insulin. With that, I think you’re really onto something.

        • Actually raphi the idea that insulin exposure causes insulin resistance is not very commonly believed by most researchers. For example, and you can read this on hyperlipid, one of the more well known ways to become insulin resistant is to EAT A LOT OF DIETARY FAT, so that beta oxidation is elevated, which induces superoxide that promotes insulin resistance of tissues (if mitochondria are beta oxidation fat, it doesnt make sense and will destroy them toxic if they accept sugar too, correct?)

          As for how IR develops? It is not at all going to be 1 mechanism. But burning fat, eating a very high fat diet, OR being insulin resistant in the adipose to the point FFA are elevated -> beta oxidation, are all known ways IR develops or worsens. Fat metabolism is one cause of IR.

          The state of the mitochondria organize this. Deficient/damaged or using alternative fuel sources -> IR.

          IR can also be inducted from receptor overstimulation as seen in severe hyperinsulinemia from insulinoma but it is different from conventional IR in metabolic disorders.

          Regarding non IR obese. The model for this is head trauma/hypothalamic injury, as they do in some rodent models, or humans with rare gene defects or head trauma. In this case, the fat cells become pathologically insulin sensitive which is induced from CNS damage to leptin / adipokine signalling. They are globally insulin sensitive but if you examine tissues, the liver is abnormal not respond, the fat is very sensitive, the muscle is resistant: their body is oriented to gaining fat. However, if you test them metabolically, they wont be hyperinsulinemic, their sensitivity is “good”, but what you cant see is this huge abnormality in individual tissues that just doesnt occur in conventional obesity.

          A recent example of this is JJ’s paper where they knocked out 75% of IRs and then calorie restricted the rodents. They got fat, but were insulin sensitive! The cause was GIP elevation that lead to a hypothalamic injury-like WAT hypersensitivity to insulin. As a result, insulin was LOW, se3nsitivity was HIGH, but it was because the WAT of these rodents was abnormally growing , sensitive to insulin.

          So, its really not imo a question IF IT EXISTS, its more 1) how common is it, is it really representative of most obesity syndromes? IMO no, not at all. Its a very rare form of obesity probably.

          The fact most obesity is NOT insulin sensitive is exactly why LC diets tend to work so well for so many people. Most involve insulin excess as a key pathological factor (see my previous reply to bill) and so systematically creating a therapy to ablate insulin is a key therapy for us.

          • rs711

            i agree with all the examples you give.

            By the way I realized i was saying “IR” without specifying Pathological IR, oops! That’s very different from the Physiological IR you correctly describe (beta-oxidation negative feedback).

            I love that JJ paper! He was kind enough to have a short twitter exchange with me on it.
            What i took away from it is that despite 75% of IRs knockdown, the mice remained insulin sensitive. This shows that what we really care about is the ‘insulin signal’ end-point, whether that’s primarily modulated by b-oxidation negative feedback, hyperinsulinemic secretions or CNS ‘trauma’. His paper also beautifully demonstrates 1) ‘calorie partitioning’ & 2) how central the network of individual tissue IR/IS is to producing a phenotype over another.

          • Re: fat oxidation IR, this is present as a mechanism for IR of obesity. As the WAT become distended and IR, FFA are elevated and this is probably a primary driver of the insulin resistance of obesity. 1) the resistance of the WAT to max fat growth genetically and 2) the resulting high FFAs and beta oxidation.

            So even in “pathological” IR, it is still related to fat oxidation. The real reason its pathological is that this fat burning is occurring OUTSIDE of a high fat ketogenic diet. Thats the pathological part.

            See my comment to bill why that might occur – e.g. , insulin resistance inducing factors that block the body from normally burning glucose, triggering hyperinsulinemia and fat storage. When fat storage is critical, your own body fat is a source of IR from WAT failure and beta oxidation.

            This is a big reason the VLC is so palliative. If the body REFUSES to normally use glucose, simply dont eat it. Hyperinsulinemic-> hyperphagic/fat storage trigger in the cascade is now averted.

          • rs711

            the distinction between our ‘own fat’ vs ‘dietary fat’ in the context of WAT failure is helpful – i think i understand your point better now.

            lots to think about 🙂

          • Ben Green

            Lustig’s research shows Insulin and Leptin colocate on the same neurons on the VMH..

            Leptin Depolarizes. Insulin hyperpolarizes. If both are present, Insulin wins. IOW, insulin (and triglycerides) block leptin.


            I think it’s the seasonal adaptation of low light in autumn, dropping D2 and rising Triglycerides/Insulin from the autumn harvest diet (think lots of fat/sugar/starch together) that trigger the leptin resistance. In modern times, many are in that pattern 24/7..especially with circadian disruption.

  • Greta

    Look at bears, which become very insulin sensitive in late summer and pack on the pounds while not eating a lot more. It’s only when they’re hibernating that they become IR.

  • Amy B

    Seems like IR *is* causal, at least in *some* people, but not all. Meaning: IR is *one* cause — among many — of obesity. Just because it doesn’t cause obesity in *everyone* doesn’t mean it isn’t causal in *anyone.* And as I am so fond of pointing out, even if crazy high insulin doesn’t make someone accumulate inordinate amounts of subcutaneous or visceral adipose, it could still be affecting them in a ton of other ways that all boil down to bad, bad juju, regardless of body size or shape:

    • how does IR cause obesity? what is the mechanism

      • My opinion is conventional garden variety obesity is a CNS executed conservation syndrome which is evolutionary conserved, and triggered by certain factors which evoke IR. Its probably rather similar to the hibernation response of animals – adaptive fat storage that is evolutionarily logically termination by the manifestation of the stressor the body is intending to prepare for.

        IR is involved but its likely specific IR of the liver and skeletal muscle. A cycle becomes in place of elevated insulin in the CNS, disordered leptin function in the body (hepatically specifically) , glucose and more insulin excess.

        A clue is that insulin in the brain is colocalized with leptin receptors except to oppose their actions. Right away this may suggest CNS insulin if elevated can lead to adaptive leptin disruption.
        Peter also described CNS IR knock out rodent with upregulated leptin receptors in the liver. The liver being disordered is a common initiating factor in adaptive fat storage syndromes. It suggets that if insulin is elevated in the brain (via one of these “triggering factors”), the liver becomes less leptin sensitive manifesting glucagon / sugar excess, with hyperinsulinemia further responding to that.

        Again i think when it comes to IR and obesity its probably more useful to consider each specific tissue vs overall IR because you point out IR of the fat LIMITS weight gain.

        Let me go back to my description of “evolved triggerintg factors” for this ancestral fat storage cycle to prepare for stressors.

        One common trigger of the fat storage cycle is DOPAMINE D2 RECEPTORS VS MELATONIN. This is true of hibernating animals, and it is also true of humans. You can block hibernation fat storage preparation in some animals with d2 agonists. The evolved cycle is disrupted.

        What blocking the d2 receptor does, is induce insulin resistance in the mitochondria and liver. If D2 is subs stimulated the liver overproduces sugar (from IR/leptin fail) and the mitochondria refuse to burn sugar for energy instead remain burning fat. This increases the insulin responses to glucose which is consumed, assisting with storage of body fat through hyperinsulinemia which is a direct result of liver and skeletal muscle metabolic shifts that amount to insulin resistance.

        There are MANY “evolved triggers” for these liver and muscle changes. D2:mel is one. Progesterone, cortisol, basically if it was an ANCESETRAL STRESSOR that would expect to lead to nutrient deprivation/stress, odds our that our body responds to it by amping up insurance policy in the fat tissue (Selective tissue IR -> Hyperinsulinemic responses & hyperphagia -> fat gain WHILE FOOD STILL AVAILABLE).

        So, sorry to prattle on so long in response to your very simple inquiry.

        But IMO everyone conceives this inappropriately. IR is not “absolutely bad” nor is it equal in all tissues, nor does IR DIRECTLY induce obesity (it does so indirectly, when expressed in certain tissues like liver/muscle to manifest hyperinsulinemia). The majority of obesity cases are likely best described as an errant , pathological expression of what is an ancestral evolutionarily conserved energy thrift anticipation response. In the natural world this is a healthy , functional, life saving genetic instruction. IN the modern world is is disabiling and death inducing, as we are constantly triggering it with abnormal lifestyle patterns in the context of hyperinsulinemic nutrition.

        • Bromocriptine taken first thing in the morning seems pretty effective at improving insulin sensitivity and turning down liver glucose production, in part via autonomic nervous system…
          another factor regulating IR, researchers think it begins with SCN dopamine

        • “This is true of hibernating animals, and it is also true of humans. You
          can block hibernation fat storage preparation in some animals with d2

          Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters

      • gordondev

        In addition to Woo’s description, I think one of the issues in these discussions is the conflating of insulin resistance and hyperinsulinemia.

        In my personal experience, any involvement of IR in my weight gain has been connected to hyperinsulinemia (which, in my experience, has been the true/primary cause of my weight issues, or at least the measurable marker of a deeper cause directly affecting insulin levels), and like Woo mentioned, is likely, specifically, IR in the liver. This is evidenced by the efficacy of drugs like Metformin, and supplements like Inositol, both of which affect the liver’s insulin sensitivity, in people with (liver) IR (and may explain the people who show evidence of IR somewhere, but don’t respond to these treatments).

  • Chantelle

    That could somewhat explain why insulin sensitivity decreases with weight loss and with exercise. … Stephan Guyenet also wrote a great article about this …
    Love your posts, btw … so insightful!

  • Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women

  • brian mcbee

    Ir and leptin resistance go hand in hand and leptin resistance does cause obesity as it is the weight regulating hormone since they are both caused by elevated triglycerides I can see how people blame on or the other but in reality they probably both play their own roles in a complicated feed back loop.any good diet wether low car low fat whole foods Paleo ect will lower tg and lead to decreased hunger and weight loss but it’s about sticking to it that causes weight regain imho

    • “Insulin resistance and leptin resistance go hand in hand”

      not always, but I see your point

  • andrew

    I am skinny’ thru malnutrition as a celiac, diabetic likewise.
    I am addressing my advanced circadian rhythm by addressing my HPA axis which gives me high cortisol & insulin @ 1am.
    Insulinemia has given me insulin resistance with high cortisol trying to address that [chronic fatigue] with subsequent adrenal exhaustion.
    Adrenal exhaustion from a lifetime of gliadin & carb induced inflammation which induced insulinemia as a symptom not a cause.