February 15, 2021

Nutritional Biochemistry

#149 – AMA #20: Simplifying the complexities of insulin resistance: how it’s measured, how it manifests in the muscle and liver, and what we can do about it

"If you're in the business of wanting to live the healthiest life you can live, which means longer and better, you've got to be insulin sensitive, full stop." — Peter Attia

Read Time 25 minutes

In this “Ask Me Anything” (AMA) episode, Peter and Bob discuss all things related to insulin resistance by revisiting the important points made in the fascinating, yet quite technical, episode of The Drive with Gerald Shulman. They devote the entire discussion to understanding the condition known as insulin resistance, how it’s measured, how it manifests in the muscle and liver, and ultimately, what we can do about it.

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AMA #20 Sneak Peak:

We discuss:

  • Explaining the format of this AMA: Extracting insights from Gerald Shulman’s masterclass on insulin resistance (2:00);
  • The basics of insulin, defining insulin resistance (IR), and gold-standard methods of quantifying IR in the muscle (7:15);
  • Practical ways to test for insulin resistance in a normal clinical setting (15:45);
  • How insulin resistance manifests in the muscle (23:00);
  • The biochemical block in glycogen synthesis—drivers and mechanisms resulting in insulin resistance in the muscle (30:45);
  • The disparity in fat oxidation between insulin-sensitive and insulin-resistant individuals (44:45);
  • The fate of the ingested carbohydrate in someone who is insulin resistant (51:00);
  • The prevalence and clinical phenotype of insulin resistance (1:00:15);
  • The role of exercise in mitigating and reversing insulin resistance (1:05:00);
  • How insulin resistance manifests in the liver (1:09:15);
  • Biggest takeaways: what we can do to mitigate and prevent insulin resistance (1:20:45); and
  • More.


Explaining the format of this AMA: Extracting insights from Gerald Shulman’s masterclass on insulin resistance [2:00]

Peter recently did a podcast with Gerald Shulman: #140 – Gerald Shulman, M.D., Ph.D.: A masterclass on insulin resistance—molecular mechanisms and clinical implications

  • Listening to that discussion was like “drinking through a fire hose” with so much info, so many mechanisms, etc.
  • Today’s AMA will be designated to going through the important points of that podcast in a slower way to unlock the takeaways
  • Prep for this AMA largely came from Shulman’s Banting Memorial Lecture

Questions to answer today:

How does insulin work under normal circumstances?

What does insulin resistance really mean? 

How do we even measure it? 

How is insulin resistance manifested in muscle? 

How is it manifested in the liver? 

How are those the same or different, and what are the consequences of this? 

What should you do about this?

“Once you understand the consequences of this, you’ll appreciate how central this is to your health.” —Peter Attia


The basics of insulin, defining insulin resistance (IR), and gold-standard methods of quantifying IR in the muscle [7:15]

The basics of insulin

  • Insulin is secreted as what’s called a pro-peptide
  • The pancreas secretes something that is inactive and it gets split into insulin and C-peptide (insulin is the active thing)
  • Insulin as a very anabolic (building/growing) hormone, and does the following:
    • Drives glucose into muscles where it can be turned into glycogen
    • Plays a role in glycogen synthesis in the liver
    • Increases fatty acid uptake into fat cells
  • In short: Insulin makes fat cells more fat, it makes muscle cells more glycogen rich, and it makes the liver more glycogen rich
  • It’s a pro-building hormone

Figure 1. Effects of Insulin on Glucose & Lipid metabolism (left, 2019); Critical actions & pathways controlled by insulin (right, 2018).

Defining insulin resistance (IR) and how it’s measured


  • Insulin resistance is probably best defined as an impaired ability for insulin to do some of the things listed above
  • E.g., if insulin’s job is to take glucose into a muscle so that a muscle can make glycogen, when that gets impaired, that is insulin resistance in the muscle
  • However, fat cells and liver cells have a slightly different explanation/manifestation of insulin resistance

How insulin is measured (Focusing on the muscle for this discussion)

There are a couple of gold standard ways to measure and quantify insulin resistance that are done in clinical trials (i.e., not something done at the doctor’s office as part of any regular checkup)

1-Hyperinsulinemic-euglycemic clamp technique

  • Using to separate IV lines…
  • The plasma insulin concentration is acutely raised and maintained at 100 μU/ml by a continuous infusion of insulin. 
  • Meanwhile, the plasma glucose concentration is held constant at basal levels by a variable glucose infusion. 
  • When the steady-state (i.e., euglycemic/normal) is achieved, the glucose infusion rate equals glucose uptake by all the tissues in the body (almost exclusively into their muscles)
  • This is a measure of tissue insulin sensitivity, and the more insulin sensitive you are, the higher that glucose disposal rate will be

Figure 2. [UpToDate]

  • The figure above is actually showing glucose disposal, not glucose
  • And that’s why the more insulin-sensitive person at a fixed level of insulin requires more and more glucose to maintain glucose homeostasis

2-Insulin suppression test

  • Two IV lines
  • In one of them you’re infusing epinephrine, propranolol (which suppress your endogenous insulin release) as well as insulin
  • in the other IV, you’re infusing glucose
  • This is done until you have a steady state level of glucose and insulin
  • The way this test works is kind of the opposite of the euglycemic clamp, which is you fix the level of glucose and you’re trying to see how much insulin is required to do that
  • Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance.
  • NOTE: When Peter did this test, he got very, very hypoglycemic and it got a little dangerous

{end of show notes preview}

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  1. A world class presentation and analysis with world class comments! Kudos!

    My perspective as a veterinarian is from an animal point of view, specifically horses where EMS (Equine Metabolic Syndrome) and IR (insulin resistance) are epidemic. One of the most common results is laminitis where the hooves become painful to the point of the horse being unable to walk or stand with subsequent euthanasia. Every horse with laminitis is IR.

    At a lesser level to laminitis is what I have been calling “Chronic Protein Deficiency.” It is represented, in my view, by several diseases including sarcopenia (in the horse – loss of the top line muscles and a “hay belly”). This too is very prevalent in our older human population (flabby triceps and falling down).

    Up until now I had blamed excessive glucose (in the form of starch – the plant equivalent of glycogen) intake leading to IR and subsequent GNG (gluconeogenesis) which would consume all proteins from connective tissue to neurotransmitters to enzymes, etc. But in these presentations, GNG is inhibited by IR in the liver. So where is the protein loss occurring?

    Is there any chance one of you could take a moment to plug this hole in my thinking by replying or emailing me either a podcast episode, a reference or thoughts this week? I am podcasting/Zooming next weekend to my very small but international crowd of horse followers on “Aerobic exercise and its role in insulin resistance.” Just paying it forward my friends…

    • Hi Geoff, I make no claims of any expertise in this area, but found your question very interesting.
      My thoughts would be that IR impairs anabolism both directly by reducing insulin signalling in the target cell(s) and indirectly via attenuation of GH secretion.

      • This was a *fantastic* AMA episode. I went back and listened to Gerald Shulman EP 140 a second time, and probably will a third time. But hearing you two restate what Dr. Shulman shared has been helpful beyond measure. I too listened to this while driving, but it moved the dial for me from understanding 50 percent of what he said to 75, and now having listened to Peter and Bob I’ll be listening to Dr. Shulman with much better insight. I don’t know that I’ll hit 100 percent on my third listen, but is the 80-20 rule applies there I would probably never have gotten there, and definitely not as quickly and efficiently, without this AMA episode. There was another angle on this for me: something that Bob and Peter thought was so important that they’d devote an AMA to (to say nothing of the prep) speaks volumes to me, and underscores the importance of Dr. Shulman’s outstanding talk. My only regret is that you guys don’t share your research notes. In the AMA Peter talked about being on page so-and-so, and I found myself wishing that I could see what he was describing. Maybe this is one of the episodes that so needs to be video as well as audio?

  2. Thanks for the lecture.

    “At the short-term level, insulin is coming into the cell and it’s leading to glycogen synthesis which reduces glycogen production or hepatic glucose output”

    do you mean ‘reduces glucose production’?

    Thank you

  3. Great background to understand mechanisms, as always. I find myself wanting more in terms of reversibility of IR (and prevention). How reversible is it? What recommendations for embarking on counteractive measures? How to monitor these? Especially for “sedentary, old codgers,” beginning retirement, seeking the longevity bandwagon.

  4. Guys, I enjoyed listening to this, but maybe it’s just that I am too far out, or that I was driving — I understood maybe 5-8%, and I realize this may have been for a specialist audience, and for them it seems to work very well (see comment above), but my sense was a bit that starting this from “what are the take-home messages?” may make it a bit easier (if the audience is not fellow doctors, which maybe it was) to absorb the content. Again, not meaning this as a criticism, it’s fun when people nerd out — I just thought it would be useful to give feedback from the non-medical/expert segment of your audience.

  5. being a t2d. this was enormously interesting . The exercise part is what is missing in my regimen for treating my ir. I would like to hear nutritional guidelines discussed more, this seems tp be an area where traditional beliefs are conflicting on evidence based guidelines .

  6. I loved this deep dive. As an accountant that is trying to stay healthy and understand the workings of the human body I found this so informative. There are a lot of people who do not have a science background that enjoy learning and this an excellent way to gain such important knowledge. I would love to see a deep dive into Lipids and cholesterol.

  7. Based on the idea that insulin resistance begins in muscle and how much change simple exercise helped with glucose disposal: what are your thoughts on building/increasing muscle mass, glucose disposal and insulin resistance? Would more muscle help in prevention or reduction of insulin reduction? In your podcast with Layne Norton it seemed like you might be looking to address this idea but didn’t quite get there. Would greatly appreciate hearing a podcast looking at this. THANKS!!!

  8. Highly recommend interviewing Dr. Benjamin Bikman on the topic. This has been my favorite podcast AMA yet! Your ability to explain things simply is an art. I had to look up how FAs are oxidized (carnitine shuttle?) but rest made sense. It’s interesting first article I found on protein kinase C theta found that it was responsible for activating T cells. This lecture combined with “ninja nerd” youtube has finally brought this topic full circle. I could cry tears of joy, really, I’ve been trying to understand this for soooo long. It clicked!

  9. Wondering if there is an association between hormone-sensitive lipase and insulin resistance since HSL is responsible for breaking off FA bond to convert to MAG.

  10. Gerald Shulman wrote an excellent review


    Ditto Nir Barzilai

    I think Shulman makes a great case how Metformin inhibits hepatic gluconeogenesis in vivo in a redox-dependent i.e., an Increased cytosolic redox state, due to metformin inhibition of glycerol-3-phosphate dehydrogenase, at clinically relevant concentrations.

    That said – Barzilai is no less cogent when defending Metformin’s effects on Mitochondrial Complex 1:
    “… micromolar concentrations of the drug are effective in achieving a dose- and time-dependent weak, reversible and selective complex I inhibition”

    I am over my head here, but I suggest that Talmudic precision is required to parse Metformin’s immediate effects (inhibition of Hepatic Glucose production) from delayed downstream effects (including AMPK activation in the periphery secondary to what already happened in the Liver – a subtlety of distinction which Shulman acknowledges – if I read him correctly)

    Shifting our focus momentarily from the Liver – Metformin’s delayed downstream effects on White Adipose Tissue may prove especially exciting, especially because activated AMPK limits fatty acid efflux from adipocytes and favours local fatty acid oxidation (which could go a long way to explaining Metformin’s benefits for NAFLD patients).

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