December 7, 2020

Nutritional biochemistry

#140 – Gerald Shulman, M.D., Ph.D.: A masterclass on insulin resistance—molecular mechanisms and clinical implications

“If we can understand insulin resistance, then that's going to be the best way to fix diabetes, heart disease,. . .fatty liver disease, and slow down cancers.” — Gerald Shulman

Read Time 31 minutes

Gerald Shulman is a Professor of Medicine, Cellular & Molecular Physiology, and the Director of the Diabetes Research Center at Yale. His pioneering work on the use of advanced technologies to analyze metabolic flux within cells has greatly contributed to the understanding of insulin resistance and type 2 diabetes. In this episode, Gerald clarifies what insulin resistance means as it relates to the muscle and the liver, and the evolutionary reason for its existence. He goes into depth on mechanisms that lead to and resolve insulin resistance, like the role of diet, exercise, and pharmacological agents. As a bonus, Gerald concludes with insights into Metformin’s mechanism of action and its suitability as a longevity agent.

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We discuss:

  • Gerald’s background and interest in metabolism and insulin resistance (4:30);
  • Insulin resistance as a root cause of chronic disease (8:30);
  • How Gerald uses NMR to see inside cells (12:00);
  • Defining and diagnosing insulin resistance and type 2 diabetes (19:15);
  • The role of lipids in insulin resistance (31:15);
  • Confirmation of glucose transport as the root problem in lipid-induced insulin resistance (40:15);
  • The role of exercise in protecting against insulin resistance and fatty liver (50:00);
  • Insulin resistance in the liver (1:07:00);
  • The evolutionary explanation for insulin resistance—an important tool for surviving starvation (1:17:15);
  • The critical role of gluconeogenesis, and how it’s regulated by insulin (1:22:30);
  • Inflammation and body fat as contributing factors to insulin resistance (1:32:15);
  • Treatment approaches for fatty liver and insulin resistance, and an exciting new pharmacological approach (1:41:15);
  • Metformin’s mechanism of action and its suitability as a longevity agent (1:58:15);
  • More.

§

Gerald’s background and interest in metabolism and insulin resistance [4:30]

  • Gerald has an MD and a PhD, did a residency in medicine at Duke, and a fellowship in endocrinology at Mass General Harvard
  • Gerald’s father was a diabetologist, which exposed Gerald to metabolism and diabetes at a young age
  • Although Gerald’s father wanted him to become a radiologist because of his physics background, Gerald ended up staying in the field of metabolism and endocrinology

When did the idea of understanding what insulin resistance means and being able differentiate between some of these phenotypes of insulin resistance begin to intrigue Gerald?

  • Dating back to medical school, Gerald was interested in biochemistry and physiology
  • While visiting a medical student at Vanderbilt in the 1970s, he became interested in in vivo metabolism – observing metabolism in living animals – particularly glucose and fatty acid turnover
  • Since diabetes is a metabolic disease with significant consequences (blindness, renal disease, limb amputation, etc.), Gerald considers working in this area to be an easy transition for someone like himself who is already interested in metabolism
  • Gerald’s interest in metabolism led him to nuclear magnetic resonance spectroscopy (NMR), which is a technology that can be used to observe metabolism within a cell
  • At the time, this technology was being developed to look at yeast cells, but Gerald envisioned using it to look at human cells — “In medical training, you go back to medical school, you learn how to become a good doctor, take care of patients. But then in your fellowship years, you’re back in the lab and I really wanted to get back to understand the metabolism by looking inside the cell.” 

“I think [insulin resistance] is such an important metabolic disease, the most common metabolic disease, so if someone’s who’s interested in metabolism it’s a natural segue way.” —Gerald Shulman

 

Insulin resistance as a root cause of chronic disease [8:30]

How Peter describes the insulin resistance to people:

  • Peter sometimes describes insulin resistance to his patients as “the foundation upon which the major three chronic diseases sit”
  • In addition to the direct complications of diabetes, Peter believes that the majority of diabetes-related mortality comes through amplification of atherosclerotic disease, cancer, and dementia – all of which are “a force multiplied in spades by type 2 diabetes”
  • Peter also describes insulin resistance as a continuum starting with hyperinsulinemia and leading to impaired glucose disposal, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and eventually type 2 diabetes

That continuum makes up a plane upon which all chronic disease get worse. If we’re going to be serious about the business of delaying the onset of death, we have to be serious about the business of delaying the onset of chronic disease. If we want to do that, we must fix our metabolisms, and that’s my thesis.” —Peter Attia

Gerald’s thesis:

  • Gerald fully agrees with Peter’s “thesis” and refers to Jerry Reaven’s 1988 Banting Lecture, which was where he first generated interest in insulin resistance not only leading to diabetes but also hyperlipidemia, inflammation, elevated uric acid, polycystic ovarian disease, and cancer
  • In regard to NAFLD, Gerald prefers to instead call it metabolic-associated fatty liver disease, or MAFLD—the most common cause of liver disease, liver inflammation, end stage liver disease and liver cancer.
  • Gerald says that insulin resistance is driving the huge increase in cancers which are associated with obesity, such as breast, colon, pancreatic, and liver cancers and that there is strong preclinical evidence for this in animals
    • Insulin resistance is not necessarily causing the cancer, but is promoting its growth
  • Rachel Perry, a former student of Gerald’s, has used insulin pumps in mouse models of breast and colon cancer to show that insulin accelerates tumor growth and insulin-sensitizing agents slow it
    • Rachel and Gerald co-authored a recent review article describing the role of insulin in cancer growth
  • Gerald says that insulin resistance is quite common—he estimates one quarter to one half of the population is affected by it without symptoms

 

How Gerald uses NMR to see inside cells [12:00]

Flux and molecular labeling

  • Simply measuring the concentration of a metabolite (i.e., glucose) does not provide any information about its metabolism or flux, or the rates at which it is produced versus consumed
  • Traditionally, dating back to about 50 years, flux has been measured by “labeling” molecules, such as radiolabeled isotopes
  • This approach is great for assessing flux in general, but does not give good indication of what is going on inside of cells

{end of show notes preview}

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Gerald Shulman M.D., Ph.D.

Dr. Shulman is the George R. Cowgill Professor of Medicine and Cellular & Molecular Physiology at Yale. He is also Co-Director of the Yale Diabetes Research Center. Dr. Shulman has pioneered the use of magnetic resonance spectroscopy combined with mass spectrometry to non-invasively examine intracellular glucose and fat metabolism in humans and transgenic rodent models that have led to several paradigm shifts in our understanding of type 2 diabetes (T2D), including the molecular mechanisms by which ectopic lipid promotes liver and muscle insulin resistance, as well as developing new drugs for the treatment of T2D, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Dr. Shulman is the recipient of the Stanley J. Korsymeyer Award from the American Society for Clinical Investigation, the Outstanding Clinical Investigator Award from the Endocrine Society, the Solomon Berson Award from the American Physiological Society and the Banting Medal for Lifetime Scientific Achievement from the American Diabetes Association. Dr. Shulman is a Fellow of the American Association for the Advancement of Science, Inaugural Fellow of the American Physiological Society and he has been elected to the American Society for Clinical Investigation, the Association of American Physicians, the National Academy of Medicine, the American Academy of Arts and Sciences and the National Academy of Sciences. [yale.edu]

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22 Comments

  1. In the podcast peter suggests “a starving human would quickly die (10m?) without gluconeogenesis” (paraphrase). Haven’t there been an experiment where fasting subjects had their glucose levels driven down to unmeasureable levels with insulin injections without any negative observed consequence (much less hypoglycemic coma.)? If yes, how do you square your claim about gluconeogenesis and the “unmeasureable glucose levels” experiments?

    • ”’One of the interesting things about the experiment: he was able to give insulin (referenced in Cahill and Aoki), lower glucose levels, but not generate CNS trauma;
      Infused insulin to push glucose to ~ 1 mmol (like less than 20 mg/dl) which is basically FATAL in most cases (2 mmol puts you in a coma normally);”’

  2. The lipid induction studies seem to rely on PUFA lipids like soybean oil. Have the studies been reproduced with saturated fats or coconut oil? Is it possible that insulin resistance is easier or harder to induce with saturated fats?

  3. So many questions come to mind. Should have taken notes while listening. As you suggested, I’ll definitely have to give this one another listen (or ten). One thing that struck me as peculiar was the claim that fasting induces insulin resistance at the liver by lipid accumulation (don’t remember if it was both inter and intracellularly or just intracellularly). That makes absolutely no sense at all. If you’re starving, why wouldn’t your liver be converting all the fatty acids it can into ketones as a source of fuel for peripheral tissues? It doesn’t make sense from a flux perspective. Are fat cells releasing more fat than our liver can metabolize? Why don’t we all get keto acidosis instead of just type 1 diabetics if this was the case? Wouldn’t our muscles become fat burning machines under such a scenario, meaning our liver isn’t getting hit with all of that substrate? Why would our liver need to become insulin resistant in an environment (fasting) where very little insulin is circulating to begin with? Also, wouldn’t you see tons of NAFLD in people following ketogenic diets along with rising ALT/AST, CRP, and fibrinogen if this were the case?

    Also would have liked to you to have gone down the rabbit hole of metabolic flexibility. What’s going on at each stage of insulin resistance with fuel selection. You’ve mentioned before that fasting type 2 diabetics will be oxidizing glucose based on RQ data when a metabolically healthy person will be oxidizing fat. Probably insulin mediated as we know insulin will inhibit beta oxidation. Could that be a quick, easy to measure, non-invasive proxy for insulin resistance? Obviously OGTT with measured insulin response is the gold standard, but short of that, might be a pretty good down and dirty biomarker to look at.

    I’m sure there’s more, but again, I’ll have to go back for another listen and write stuff down. Amazing episode!

  4. Is it possible that some pathways in the liver get resistant (DAG mediated inhibition of glucose receptor translocation for example) while others remain sensitive? You don’t see type 2 diabetics having any trouble synthesizing triglycerides for example, which last I checked, is an insulin mediated phenomenon.

  5. But of course, the insulin resistant liver does not stop cranking out glucose via gluconeogenesis, which is normally inhibited by insulin, so obviously that pathway has become “resistant” to insulin signaling. Maybe that’s just the liver attempting to protect itself from too much substrate? Increasing the synthesis of both triglyceride and glucose simultaneously, which wouldn’t occur in an insulin sensitive person.

    And the metformin thing. Literally being taught in med school right now that it is a complex 1 inhibitor, which just goes to show you how irrelevant or outdated the information we learn today will be in a few short years.

    Is it working on other tissues besides the liver? Would be interesting to see muscle biopsies to see if glycogen stores are increasing if AMPK is being activated. I’m so confused as to what’s going on in the liver as well, working from the model that there’s simply too much substrate for the liver to metabolize. Lactic acidosis is a common side effect. Is excess lactate making it out of the liver and to the kidney for excretion?

  6. Relating (some) cancers to impaired mitochondrial function, how does metformin *lower* the incidence of liver cancer while it also diminishes mitochondrial breathing and increases lactate ?

  7. Overall, excellent podcast. The one point I would like to clarify is that although muscle tissue becomes insulin resistant before liver tissue (in humans), adipose tissue becomes insulin resistant even before muscle tissue (so muscle tissue is not “first”). When adipose tissue is “nutrient overloaded”, fatty acids begin to overflow causing DAG accumulation in muscle tissue [1, 2]. This is associated with adipose hypertrophy as opposed to hyperplasia, but the exact mechanism causing adipose tissue dysfunction is not fully understood [3, 4].

    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972445/
    2. https://pubmed.ncbi.nlm.nih.gov/20056169/
    3. https://pubmed.ncbi.nlm.nih.gov/26292076/
    4. https://journals.physiology.org/doi/full/10.1152/physrev.00063.2017

  8. Dr Attia:
    Thank you very much for conducting this wonderful interview/biochem class with Dr Shulman. I’m going through it slowly, hitting playback frequently with extended stops to research terminology that’s new to me. I am learning a lot.

    At 1:06:01 you discuss the exercise experiences of some type 1’s in your practice, stating “…and obviously restricting carbohydrates.” Please, take <5 minutes to listen to a man who has a PhD in nutritional biochemistry from UC Berkeley, (a bachelor's in mechanical engineering from Stanford) and has had type 1 diabetes for 18 years.
    Just listen from 01:50-06:25.
    https://www.youtube.com/watch?v=5x_zbY7Mjr0

    I have what I call a form of 'genetic dyslipidemia' because I'm APOE4+/+. I find that if I ride my exercise bike to keep my HR average @ 130 BPM (70% maxHR – Polar estimates I'm burning about 30% fat at that level of exertion – the top of my Zone 2) for 60 minutes daily AND eat a VERY low fat WFPB diet with just 14 grams ground flaxseed and 720 mg algae DHA, my fasting BG runs in the 70's. When I'm not exercising consistently and my dietary fat intake creeps up (from nuts and tahini), my FBG goes back into the mid 90's. [I am a very healthy 65 yr old athletic female, BMI 20 my whole life, BP ~105/65, TC ~ 150, fasting TAG always <100, can get to 1:1 ratio of TAG/HDL (76:76) when I'm exercising regularly.] It appears that I have to keep my serum fatty acids low with a very low fat diet to keep my intramyocellular lipids low (including DAG levels) which maintains PI3K activation and efficient GLUT4 translocation so the serum glucose goes right into my muscles and there's no excess to mess with my liver. And just like Cyrus Khambatta, I'm doing this by eating LOTS of complex carbohydrates.
    FYI:I am a retired RN and CDC&ES

  9. I agree with you, the more you listen to IR topic the less you understand it. You both described IR here as the protection mechanism to save glucose for the brain. It is well known that Alzheimer is called T3DB of the brain and it is caused by IR of the brain, so in that case the brain is not protected by IR, is it? Is there any difference between IR in overfed state and in ketogenic state? Tom Dayspring said in your podcast that Tg/HDL ratio is the best marker of insulin sensitivity, which shows usually the best values in nutritional ketosis. How can you explain that?

  10. Wondering if anyone has thoughts on what the work-up should involve if investigating a patient with suspected insulin resistance but not type 2 diabetes?
    Mike

  11. This was a FABulous podcast, not that they all aren’t, but this one especially so. The bit about DGY was a mind blower. Thank you so much.

  12. Peter, this is Antonio Prince from Mexico City. I have been following your work from your first TED Talk a few years ago…

    Would you please expand on the following announcement:
    Novartis receives EU approval for Leqvio®* (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year.

    Looking forward to hearing from you.

    Merry Christmas 🎄

  13. I feel like I accidentally sat in on a medical lecture while being a phys. ed. major. However, I did actually listen to this twice and I’m not clear on many things, but have a couple of questions on what’s likely relevant to how to reverse this. How to get IR diagnosed? If plasma glucose is meaningless, is a GTT the only real test that exists? Then, is it exercise, low carb and weight loss to try and reverse IR?

  14. If exercise induces glycogen synthesis in the muscle.
    Does use of a heated spa induce glycogen synthesis in the muscle?

  15. Regarding the question of clinically relevant doses of METFORMIN hitting on Complex I: from a biophysics perspective it should be a no-brainer.
    The plasma concentrations of Metformin in patients taking 1 gr/day are in the 30-50 and up to 100 microM range (as pointed out by Dr. Schulman)
    Metformin is a positively charged organic CATION (2 positive charges dislocated in the two guanidine moiety). In the clinical form, it will have 1 positive charge (it is given as a chloride salt).
    Thus, based on Nerst potential and provided there is a transporter to carry it into cells, metformin will accumulate into cell compartments based on the membrane potential.
    OCT1 is highly expressed in hepatocytes, the membrane potential of energized mitochondria is in the -180-200 mV range, so 30 microM plasma METFORMIN will translate into some 33 mM into liver mitochondria. 50 microM will be 42 mM and 100 microM will be 84 mM.
    Any of the above concentrations will hit upon Complex I, so there shall be little doubt that the clinically relevant plasma concentrations of METFORMIN will reach complex I at mM range in liver mitochondria. This is the way positively charged drugs accumulate in any cell compartment that has a negative membrane potential, provided there is a transporter to get them in (the liver, the gut, and the kidney shall all be exposed to mM Metformin as they express OCT1)
    One way to know is not to measure whole liver concentrations of the drug (the total Volume is different) but to monitor and measure accumulation specifically in mitochondria.
    Whether metformin hits upon other targets in the cytoplasm could well be the case obviously, however, there should be no question that clinically relevant doses of Metformin will get to mitochondria in mM range and do the job at complex I.

  16. To the point of Greg, Steve and Justin – Intralipid (Fresenius-Kabi), the US standard lipid emulsion for TPN nutrition, contains a 7:1 ratio of n-6/n-3 ratio of polyunsaturated fatty acids (PUFA).
    PUFA and fat cell insulin resistance is emerging science; it “kinda” throws a glitch in Dr Shulmans young healthy IR studies.
    Overall FANTASTIC podcast though. learned a lot.

  17. re cancer in “In addition to the direct complications of diabetes, Peter believes that the majority of diabetes-related mortality comes through amplification of atherosclerotic disease, cancer, and dementia – all of which are “a force multiplied in spades by type 2 diabetes””,

    my understanding is that cancer rates are lower in diabetes people, incl. those taking metformin. This recent paper states angiogenesis impaired under hyperglycemia. So, how do you get organ/systemic cancer w/o angiogenesis???

    https://onlinelibrary.wiley.com/doi/full/10.1111/jdi.13477
    In addition, we found that the number of blood vessels in the gingival tissue of the diabetes mellitus group significantly decreased when compared with those in the non‐diabetes mellitus group, indicating that hyperglycemia affects angiogenesis, which is also consistent with previous reports40, 41.

    We showed that diabetes mellitus significantly changed the DNA methylation level of the periodontal tissue, with 599 genes upregulated and 564 downregulated. Functional analysis of the hypermethylated genes revealed that the changes were closely related to lipid transport, hormone secretion, immune system, inflammatory response, angiogenesis and metabolic activity, which are vital processes in the development of periodontitis27, 43, 44.

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