Insulin resistance is a defense mechanism where the cells say there is too much electron pressure. The energy resistance principle approach to type 2 diabetes management is twofold: (1) increase flux by moving, (2) fasting. Fasting is probably the most underrated & the most underused intervention in medicine Nick Jikomes, PhD: "[…] What is insulin resistance in your view from an energy resistance perspective, and how do you think about it?" Martin Picard, PhD: "[…] Look at this energetically. What's happening? Why is the cell trying to block itself from being able to sense insulin? And then when insulin is stimulated, and the signaling axis is properly mobilized, you get glucose transporter that go to the cell membrane, and then the cell can take in glucose. That's the main point of insulin signaling. "The second interpretation you have that cells are trying to, this is an adaptation, and that adaptation likely is an anti-energy resistance defense mechanism. So insulin resistance is likely a defense mechanism where the cell says there's too much electron pressure. I'm being fed too many electrons, too much glucose, relative to what I can sustain with my mitochondria, and relative to the flux that is being demanded of me. Right? If a cell doesn't burn energy, like we said earlier, ATP is very high. The ATP synthase doesn't turn, the membrane potential is really high. The electrons have nowhere to flow. There's too much resistance. So that resistance propagates like it would in an electrical circuit, and then propagates upwards. Then the resistance manifests at the level of the cell's surface, the plasma membrane, by removing the transporters for glucose, which effectively increases resistance. "There's this beautiful paper from 2009. The title was, 'Insulin Resistance is an Antioxidant Defense Mechanism.' That's in PNAS. They were saying the reactive oxygen species that mitochondria spit out when there's excess energy resistance. It didn't use those terms, but they did the same kind of experiments I mentioned earlier where you feed mitochondria lots of electrons but you don't let them respire, you don't let them produce ATP, spit out tons of reactive oxygen species, and then they showed how this then propagates to the plasma membrane, and then the cell becomes insulin resistant. The pathology of insulin resistance starts in the mitochondria, somewhere along where the flow of electrons is not high enough to support the pressure. So it's a pressure to flow issue, and the core driver of pathogenesis is the system is overloaded." Nick Jikomes, PhD: "Right. The cell's saying, 'I can't handle all these electrons from all this glucose or whatever, so stop giving me so much.'" Martin Picard, PhD: "Exactly. So the insulin resistance really is the manifestation of a deeper seated energy resistance." Nick Jikomes, PhD: "So then from a therapeutic standpoint, you'd want to focus your attention on fixing the mitochondrial problem rather than trying to. . ." Martin Picard, PhD: "There's no mitochondrial problem." Nirosha Murugan, PhD: "Like a selective pressure problem of the flow of electrons." Nick Jikomes, PhD: "Yeah. The flow problem as opposed to trying to undo the insulin resistance." Martin Picard, PhD: "Yeah. And I've heard you know a couple clinicians who were reflecting on the use of insulin therapy in diabetes, because the standard of care nowadays, which is from a molecular perspective and how you started that question, there's an issue at the cell surface like insulin signaling is not happening. Let's restore, let's fix this, right? "And then one approach is to say the cells are insulin resistant to the effect of insulin, so let's give more insulin. Like that is the mindset that biomedicine is using to counter that problem. What this does at the cell level, you have the cell here, it says, 'Oh, the pressure of glucose, of electrons is so high. Let me protect myself.' And then the cell kind of finds some respite, probably in becoming insulin resistant. And then there's like 10× the amount of insulin that comes in and then it's overloaded. Then you start to damage your mitochondria. "There's some notion in diabetes management that giving insulin is useful at decreasing blood glucose. So HB1C goes down, but now peripheral organs starts to suffer, and there might be more nerve damage like neuropathy, and more of the other damage in some tissues that are insulin sensitive because you're forcing glucose into cells effectively that are trying to protect themselves. "So the energy resistance principle approach to disease management is twofold. Either you increase flux, right? How do you increase flux? You increase flux by moving. if you contract the muscles, that's going to increase the flux. You're going to breathe harder. So anything that kind of makes you breathe harder should be good to increase flux in the system. "Or the other approach is to the decrease the numerator, the energy potential, and you do that by eating less sugar, the source, the energy that we know insulin resistance. I don't know what the percentage is, more than half of people with diabetes, pre-diabetes, it is reversible. "Type 2 diabetes in many cases is completely reversible if you fast, and we know in normal healthy people you go through phases of more insulin resistance, and then insulin sensitive, and that's normal fluctuations with feed and fasting. If you fast for a day, or fast for two days, you become extremely insulin sensitive. Your tissues are like, 'OK, there's not too much pressure. Let me become receptive and sensitive to the influx of glucose.' I think fasting is probably the most underrated and the most underused therapy or intervention in medicine. So that's from first principles, ERP-based thinking, you can reduce the pressure by eating less, or eating less sugar, or you can increase flux by moving more. That's an ERP-like, first principles-informed strategy to addressing a medical issue in this case." Martin Picard, PhD & Nirosha Murugan, PhD with Nick Jikomes, PhD @ 01:39:34–01:46:00 (posted 2025-10-29) https://youtu.be/GiwDfsIgziA&t=5974