Yes. Gout is systemic and local. Here we are talking about the systemic driver. In 2015 it was shown that polyol is in the chondrocyte. So the hyperglycemia propagated downstream can activate fru-UA in the chondrocyte and therefore, gout.

@@DrPetesKetoKlub Thank you Dr that was a quick response. I see your videos all the time, continue your outstanding work. Gout sufferer since 2008, strange thing I stopped 95 percent of carbs and sugar last year never had a gout flare up. I started eating sugar again since my wife is pregnant and craves a lot of stuff sugary and got gout so I believe everything that you are saying in this video, trial and error see what happens.

The polyol pathway is ubiquitous from yeast to humans. Its operational in all of our main organs, everywhere its been looked for. I agree with you about the low bar. I arrived at this estimate based on the optimal intracellular glucose concentration under which both glucokinase and aldose reductase are active when a bolus of glucose enters the liver. I also think this is just a starting point of discussion. I think there is a difference in states: burning state vs. storage. The storage state requires activation which accompanies a meal. This pathway is the main way that we produce and store fat and glycogen. So what is the threshold? It can't be determined by average circulating values of glucose because of the literal difference in how investigators define and determine these values. We need careful biochemical studies to see the interplay between these enzymes and the dynamic flux of glucose in the context to the sudden rise post meal. I think activation of polyol-Fru-UA by glucose is lower than how it is normally considered and also in the context of the standard American diet. If you are low carb you rely mostly on gluconeogenesis for circulating glucose based on demand and spend the majority of your time in the burning state unlike someone eating SAD. The SAD person spends the majority of their time in the storage state and their burning state is heavily influenced by the storage state.

I would assume the actual value is individualized. The 90mg/dl is a more general statement. I think the symptoms of the patient matters. I am one of those people who has to stay < 5g carbs/day to get into ketosis. But simply thinking hard can increase my glucose to 105-115mg/dl. Even while fasting. So I doubt Dr. Pete is being perfectly definitive in the amounts. For some, it's probably higher, and others it's lower. And it could be dependent on other variables. Diseases like CIRS. Having an inflammatory response (allergic response), or just being morbidly obese would likely affect what/when these things are activated. But the process is important.

The starch of ancient societies have high fiber and low glycemic index.

Let me clarify: Glucose can activate this mechanism. The 90 mg/dL estimation comes from the glucose concentration that is known to activate both glucokinase and aldose reductase. I would argue that we need much better research on the question of this threshold but the data is strong that there is a threshold and its lower than what most investigators think. I'm saying that this mechanism is functional in everybody but the magnitude of activation will be dependent on individual genetics, how someone is eating, and exercise, etc. One of the key issues here is limiting time in the storage state and maximizing time in the burning state. Ancient societies have differences with us: 1) the nature of the starch that they ate. 2) workload and other variables. Insulin resistance is a natural function of human biology that is healthy when not chronically activated. Its function, among other things, is to proportionate nutrients to the organs that have demand and to modulate storage and growth. This mechanism, polyol-fru-UA, was instrumental to the survival of humans because it allowed us to rapidly store energy, water, to be accessed during workload. It was not meant to be activated chronically in the absence of workload. BTW Johnson and I are collaborating on the subject of this video.

@@DrPetesKetoKlubGreat, thanks. I kind of get it, but I'm no scientist. Great video, like usual.