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Ketoacidosis Pathophysiology

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Ketoacidosis Pathophysiology

Introduction Diabetic ketoacidosis Diabetic ketoacidosis is a serious, life threatening condition - successful treatment requires attention to metabolic consequences. Ketone production In the normal animal free fatty acids (FFA) are released from adipose tissue in the process of lipolysis and are used as fuel or assimilated by the liver in the presence of reduced insulin concentrations and increased glucagon concentrations. They are used to build triglycerides, metabolized in the tricarboxylic acid cycle or converted to ketone bodies. In the face of a relative or absolute insulin deficiency the cells are unable to uptake and utilize glucose. Ketone bodies can be used by peripheral tissues and the liver as an alternative source of energy and are therefore life-saving in the short-term. Production is normally carefully controlled by a homeostatic mechanism. If this balance is disturbed a number of processes are activated which together produce a decompensated state which inevitably progresses towards death unless averting action is taken. As the rate of ketone body production begins to exceed the rate at which they can be used, ketonemia develops with associated acidosis. Once the co Continue reading >>

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  1. RawNut

    Humans are unique in their remarkable ability to enter ketosis. They’re also situated near the top of the food chain. Coincidence?
    During starvation, humans rapidly enter ketosis; they do this better than king penguins, and bears don’t do it at all.
    Starvation ketosis
    Humans maintain a high level of functionality during starvation. We can still hunt & plan; some would even argue it’s a more finely tuned state, cognitively. And that’s important, because if we became progressively weaker and slower, chances of acquiring food would rapidly decline.
    Perhaps this is why fasting bears just sleep most of the time: no ketones = no bueno..?
    Observation: chronic ketosis is relatively rare in nature. Angelo Coppola interpreted that to mean animals may have evolved a protective mechanism against ketosis (if you were following along, please let me know if this is a misrepresentation).
    But I think that is misguided. Animals with a low brain/carcass weight ratio (ie, small brain) don’t need it. Babies and children have a higher brain/carcass weight ratio, so they develop ketosis more rapidly than adults. Is this a harmful process? No! It’s an evolutionary adaptation which supports the brain.
    The brain of newborn babies consumes a huge amount of total daily energy, and nearly half comes from ketones. A week or so later, even after the carbohydrate content of breast milk increases, they still don’t get “kicked out of ketosis” (Bourneres et al., 1986). If this were a harmful state, why would Nature have done this? …and all those anecdotes, like babies learn at incredibly rapid rates… coincidence? Maybe they’re myths. Maybe not.
    Ketosis in the animal kingdom
    Imagine a hibernating bear: huge adipose tissue but small brain fuel requirement relative to body size and total energy expenditure. No ketosis, because brain accounts for less than 5% of total metabolism. In adult humans, this is around 19-23%, and babies are much higher (eg, Cahill and Veech, 2003 & Hayes et al., 2012).
    A possible exception to this is ruminant ketosis, but that’s for a different reason. They become ketotic because: 1) their gut turns much of what they eat into a ketogenic diet; and 2) this frequently happens during lactation, which combines very high energy expenditure and an enhanced draw on the oxaloacetate pool to make lactose.
    Whales? Nope. Despite eating for like, 1 month out of the year, they don’t develop ketosis.
    Snakes will enter ketosis, not due to high brain needs per se, but likely because even though small brain, total energy expenditure is so low that brain metabolism easily surpasses the [theoretical] 5% threshold (McCue 2006):
    Fasting baby elephant seals get ketotic, because their babies (Castellini and Costa, 1990):
    Hypercarnivores (eg, cats) don’t develop ketosis on very low carb diets, like humans would, which seems to be due to their inability to down regulate protein catabolism (urea cycle takes care of the nitrogen; gluconeogenesis the carbon)… but they will do so readily during starvation because of relatively big brains (Blanchard et al., 2002):
    Similar to cats, dolphins are carnivorous and also exhibit what appears to be a pathological inability to reduce protein catabolism when necessary. However, unlike cats, dolphins fail to develop ketosis of any sort, whether it’s on their typical low carb diet of fatty fish, or even complete starvation!
    Dolphins are the exception to a lot of rules. I don’t know why. Most animals with big brains have the ability to enter ketosis, but none do it as well as humans.
    Historically, while intermittent or cyclical ketosis was likely more common than nutritional [chronic] ketosis in humans, this doesn’t mean one form is better than another. Common =/= optimal.
    Starvation ketosis isn’t nutritional ketosis, but much of what we know about the latter stems from our understanding of the former… this is getting better, with more and more studies of longer and longer durations being published regularly. And hint: chronic ketosis doesn’t dissolve bones, deteriorate cognitive function, or break your metabolism.
    Are ketones the brain’s preferred fuel?
    Well, let’s just say this: when there are more ketones than glucose, brain uses more ketones than glucose. This happens in both starvation and nutritional ketosis.
    Ketosis proportionately spares glucose utilization in the brain (Zhang et al., 2013)
    If ketones were harmful, Nature would’ve surely devised a way to protect the brain!
    Disclosure: I’m not keto, not even very low carb in the summer really, so this obviously isn’t some sort of confirmation bias or logic fail or whatever you call it. I don’t practice what I preach. Sue me.
    Most of the time, I advocate a plant-based low-carb Paleo-like diet for health; keto if obese insulin resistant. High[ish] protein for all (ymmv). Seasonal when possible.
    Impact of ketones on cognition
    Would our ability to plan and set traps to acquire food, or quickly devise a strategy to escape predation have been negatively impacted during periods of intermittent or cyclical ketosis? I think not; more likely the opposite. And while I [still] believe the physical feats required to do these is not hindered after ketoadaptation, I also [still] believe it’s because we *out-smarted* them, not out-ran them. Compared to many other species, humans suck at speed.
    Some evidence:
    1. acute: in patients with moderate cognitive impairment or Alzheimer’s disease, given 40 mL MCTs to bolster ketoneshttp://ir-na.amazon-adsystem.com/e/...=1&a=B0019LRY8A: cognitive performance improved roughly in parallel with increasing ketones (Reger et al., 2004).
    2. chronic: 20 grams of Axona (purified MCTs) daily for 90 days improved cognition in people with age-associated memory impairment (Constantini et al., 2008).
    3. cruel and unusual: expose a group of type 1 diabetic patients to experimental hypoglycemia and give half 40 grams of coconut oilhttp://ir-na.amazon-adsystem.com/e/...=1&a=B003OGKCDC (which is like a longer-chained version of MCTs) (Page et al., 2009). Result? Hypoglycemia impairs cognition; however, this is largely offset by increasing ketones with coconut oil. This group experienced improved: 1) verbal memory; 2) delayed verbal memory; and 3) verbal memory recognition.
    4. nutritional ketosis: 6 weeks of a bona fide ketogenic diet in patients with mild cognitive impairment = improved verbal memory performance, and this positively correlated with ketones (Krikorian et al., 2012).
    Optimal, harmful, or somewhere in between? You decide (but if you choose harmful, please provide a link! or at least explain why, very clearly…)
    Hint: nutritional ketosis isn’t harmful. FOR. FIVE. YEARS… 1) that’s not cyclical or intermittent ketosis; and 2) five years is probably much longer than the diet you’re following has been tested for “safety.”
    Ketones in evolution
    Without our ability to rapidly enter a robust state of ketosis, we wouldn’t be here, or we’d be some weaker subhuman species. But ketones have been around for a while… some bacteria store energy in the form of poly-beta-hydroxybutyrate. Some prokaryotes use ketones instead of triacylglycerols. Archaea also use ketones; and they’ve been around for billions of years… it’s estimated that we’ve been doing it for quite a long time, too (from evidence on when our brain would’ve surpassed the [theoretical] threshold). I’d cite a study by George Cahill here, and maybe you’d read it. But you should really read all of the studies by George Cahill (it’s not a-whole-lot). Sorry, I know that sounds ‘preachy.’
    Would ketosis have hindered our ability to hunt prey and avoid predation? My thoughts on our ability to perform high intensity physical activity after ketoadaptation have been thoroughly expressed in the past. And ketosis clearly doesn’t hinder cognitive functioning.
    So, from both a mental and physical perspective, ketosis, chronic or otherwise, did not stop us from becoming who we are. Indeed, it probably contributed to how we did so. Well, that and seafood.
    http://caloriesproper.com/?p=5078

  2. keith v

    Wow thanks Rawnut, that was very interesting.
    It especially makes mouse studies suspect due to the mouses small brain

  3. teaser

    An aspect to this that I find interesting is the idea that ketones spare fat. An animal like an elephant seal with its relatively smaller brain and larger fat mass can afford to fuel its glucose cycle from glycerol almost exclusively. If we wanted to do the same trick, and needed 100-125 grams of glucose a day to fuel our brains--at around ten percent of triglyceride calories as glycerol, we'd have to burn through 4000-5000 calories of fat a day during complete starvation, obviously not a good strategy for a person with what used to be "normal" fat stores.

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