Does a healthy ketogenic diet cause irreversible insulin resistance?

(Michael) #303

Thank you for the link (I did not watch the video in the other threads). I will not bother joining the discussion on duplicate link posting.

@PaulL Ben was pretty clear about two things in this video, which I would appreciate some acknowledgement since we have discussed this a few times (and I know you respect Ben’s perspective). Protein (for some people at least), causes spikes in glucagon which therefore raises blood sugar. Also, clearly (from his perspective and in at least some cases), since some people have larger glucagon release from protein consumption than others, GNG depends on protein intake and is therefore NOT demand driven in those cases, and therefore cannot be called demand driven in general (or at least not for everyone, in particular those with metabolic disorder).

I have recently done found a few articles confirming Ben’s perspective (and yes, a few stating the opposite of course), but the fact that FAT intake (yes fat, woah) directly influences glucose production, this verifies that GNG is not demand driven. Here is the link (from diet doctor which links to paper if interested):

#304

Thank you for the link, @Naghite.

The more I read these papers, the more convinced I become that at least for a huge chunk of the population, glucose is the preferred source of energy, not fat. Just look at all the things the body does to get glucose, no matter what one eats.

On the opposite side of the story, look at the effort we need to do to force our bodies to use more fat for fuel! And any slip from a very low carb diet will throw you off and your body will go back to doing what it prefers: using sugar as fuel, not fat.

Also, I hope people will realize most things these internet doctors/influencers tell you is wishful thinking, because they don’t know the answers and instead of admitting this, they more often than not extrapolate on the little known to create content. Gotta feed the followers! At least in the video in the link he did admit he doesn’t have all the answers.

Talking about internet doctors, I’ve just seen a video of Dr Cywes with an explanation as for why gluconeogenesis happens even when our blood glucose is already high, making it go even higher. I’m curious to check if it is true. I’ll try to write his explanation here in case one of you has a link to a paper that could confirm this mechanism. I’ll search for one, too.

He said that the glucose level in the blood isn’t the glucose level being seen by the glucagon releasing cells. The cells that release glucagon see as if one had low BG, because insulin didn’t succeed in pushing glucose to them. So, that cell thinks one’s BG is low.

Like one not seeing daylight because of very dark glasses, then switching the lights on. The dark glasses prevented one from seeing that there was already light enough in the room.

It makes sense, but is it really what happens? I suppose it could be one of the things going on, together with many other mechanisms the body will find to get sugar, as much as it can. Cells have a sweet tooth.

(You've tried everything else; why not try bacon?) #305

Interestingly, while we both watched the same video, we appear to have understood him as saying very different things. I don’t recall him saying anything about gluconeogenesis being purely supply driven, for example. Guess I’ll have to go back and listen again.

#306

Bikman says that some people like type 2 diabetics “have a much higher than normal glucagon response” to eating protein specifically. If someone wants to hear that protein causes higher glucose levels in some, or that glucose is ‘supply driven rather than demand driven’, then that’s what they hear. What they don’t hear is “much higher than normal”. In other words, this is not the normal response to eating protein. It’s a dysfunctional response and symptom of some underlying metabolic problem.

Bikman’s hypothesis is that non-normal interaction of glucagon and insulin is a symptom of some underlying disease/conditioin - he’s not saying that the rise of glucose is simply due to eating protein. The study that he and Levels have initiated is designed to test that hypothesis and further to try to determine just how the interaction of glucagon and insulin affects the response not only to protein but carbs and fats as well. They also hope to discover what actually causes the glucagon/insuin interaction and whether or not the resulting range of glucose indicates metabolic disease or just a normal and healthy range.

(You've tried everything else; why not try bacon?) #307

Having just replayed the video, I can say that gluconeogenesis is not mentioned at all. I know from Bikman’s other lectures and interviews that he is primarily concerned not so much with the absolute values of glucagon and insulin, but rather with the ratio between them. A low ratio of insulin to glucagon puts the body in a state that is primarily catabolic (a fasting-mimicking state), whereas a high ratio puts the body into a primarily anabolic state (naturally, neither anabolism nor catabolism ever completely stops; this is more a question of which is predominant).

What actually struck me most, this time around, was Bikman’s statement that any level of glucose under 150 used to be considered normal. He also appears to be saying that glucose in the range of, say, 100-110 but with low glycation (HbA1C around 3.3, if I heard aright) would not be a problem.

He also reinforced an impression I have been forming, that the real issue is what insulin is doing, and that glucose, while by no means benign, is of lesser importance.

(Joey) #308

Stipulating that this may be the case, it doesn’t preclude that such tissue “preference” is met more healthfully through liver production of glucose (GNG) as opposed to dietary glucose, does it?

Gluconeogenesis puts glucose into the bloodstream when dietary glucose is absent - and it is not triggered in response to rising insulin. On the contrary, dietary glucose triggers insulin release, and eventually tissue resistance to insulin.

What tissues might prefer as an energy source (which would seem to be a function of mitochondrial “preference” expressed through adaptation) versus where this energy source comes from strike me as two separate issues.

(Michael) #309

Hi Belisarius,

You jumped into a conversation that has been debated/going on for a while between @PaulL and myself. Paul is someone with whom I feel comfortable he is trying to give appropriate info and believes what he is posting is correct with usually some good evidence or reference. While you state Ben did not say “higher glucose” - you are right, in this video. Here is where he has clearly stated (yes, probably non normal with an underlying metabolic condition like almost half the population in the US and Canada), eating protein causes higher glucose for some people at 21:30 https://youtu.be/rkQxqodIADI?list=PLPTndB1S1lEB6H0qr8SBAcpPYZPRSPqVS. My statements looked at Ben’s statements in this video in conjunction with other videos of his explaining the same/related topics. In regards to not hearing “much higher than normal” - I heard it, that is what I am talking about. You cannot argue demand driven, except when it is not, and still call it demand driven when a large percentage of the population fits into the metabolically unhealthy subset.
When you watch both videos (and I have linked this video in the past) then we see quotes saying that 1) some people have huge glucose spikes from protein 2) some people have huge glucagon spikes from protein. If we combine these two statements from Ben with the knowledge that GNG is determined by glucagon (hence causing the glucose spike mentioned), then we get the connection between his two videos and a clear explanation that this happens (again, I concede for metabolically damaged people like so many are from eating high carbohydrate meals).
I will also note that I never said “supply driven rather than demand driven”. What I said was not (just) demand driven in those cases or a hyper-glucagon response. If it was JUST demand driven, then it would not matter if someone was metabolically damaged since there is or is not a need/demand for it to be created. With these people (mostly T2 diabetic) there is more GNG than needed and hence the high blood sugars. One could parse any video to individual words and take what they want, I think we all agree you have to look at the sum of the parts and not on any one phrase independently.
Separate from protein, the linked diet doctor episode shows that in the experiment, GNG (sugar from fat in this case), was totally intake dependent. Again, if GNG from fat is intake dependent then GNG cannot be claimed as demand driven in reference to fat at a minimum. This in conjunction with Ben’s statements (and others) is that for many T2 people, demand is not what solely determines GNG but insulin resistance of the alpha pancreatic cells overshoots any possible demand. In either event, I will be quite interested in his experimental results - if anyone can pin this down currently, it is probably him.

@PaulL Perhaps you have a different understanding of “glucagon spike”. Would this not cause GNG - is that not the purpose of glucagon in the first place, to regulate GNG?

@SomeGuy Gluconeogenisis puts sugar into the bloodstream when the ratio of Glucagon to Insulin is high. This does not mean that someone could not have GNG with high blood glucose. In fact, if you follow my CGM experiments late last year, I was having my blood sugars go from 5.4 while sleeping to over 6 upon waking - the dawn effect as we call it, which persisted well into the day. Since going full carnivore, my glucose is generally over 6 upon waking and stays high until I eat in the afternoon. Since I am not eating, any glucose is GNG generated, and with a level above 6 for hours, clearly not demand driven since it is higher than “normal” and not being used readily if not exercising.

P.S. Aye Paul, the statement that 150 used to be normal struck me as well, but also concerned me somewhat. I was planning on looking more into that…sometime … someday.
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(Joey) #310

Agree fully that this certainly would not represent exercise-related “demand” since you’re not exercising.

But does this mean your body isn’t requiring (i.e., demanding) energy at a level that is sufficient to stimulate GNG?

After all, there’s no activity-related “demand” that prompts the dawn effect - yet it happens like clockwork each morning. To my way of thinking, the body is demanding it. :thinking:

In other words, perhaps you’re getting too hung up on this notion of demand-driven. The body has ways of supplying what is required (and sparing resources that are not required). Whether that’s a supply-driven or demand-driven focus may have more to do with semantics given the miracle of our self-regulating endocrine system.

#311

Prevalence of widespread metabolic syndrome in the pop of US and Canada would not surprise me in the least. Obesity, near-obesity, diabetes and pre-diabetes have been pandemic for decades and getting more so. That many or most of these people eating the standard approved diet have abnormal glucagon/insulin response to eating protein and in addition insulin resistance should also come as no surprise. What interests us here most, of course, is what causes apparently similar response among some of those who eat a ketogenic diet rather than SAD.

Hopefully, Bikman’s study in conjunction with Levels will help answer some of the questions about the underlying causation(s). And help us better understand the processes of how low carb and keto affect matters. And possibly assist those whose responses are problematic - or not.

#312

But the problem, @SomeGuy, is that many of us end up with high glucose for many hours. For many of us, until we eat, or even all the time, making our A1c go up.

It is as if high BG triggered insulin only if it comes from food. When our BG is high due to GNG, insulin isn’t triggered and therefore BG stays high.

The area under the curve ends up being greater than with food that had a little carb.

That was my personal experience. My highs weren’t related to food. When I’d eat, my insulin thing would work and bring BG down. When my BG was high due to GNG, it stayed high for an alarmingly long time. And the trend, as measured by both A1c and fructosamine, was upwards.

If a person has type 2 diabetes (T2D) and has high blood glucose (BG) anyway, controlling that with a very low carb diet (VLCD) and seeing still high BG due to gluconeogenesis (GNG), but lower than it used to be on high carbs, that’s perhaps not worrisome. Example: a T2D patient has an average BG of 400 mg/dL. He goes into a VLCD and now has BG of 130 mg/dL. It is a fantastic win!

However, let’s see the case of a person who had normal BG, or close to normal, say an average of 105 mg/dL, or 110 mg/dL. With a VLCD, that creeps up to 120. Isn’t it cause for concern? Are you sure?

The problem seems to be that when you eat your glucose, insulin kicks in and brings BG down. But when you get your glucose from GNG, it stays up, or comes down very slowly. For many of us, it only comes down when we… eat.

I see at least 3 groups of reactions to a keto diet:

  1. it works as it should, keto keeps A1c and fasting blood glucose (FBG) down. It is the group I want to be in, when I find what the problem with me is.
  2. it doesn’t work as it should and A1c and FBG goes up. I was here. I’m trying to get closer to group 1.
  3. it works ok-ish: A1c is lower, but FBG is higher. If I understood, many of you are here. I’d be super happy to be here, if I couldn’t be on group 1.
(Joey) #313

A1c is a measure of glucose. So, not to be flip, but higher glucose means a higher measure of glucose.

I say this not to minimize your concern, but to simply get us to recognize that the only potentially “bad” thing going on when your body produces its own glucose is that your body might be “being bad” to itself.

To be sure, we have no research on this specific (somewhat narrow) question that affects otherwise highly healthy people whose bodies are doing better on carb-restriction than on their previous eating patterns.

But I continue to put my betting money on the notion that my body wouldn’t be producing something that is bad for itself.

Whether it’s measured at any particular moment through a single finger prick, or measured through a lab result approximation of what all those finger pricks might say on average.

I’m not ignoring your concern. But as someone experiencing a similar phenomenon, I just don’t happen to share the concern. :vulcan_salute:

#314

I ate the typical standard approved diet for 70+ years before I started eating keto. Fortunately, either due to genetics (thank you, ancestors!) or just dumb luck I did not experience any noticeable metabolic problems. During the decade of my 60s I gained about 25-30 pounds of excess weight and now, with the knowledge I have gained by much learning, I attribute that to insulin resistance. It took me about 6 months on keto to return to approximately the same overall body weight and comp I was at the age of 18. Overall I’m healthy and fit, much more so than others of my age. I am supremely grateful for it.

That said, I don’t measure glucose frequently, but when I do so it’s within the ‘normal’ range. I add the scare quotes because as Bikman has pointed out, ‘normal’ is defined in terms of eating SAD. I no longer eat SAD so what’s normal for the people who do so may or may not be normal for me. Also, as Bikman has again pointed out, ‘normal’ is a moving target and it didn’t necessarily move from ‘150 or below’ to ‘110 or below’ because scientists and doctors discovered something we did not know previously. It may have moved simply to sell more drugs - cynical interp. But whatever it is, I feel healthy and energetic, don’t exhibit any signs of ill health and enjoy eating the foods I eat that keep me consistently in ketosis.

My suspicion is that damage caused by eating SAD for years/decades is not and can not be resolved quickly or easily for many people either because the extent and/or severity of the damage is too great or simply because they drew a short straw from the genetic pool. The problem is not keto. Keto is the solution, but it’s not magic nor a miracle. It’s a biochemical process that given sufficient time will normalize one’s metabolism. Still, if something is broke beyond total repair, it will never get totally repaired.

(Joey) #315

I think this is the crux of the matter.

The “may or may not” part is what troubles some - but not all - of us who are witnessing higher (naturally self-produced) glucose levels.

#316

Hmm, what about auto-immune conditions? (It’s what I’m dealing with, and it feels hopeless at times.) Auto-immunity is so poorly understood. Why on earth would the body continue to attack itself for years and decades after an infection or whatever other (unknown) trigger?

(Joey) #317

That’s a powerful point! I’m much humbled by your reply.

#319

Exactly!

I’m sorry you have to go through it!

My mother and one brother also suffer from autoimmune diseases. My husband, who has no insulin resistance (measured with insulin and plasma glucose tests) and is healthy and does a lot of exercising, also. Was hospitalized for almost 3 weeks, almost died.

What about cancer? Dr Hallberg (Virta) said she did all the right things (interview with Peter Attia). She was diagnosed with stage 4 lung cancer.

All those people with type 1 diabetes…

Etc.

(You've tried everything else; why not try bacon?) #320

A very interesting study, thanks for posting the link. My questions about it are that it seems to have been of short duration, since they say it ended on day 3. That is by no means long enough to reach fat-adaptation, and I wonder what the results would have been if the study had run a few months. (Which would have been difficult and very expensive to do.) There also doesn’t seem, at least to my cursory glance, to have been any checking to see how insulin-resistant the subjects were. I’m sure that would have had an effect on the results.

On the other hand, I was surprised to see that fat was 70% and protein 30% of calories in the intervention diet. These are the proportions of a carnivore diet, representing equal amounts of protein and fat by weight. Usually “low-carb” in such studies means nothing of the sort, as we would see it. The complete absence of carbohydrate is probably the reason they called the intervention diet “high-protein,” because otherwise critics might have objected, on the grounds that carbohydrate is an essential nutrient.

One fascinating result was not what I would have expected:

Endogenous glucose production, ie, glucose derived from glycogenolysis and from gluconeogenesis, was lower when subjects were in the H condition [carb-free intervention diet] than when subjects were in the N condition [standard diet].

Very interesting.

(Joey) #321

@PaulL I track with all of your comments and observations about this interesting study, although I didn’t find the results to be quite so surprising. Especially as you properly note that the zero-carb (“H”) subjects were not likely fat-adapted (in ketosis) immediately prior to the experiment.

Therefore, the result that the zero-carb subjects’ bodies were producing lower overall levels of (endogenous) glucose during this experiment seems like a reasonable observation.

Not being fat-adapted, they were experiencing what any carb-rich eater would likely suffer from - perhaps even early signs of a modest “keto-flu” as their mitochondria were being deprived of their customary energy source.

But looking at the entire summary statement taken together, I found it encouraging to see what was observed during the span of just a few days:

“Endogenous glucose production, ie, glucose derived from glycogenolysis and from gluconeogenesis, was lower when subjects were in the H condition than when subjects were in the N condition … whereas fractional gluconeogenesis was higher. …As a result, absolute gluconeogenesis tended to be higher when subjects were in the H condition than when subjects were in the N condition.”

[For background: gluconeogenesis is the derivation of glucose from non-carbohydrate sources whereas glycogenolysis is the breaking down of stored glycogen into available glucose.]

To me, this demonstrates that the body’s liver will produce a higher level of glucose on demand from non-carbohydrate sources very quickly when subjects are placed on a carb-free diet. As glycogenolysis (glucose produced from carb-based stores) was lowered, the overwhelming proportion of their own glucose production came from gluconeogenesis (non-carb dietary sources) when exertion demanded it.

This simply underscores that (1) the body does not need dietary carbohydrates to power itself and (2) absent carbs, gluconeogenesis kicks into gear upon demand in short order … even if one is not (fully) fat-adapted.

Separately, I found it interesting that the zero-carb subjects were measured as having a markedly higher metabolic rate while sleeping and while resting. Yet these subjects produced less heat while exercising.

One point of curiosity: Since all of the subjects were exercised to the point of exhaustion, I wish there were some discussion of whether there was a meaningful difference between the two subject groups in reaching their respective points of exhaustion (a variation on the Phinney/Volek findings?). If it was covered, I missed it.

Anyhow, this was a fascinating study indeed. It’s great to see that a carb-free eating study of this kind was conducted - back in 2009.

(You've tried everything else; why not try bacon?) #322

Well, going on what Bikman says about how glucagon increases in the absence of carbohydrate, thereby stimulating gluconeogenesis, I found it surprising. One would naturally expect a decline in serum glucose when dietary intake drops, but a drop in endogenous production? And I took Phinney’s warnings about salt to heart, so I never experienced any symptoms of hyponatraemia, which is what he says the “keto flu” really is. Nor did I actually experience any symptoms of what might be called carb withdrawal. And not being an endurance athlete, I never noticed a hit to my muscle power, either. I just felt really good, even better than when I had cut out sugar and sweets.

(You've tried everything else; why not try bacon?) #323

This would have been my expectation, except that the study seems to be claiming the opposite, that gluconeogenesis was less on the carb-free diet.

If the liver has glucose stored in the form of glycogen, sharing it is not gluconeogenesis, since the latter is a specific process of converting amino acids (and sometimes fatty acids) into glucose, not releasing existing glucose from storage.

Though come to think of it, it is possible that the subjects had enough stored glycogen in their livers to render gluconeogenesis less important for the first few days of a ketogenic diet. That could well explain their findings.

Also, since gluconeogenesis and ketogenesis are both stimulated in the liver by glucagon, it would have been nice if they could somehow have measured the production of ketone bodies independently of the production of glucose.