High Blood Sugar In Ketogenic Dieters! Plus A Special Surprise (Hint: Genotypes And Metabolism)!

A while ago Michael and I were discussing future article topics. There are truly a plethora of avenues to go down in this area of research and there is no lack of things to research and comment on. But even though I have a couple of pretty cool MCT articles sitting around on my desk, I want an interesting topic. I want something new. Something challenging. Besides, everyone is drinking the MCT koolaid these days. It’s become passe. (Also, it upsets my stomach and I have a personal vendetta against it. So there.)

What’s new? There has to be something new!

Michael pointed me to one of his old articles on physiological insulin resistance as an idea. I brushed it off at first. Dismissed it as a quirk.

But then I thought about it. WHY does blood glucose rise in response to a low carb diet? It truly is an interesting question. What does it say about low carb diets if they induce an almost diabetic effect on circulating glucose?

Thus my research began. This short abstract  confirmed that it is normal for people on low carb diets to experience a rise in blood glucose levels. Because it’s a non-open journal (shame!), there’s a one-sentence explanation given:

A decrease in first-phase insulin secretion may partially contribute to the short-term LC/HFD-induced increase in postprandial plasma glucose levels.

First phase insulin secretion? There’s a first phase? So… There’s more than one phase to insulin secretion? I had no idea. Call me ignorant but I had no idea until this point that there was more than one phase to insulin secretion.

This article delves deeper into the signaling involved in (what I learned is called) biphasic insulin secretion. The first phase of insulin secretion lasts approximately 10 minutes, and the second phase of insulin secretion picks up after the first and lasts for several hours. This is initiated by the influx of glucose into the beta cells of the pancreas, leading to an eventual depolarization and activation of calcium channels that regulate insulin release.

Type 2 diabetes is associated with a shift from biphasic, to monophasic insulin release, and it is therefore important to establish the cell biology of insulin release kinetics.

O rly? This is where I become instantly hooked… Their experiment involved a particular calcium channel and studying a mouse knockout version of it, which was heavily responsible for the second phase of insulin release. The first and second phases are related, yet separate processes, it turns out.

The conclusion we can now make in low carb dieters: a similar process is happening. People become monophasic in their insulin releasing, like diabetics. Let’s tease out the particulars now…

When sugar is ingested, there are two very important proteins that are released: GIP and GLP-2. These two work in a similar manner, acting on the beta cells to release insulin. I would like to add now that GIP is also released in response to fat intake. We’ll come back to that point.

While infusions of GLP-1 seem to increase the insulin release in diabetics significantly (source), Lewis et al. argue that the rise in GIP levels following glucose is greater in magnitude and appears to be more insulinotropic than GLP-1 (source).

Indeed, it has recently been suggested that the primary physiological role of GLP-1 may be inhibition of upper gastrointestinal motor and digestive functions rather then potentiation of meal-induced insulin secretion.

I will let Ehses and Lewis duel that battle out. At any rate, the article goes on to find that GIP is very important to a rapid beta cell response to glucose, and it increases absorption of glucose in the intestines. Interestingly enough, neither acute nor chronic impairment of GIP seems to alter fasting plasma glucose levels, but in mice with disrupted GLP-1 receptors, they are often accompanied by fasting hyperglycemia. Even the null mutation in the GLP-1 receptor will exhibit high blood glucose levels.

Therefore, while GIP appears to act as an acute insulinotropic hormone in order that β-cells may anticipate the absorption of glucose from the gut, GLP-1 signaling appears to be additionally important for the maintenance of normoglycemia, irrespective of the site of glucose entry into the circulation. This ability to promote glucose disposal makes GLP-1 a candidate therapeutic for the treatment of the abnormal glucose homeostasis associated with diabetes mellitus.

Follow me here for a little bit: If low carb dieters are not intaking glucose (for the very purpose of reducing an insulin response!) and not activating GIP accordingly, possibly not activating a second phase insulin response (depending on the genetic variant), then according to science, the absolute natural reaction of the body would be to have higher blood sugar levels. While diabetics and ketogenic dieters have the same symptom, one is a purposeful manipulation of the chemical signaling in the body, and the other is a distinct disregulation caused by a complicated clusterfuck of issues (diabetes).

So that solves that question! Now to return to GIP, because I stumbled across something truly fascinating here: GIP is released from glucose…but also from fat consumption. Ah hah! Interesting!

In this article (http://ajcn.nutrition.org/content/95/2/506.short) the researchers examine the relationship between genetic variants of the GIP receptor in response to different diets (low carb, low fat, and low/high protein). If you have ever hated someone for their ability to lose weight on a low fat diet, if you have ever wondered why such huge gaps in beliefs and attitudes exist towards low fat and low carb diets, here’s why: different people respond (metabolically) differently to different diets.

Sometimes in papers, the graphs are worth a million words. Essentially if you have a certain allele (also depending on if you’re heterozygote or homozygote), it can dramatically shift weight loss, fasting glucose, fasting insulin, and insulin resistance (HOAM-IR) in response to fat and carbohydrate metabolism.

So in conclusion, having higher blood sugar levels on a low carb diet is a consequence of killing the insulin response, which looks similar to diabetics but is actually far, far different.

Also, there are some people who can eat nothing but oatmeal and potatoes and lose lots of weight, and it’s not their fault that they’re mutants. I’m quite sure there will be many more future studies showing other genotypes that affect fat and carbohydrate metabolism, but we can now all agree there is no one best diet for everyone.


18 Responses to “High Blood Sugar In Ketogenic Dieters! Plus A Special Surprise (Hint: Genotypes And Metabolism)!”

  1. Hello there and thanks for interesting the post. I follow a paleo ketogenic diet that also involves one single low carb high fat meal a day taken in the evening with no other foods consumed at all except water. To my knowledge the hyperglycaemia experienced when one switches gradually to a LCHF diet is a temporary event and should be so until ketosis is well established. I am assuming temporary here to mean short term and not temporary in the sense that sugar goes up at every meal even in a ketotic state.
    Also the paper your refer to that finds association between diet variants and weight loss the so called high fat diets are hardly that at only 40% (USDA has 30%). A ketogenic diet should go well above 65% preferably 80% and they may not be isocaloric with the lower fat higher carb variants. I ahve printed the paper and shall look a bit more closely at the experimental set up.
    Was not aware of the itnerplay between GIP and GLP and will look more into it. Thanks for

    • For the hyperglycaemia argument, Micheal has told me he’s consistently seen his blood glucose elevated on the diet- as well as lots of n=1 comments around the internet and on the article I linked at the beginning. Maybe he can further comment on this.

      You’re right, the diet variations article’s version of high fat is also fairly moderate carb. Not ideal ratios. However despite that what makes it truly fascinating to me is that it still showed a tremendous difference in weight loss and other factors. I wish they would have made it more low carb but I imagine they would have had more attrition from the study as well.

      • Indeed, my blood glucose has inched up year over year. I’m not seeing the dive that many others report, and out of concern for this, I started looking into it.

        It appears that I am not alone in this regard. :)

        • THis is really intriguing…do you consume dairy and specifically milk?
          I ahve not had my blood gluose measured and do not own one of those as I feel so stable and well…Somepeople say that high level of glucose=low ketones. What are you ketone levels and do they change with blood glucose? COuld it be that in some people gluconeogensis takes over? I am baffled and intrigued. I look a bit more into the muscle specific insulin resistance and that also whlould be a temporary event to prevent protein loss from muscle for gluconeogenesis whilst the ketones accumulate. I shall continue on this interesting trail…..

          • It IS fascinating, isn’t it?

            To answer your question: No milk. I do eat cheese. Use full cream for some things. No milk though.

            I don’t have a blood ketone meter, and I stopped measuring the urine ketones some time ago. Yes, I was consistently in ketosis…no, I def. noticed the reduction in urine ketones after about 6 months (guesstimating here…it was a long time). Phinney and Volek suggest that this is a natural transition…your body just gets better at not making _excess_ ketones. In theory, my serum ketones should still show the full story.

            Alas, at $5.00 a ketone test strip, I’m not likely to start measuring them soon.

  2. Ehi thanks for your reply. I am intrigued as I genuinely did not know about this and I am always try to maintain ketosis through diet and fasting practices so i would not wish to have glucose spikes and I msut say I feel remarkably stable through the day even adding to the fact that I go to the gym three times a week in the evening usually well within 19-20 hours of water only fasting. Yet I exercise vigourosly including resistance with not adverse effects and no immediate urge to eat. When i do eat is fat/protien. So I have always assumed my blood glucose is stable by now (have been on this regime for 6 months now).
    Thanks again very mind opening and will look at comments on previous post and do some research of my own. Report back if I find anything of interest.

  3. Report back if I find anything of interest.

    Much obliged. I’m fascinated by this topic. I had assumed my fasting glucose would have lowered as well, which is why I was surprised when it went up year over year.

    From my reading: this is not something that everyone experiences. I wouldn’t be alarmed if I were in your shoes and had no reason to suggest otherwise.

    Physiological insulin resistance may provide a helpful explanation for others who are seeing their readings go the wrong direction.

  4. Please re-read the Japanese abstract within your blog above. The High fat (low-carb) diet did NOT decrease GLP-1 (You said “If low carb dieters are not intaking glucose (for the very purpose of reducing an insulin response!) and not activating GLP-1″). Instead, it increased GLP-1 activities compared to Low fat diet.

    Which means good.

    Your long term (fasting) glucose tolerance (glucose control ability) becomes better if you follow low carb., because your GLP-1, -2 and other various incretin and gastrointestinal hormones become active than ever.

    Only when you change from HFD to HCD suddenly (which is usually unnatural because they don’t change their eating patten easily), the glucose level goes-up.

    But, anyway, the extreme HFD could have also some stress to the body of glucose metabolism slowly and/or suddenly, especially to the people, you mentioned, of genetic weakness.

    So be careful, everybody. We could be different from Inuit people or HFD prone gene.

  5. If you follow HFD couple of week, the GIP hormonal activity decrease (body adaptation to new enviro.), because it is strongly related with carcohydrate digestion and initial glucose (peak) response than fat digestion and hormonal signal (fat and/or protein digestion are more related with GLP-1 instead).

    The 2nd phase (long running and also the most important) insulin secretion induced by GLPs and other GI hormones after becomes dominant for blood sugar control and be looked to be monophasal insulin secretion. This is completely different from diebetic monophase of strong GIP (which is usually no good).

    In this new adaped body condition, if you take glucose test and check the value, the answer is clear. Oh.

    The surgical stomach by-pass treatment of diebetic patient is the same hormonal technique. The weaked GLP-1 activity is stimulated, because it is secreted at below (not upper) intestine. If the GLP secretion is activated than ever, the satiety hormonal pathway is also activated. The glucose answer then? Clear.

    Bye and cheers.

    • katkinsk

      Actually I agree completely with you, which is why I was stumped for the last hour figuring out where I went wrong. Oh I used the wrong hormone, that’s why! I wrote and edited this post in several different parts of the weekend- thus why that sentence made no sense. I fixed it for you: “Follow me here for a little bit: If low carb dieters are not intaking glucose (for the very purpose of reducing an insulin response!) and not activating GIP accordingly, possibly not activating a second phase insulin response (depending on the genetic variant), then according to science, the absolute natural reaction of the body would be to have higher blood sugar levels.”

      I’m sorry to have made you write out such an elegant comment for such a base mistake.

  6. Geoff Smith

    Having just been to ER for what turned out to be a a bladder stone I was shocked to find out my BS was 12.6 because I have been very low carb for 6 years.
    So by explanation “consequence of killing the insulin response, which looks similar to diabetics but is actually far, far different.”
    But high blood sugar has detrimental affects we are told does it matter the cause?

  7. Steven Fussner

    I’m not sure if anyone else has pointed this out yet. But in the paper looking at different genotypes for the snp rs2287019 that you got all the graphs from is not at all applicable to a ketogenic diet. If you look at the methods section for the paper and the macro-nutrient breakdown, you’ll see that there is no way any of the subjects were in ketosis. There were two “Low Fat” diets. The first was, (20% fat, 15% protein, and 65% carbs). The second “Low Fat” diet consisted of (20% fat, 25% protein, and 55% carbs). The “High Fat” diets consisted of (40% fat, 15% protein and 45% carbs) for the first and (40% fat, 25% protein, and 35% carbs) for the second. All four diets were caloric restriction diets which explains the weight loss. If you want to compare a “Low Fat” diet to a true ketogenic diet it needs to be “High fat, low carb” with carbohydrate composition of around 10% or less.

    Here is an article looking at exactly that. A “high fat, low carb” ketogenic diet has been shown to be more efficacious for weight loss than a low-fat diet and improved other serum markers such as a greater decrease in triglycerides and an greater increase in HDL cholesterol.

  8. Teresa Mallory

    I would love a follow-up, as this is complicated – Volek & Phinney’s book says that between 30-60% total fat calories, there is a reduction in insulin resistance. That’s a very easy range to fall into if you’re not counting – is it likely many keto-dieters who are experiencing raised blood sugar might be responding to this range?

  9. Teresa Mallory

    Oops, error on last comment, I meant to say reduction in insulin SENSITIVITY (not resistance).

  10. Geoff Smith

    Yes Teresa it says that but goes on to say above 50 it gets better “What we do know is that, pretty consistently, as dietary fat percent is increased from 30% to 60% in animals and in humans, insulin sensitivity does get worse. But once above 60% of energy as fat, which typically translates to less than 20% of energy as carbohydrates (assuming 1 5-20% from protein) , insulin resistance turns around and starts to improve.
    I’m thinking that we are looking at this physio insulin resistance out of it’s correct context. We tend to have people that are office bound or for a large majority of their life or athletes who are performing their exercise or not. We are not looking at from the hunter gather aspect of how their day would play out, all day every day.


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