I’ve recently came across 2 cases of people who reported elevated glucose and insulin on a low carb diet. Naturally that is alarming because if there is one thing that low carb does well for you, it is to keep glucose and insulin low.
It started with a person who recently came to the r/ketoscience subreddit with elevated glucose and insulin.
https://www.reddit.com/r/ketoscience/comments/fcvms8/2_years_on_keto_and_newly_hyperinsulinemic/
Next followed a tweet from someone with elevated insulin:
And then I searched on the r/ketoscience sub if there were any other cases and indeed… someone reported on an increase in glucose to 130 mg/dL about 4 years ago.
This was all connected to the usage of berberine.
So what’s the deal with berberine? It is considered a hypoglycaemic drug. It helps in stabilizing/lowering glucose levels in diabetics.
“Berberine in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478874/
What people are overlooking is that berberine is an adaptogen. To keep it simple, adaptogens regulate towards a certain steady production. Due to this, they lower production of a substance when there is too much being produced but the reverse is also true. They increase production when there is not enough being produced. Now the terms “not enough” and “too much” are a bit deceptive. Adaptogens don’t really measure and then adjust. They simply stimulate a steady rate of production and they can do this through modulating stress hormones.
“Understanding adaptogenic activity: specificity of the pharmacological action of adaptogens and other phytochemicals” https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/nyas.13399
As such, they may increase the production and/or release of glucose into the blood stream through various mechanisms. That is what we have observed in the anekdotes, a rise in glucose and the body tries to down-regulate that with insulin.
It should be clear that you must take caution when taking berberine. Monitor your glucose and consider not taking it because frankly, on low carb you don’t need it and it seems to have the reverse effect.
What are the effects on keto?
So it got me curious. How does berberine work, where does it get the extra glucose from and what could that mean for low carb?
This is where I have to do a lot of guess work but I’ll try to do that as good as possible. I don’t have a lot to go on except for the known mechanisms of berberine, the observed effects of our anekdotes and, if I may say so, a fairly good understanding of our biology on a keto diet.
Besides the rise in glucose and insulin we know that our first subject was still capable of producing ketones (1~2mmol) which is pretty good considering the insulin which went up to 13mIU/L from 5mIU/L a year ago. Lipids a year ago TC 7.4; LDL 4.8; HDL 1.7; TG 1.2 versus now TC 6.3; LDL 3.8; HDL 2.15; TG 0.8. Not sure if we can use this in our analysis but let’s note it down anyway.
Berberine actions:
- Inhibition of complex I in the ETC (like metformin)
- Increase glucose consumption
- Increase lactate production
- Possibly AMPK activation
- Inhibition on the HPA-axis (rat study)
- Increased skeletal muscle GLUT4 expression (rat study)
“Metformin and berberine, two versatile drugs in treatment of common metabolic diseases” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839379/#s7title
“Effect of berberine on the HPA-axis pathway and skeletal muscle GLUT4 in type 2 diabetes mellitus rats” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731988/
We also see
- triglyceride & cholesterol lowering effect
- Increase in calcitriol (active form of vit D, created in the kidneys)
Triglyceride numbers can be very variable but assuming measurement has been fairly similar (same diet, roughly same morning fasting sample) we see in our first subject the value dropped from 1.2 to 0.8. That is 33.3% and the study I found mentions 23% decrease in humans.
“Lipid-lowering effect of berberine in human subjects and rats.” https://www.ncbi.nlm.nih.gov/pubmed/22739410
I was looking for a potential link towards cortisol, more on this later, which could explain glucose production but there seems to be no direct effect from berberine. However, calcitriol, which was increased by 60% is stimulating cortisol production in adipocytes and also adipocyte proliferation. In addition it also increases GLUT4 expression in adipocytes.
Although weight gain can be attributed to many things, we do have to acknowledge that our first subject had a modest increase in weight (3kg in 3 months).
“Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study.” https://www.ncbi.nlm.nih.gov/pubmed/19918113
“Vitamin D up-regulates glucose transporter 4 (GLUT4) translocation and glucose utilization mediated by cystathionine-γ-lyase (CSE) activation and H2S formation in 3T3L1 adipocytes.” https://www.ncbi.nlm.nih.gov/pubmed/23074218
Putting things together
If our first subject was still able to produce ketones, then we can be fairly sure that oxaloacetate is low in the liver mitochondria and glucagon is still high. So we have also the necessary components to generate glucose and break down glycogen.
Our liver has a big store of glycogen but under low carb this storage is reduced. So how can berberine maintain a high glucose influx into the plasma? Given the ketone production, glycogen reserve in the liver can’t be high, its breakdown into glucose is at a low enough volume that it doesn’t disturb ketone production.
This made me think about the backup in glucose production, namely the kidneys (read here for some more info: https://designedbynature.design.blog/2019/12/22/demand-or-supply/).
And especially when GLUT4 is further stimulated in muscle and fat cells (unless those are already at their maximum). Or is the glucose sparing effect pushed even further?
Berberine inhibits pyruvate import into hepatic mitochondria. This explains why oxaloacetate is kept low and ketone production can continue uninterrupted. But, this pyruvate import is what is needed to produce the glucose through gluconeogenesis in the first place. So again, where is the glucose coming from?
If anything, although still low level, the increase in insulin also lowers glycogenolysis. That is the breakdown of glycogen from the liver to put out glucose. As said, the increase in insulin is very minor so it may not do a lot in this case.
“Berberine Reduces Pyruvate-driven Hepatic Glucose Production by Limiting Mitochondrial Import of Pyruvate through Mitochondrial Pyruvate Carrier 1” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117739/
“Role of insulin and other related hormones in energy metabolism—A review” https://www.tandfonline.com/doi/full/10.1080/23311932.2016.1267691
So how about that glucose?
One other option I still have in mind are the kidneys. Remember from our list above that berberine stimulates glucose metabolism and thereby an increase in lactate production. Could perhaps the lactate be a good source for gluconeogenesis in the kidneys?
This next research looked at lactate contribution to renal GNG in dogs under increased insulin. The insulin was infused together with other tracer glucose and glycerol to block endogenous production. Lactate accounted for 60% of the glucose production.
“Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia.” https://www.ncbi.nlm.nih.gov/pubmed/9648834
In post-absorptive humans, the researchers conclude that lactate is the dominant source for renal and systemic GNG and the kidneys are important for lactate disposal.
“Renal substrate exchange and gluconeogenesis in normal postabsorptive humans.” https://www.ncbi.nlm.nih.gov/pubmed/11788376
Finally
We have our explanation for the continued ketone production and for the source of glucose production. Our low carb diet glucose sparing state causes increasing levels of glucose due to increased contribution from the kidneys.
Keep in mind also that endogenous increase in plasma glucose is not met with an evenly high response in insulin as when the glucose comes in via the diet.
The increase in adipocytes allows for increase in weight. The increase in glucose metabolism may also contribute a bit in increased weight if that means a lower reliance/usage of fat metabolism.
And as I would expect, it has a reducing effect on plasma NEFA. This could help explain the reduction in triglycerides but I would expect it causes a bit more difficulty in generating ketones. Although this was not evidenced in our first subject.
“Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity” https://journals.physiology.org/doi/prev/20171106-aop/pdf/10.1152/ajpendo.90710.2008
The increase in weight could be partially counteracted by its activation of BAT.
“Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans” https://www.nature.com/articles/s41419-019-1706-y
Overall berberine is having some good properties for diabetics but when it comes to supplementing it on a ketogenic or low carb diet then I’m not in favor of it due to the increase in glucose.
Higher levels of glucose will increase the glycation (https://designedbynature.design.blog/2020/03/03/oxidized-ldl/) of proteins and lipids. That is detrimental to your health.
Note:
These were 3 subjects, were the exceptions? Did they take very high dosage? Do they happen to have an other conditions that contributes to higher lactate? Just be cautious and also measure your glucose. Some people take it for lowering their LDL cholesterol successfully but do be mindful of the potential increase in glucose.
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