GLP-1 receptor agonists + Berberine contraindicated?

[Muffyflowers]

I am thinking of researching a combination of Retatrutide 8mg weekly and Berberine 1500mg daily. My RS has concerns about potential for hypoglycemic interactions. Do any of you have experience with this combination or something similar to share? TIA.

Scholarly articles about the positive outcomes from 900-1500mg Berberine daily:

https://pmc.ncbi.nlm.nih.gov/articles/PMC2410097/ — Pilot RCT (type 2 diabetes): berberine (1.5 g/day) lowered fasting glucose, post-meal glucose, and HbA1c similarly to metformin and improved lipids; GI side effects were common but transient.

https://pubmed.ncbi.nlm.nih.gov/15531889/ — Nat Med 2004 (hypercholesterolemia): 3 months oral berberine reduced total cholesterol ~29%, triglycerides ~35%, and LDL ~25% in humans and upregulated LDL receptor expression in liver cells/animals.

https://pubmed.ncbi.nlm.nih.gov/23118793/ — Systematic review & meta-analysis (type 2 diabetes): pooled RCTs show berberine significantly lowers fasting glucose, HbA1c, and improves lipids versus control, supporting its glucose- and lipid-lowering effects.

https://www.frontiersin.org/articles/10.3389/fphar.2022.1015045/full — Systematic review & meta-analysis (2022): berberine consistently reduces fasting glucose, HbA1c, triglycerides and LDL; authors note heterogeneity between trials and recommend larger high-quality studies.

https://pubmed.ncbi.nlm.nih.gov/37522683/ — RCT of a phytosome (enhanced-absorption) berberine in overweight people with impaired fasting glucose: the phytosome formula (550 mg ×2/day) improved fasting glucose, insulin, lipids and reduced visceral fat versus placebo over ~60 days.

https://www.mdpi.com/1999-4923/15/11/2567 — Pharmacokinetic study of a new berberine formulation: the micellar/liposomal-style formulation raised plasma berberine AUC ~6–10× versus unformulated berberine in healthy volunteers, improving absorption and tolerability.

https://pubmed.ncbi.nlm.nih.gov/38016844/ — Umbrella meta-analysis of RCTs: across multiple meta-analyses, berberine improves glycemic control and reduces inflammatory biomarkers in metabolic disorders, reinforcing consistent metabolic benefits.

https://pubmed.ncbi.nlm.nih.gov/36467075/ — 2022 meta-analysis (type 2 diabetes): berberine significantly lowers fasting glucose, HbA1c and improves lipid profiles; authors highlight short trial durations and call for longer, larger RCTs.

This was a while ago but curious how it went. I’ve been on Reta for a couple weeks carnivore diet, I’ve noticed that my blood sugar seems a bit higher on Reta than it was with diet alone. Though I wasn’t losing any weight but I’ve never had fasting insulin taken which I’m guessing was high and probably causing the weight loss resistance. Was thinking the berberine could be helpful dropping my bs so hopefully my ketones would go back up Reta has seemed to lower those too, though could be from the higher glucose.

 

[tubby]

This was a while ago but curious how it went. I’ve been on Reta for a couple weeks carnivore diet, I’ve noticed that my blood sugar seems a bit higher on Reta than it was with diet alone. Though I wasn’t losing any weight but I’ve never had fasting insulin taken which I’m guessing was high and probably causing the weight loss resistance. Was thinking the berberine could be helpful dropping my bs so hopefully my ketones would go back up Reta has seemed to lower those too, though could be from the higher glucose.

That's an interesting place to be coming from and surprised to hear you're seeing a blood sugar increase with reta.

For me personally carnivore (vs keto or even sloppy low-carb) was a weight gain diet. I guess that shouldn't really be a surprise and I suspect that most of the people who lost weight on carnivore did so because they went straight there from a standard American diet VS losing weight with something else first.

 

[Muffyflowers]

That's an interesting place to be coming from and surprised to hear you're seeing a blood sugar increase with reta.

For me personally carnivore (vs keto or even sloppy low-carb) was a weight gain diet. I guess that shouldn't really be a surprise and I suspect that most of the people who lost weight on carnivore did so because they went straight there from a standard American diet VS losing weight with something else first.

So I was too. I mean I understand that glucagon tells the liver to release glucose. I’m not sure if that’s it. I’m definitely insulin resistant. Never T2 diabetic. I caught it and have been working on it for years. Definitely mitochondrial dysfunction which I’ve also worked at. I am wondering if it has to do with an issue or not enough nad+ or rather an inverted ratio of nadH to nad+. I had gotten seriously ill a couple years ago, and was really depleted from fighting it. From what I’m learning still could be an issue with insulin amd glucose handling. Maybe glycation end products. As far as my diet before carnivore I was low carb just really respond poorly to more. Could be damage from years of restrictive dieting and then periods of whatever goes. Health is such a puzzle. I’m considering a protocol of nad+ then ss-31 amd then motsc and run and all through and the others consecutively. If you have any thoughts or experience I’m open!

 

[tubby]

So I was too. I mean I understand that glucagon tells the liver to release glucose. I’m not sure if that’s it. I’m definitely insulin resistant. Never T2 diabetic. I caught it and have been working on it for years. Definitely mitochondrial dysfunction which I’ve also worked at. I am wondering if it has to do with an issue or not enough nad+ or rather an inverted ratio of nadH to nad+. I had gotten seriously ill a couple years ago, and was really depleted from fighting it. From what I’m learning still could be an issue with insulin amd glucose handling. Maybe glycation end products. As far as my diet before carnivore I was low carb just really respond poorly to more. Could be damage from years of restrictive dieting and then periods of whatever goes. Health is such a puzzle. I’m considering a protocol of nad+ then ss-31 amd then motsc and run and all through and the others consecutively. If you have any thoughts or experience I’m open!

You're right that the increase in glucagon (really glucagon agonism) on its own would increase blood sugar; however, what you're missing is that the GLP1 agonism (via insulin) is generally going to have a stronger impact in lowering blood sugar and will be the dominant effect for most people. If someone were to switch from another GLP1 (e.g. tirzepatide) to retatrutide it's conceivable that blood sugar might increase slightly from the glucagon effect, but it would be unexpected for a person not currently taking a GLP1 to see blood sugar go up with retatrutide. Of course, in metabolically deranged bodies, strange things can happen.

The way I think about retatrutide is that at low doses it's just another GLP1 and the glucagon agonism is likely negligible. At moderate to high doses the glucagon agonism starts to accomplish something. The clearest indication to me on that is if you dig into the phase 1 trial data, it comes with a data supplement that graphs various hormones following a single dose (of varying sizes) being administered. At the lowest doses, there's little difference in glucagon levels VS placebo, but at higher doses glucagon level is significantly suppressed. Your immediate response to this should be to question why it's suppressed rather than elevated. The reason why is because that graph is only showing you real glucagon in the bloodstream, which is going to differ from the effective glucagon level (real glucagon + glucagon agonist activity). When real glucagon level starts to go down (vs placebo) that shows your body feels that the effective glucagon level is too high and it's trying to scale back glucagon production in response. Meanwhile, the glucagon agonist is maintaining a higher effective glucagon level, overriding your body's control mechanism there.

It really is an elegant solution in that the right mix of glucagon agonism should offset some of the plateauing effect seen in GLP1 agonism. It would be interesting (although perhaps dangerous) if someone developed a straight glucagon agonist that one could dose alongside a GLP1 agonist to play around with and see how different ratios impacted them.

If I were in your shoes I might tread slowly and wait a month to months before implementing new things beyond what you're currently doing to help ensure you knew what was doing what in your body and were able to reach a new equilibrium between interventions.

Also, I might rethink straight carnivore (unless you have a specific health issue that you've resolved with it). On paper it makes a lot of sense and has a tight logical framework, but if you happen to be one of the people who finds you're not losing weight on it or your blood sugar control is poor, that would seem to suggest trying another approach. I suspect that some form of protein restriction might actually be advisable, as insane as I know that sounds.

 

[Muffyflowers]

You're right that the increase in glucagon (really glucagon agonism) on its own would increase blood sugar; however, what you're missing is that the GLP1 agonism (via insulin) is generally going to have a stronger impact in lowering blood sugar and will be the dominant effect for most people. If someone were to switch from another GLP1 (e.g. tirzepatide) to retatrutide it's conceivable that blood sugar might increase slightly from the glucagon effect, but it would be unexpected for a person not currently taking a GLP1 to see blood sugar go up with retatrutide. Of course, in metabolically deranged bodies, strange things can happen.

The way I think about retatrutide is that at low doses it's just another GLP1 and the glucagon agonism is likely negligible. At moderate to high doses the glucagon agonism starts to accomplish something. The clearest indication to me on that is if you dig into the phase 1 trial data, it comes with a data supplement that graphs various hormones following a single dose (of varying sizes) being administered. At the lowest doses, there's little difference in glucagon levels VS placebo, but at higher doses glucagon level is significantly suppressed. Your immediate response to this should be to question why it's suppressed rather than elevated. The reason why is because that graph is only showing you real glucagon in the bloodstream, which is going to differ from the effective glucagon level (real glucagon + glucagon agonist activity). When real glucagon level starts to go down (vs placebo) that shows your body feels that the effective glucagon level is too high and it's trying to scale back glucagon production in response. Meanwhile, the glucagon agonist is maintaining a higher effective glucagon level, overriding your body's control mechanism there.

It really is an elegant solution in that the right mix of glucagon agonism should offset some of the plateauing effect seen in GLP1 agonism. It would be interesting (although perhaps dangerous) if someone developed a straight glucagon agonist that one could dose alongside a GLP1 agonist to play around with and see how different ratios impacted them.

If I were in your shoes I might tread slowly and wait a month to months before implementing new things beyond what you're currently doing to help ensure you knew what was doing what in your body and were able to reach a new equilibrium between interventions.

Also, I might rethink straight carnivore (unless you have a specific health issue that you've resolved with it). On paper it makes a lot of sense and has a tight logical framework, but if you happen to be one of the people who finds you're not losing weight on it or your blood sugar control is poor, that would seem to suggest trying another approach. I suspect that some form of protein restriction might actually be advisable, as insane as I know that sounds.

True and I’m definitely coming from a background of metabolic derangement, though like mentioned im working on it. My blood sugar was well controlled on carnivore prior to taking Reta. Though no weight loss. I have had weight loss and I know the glucagon can take a little to kick in. I wasn’t sure whether I was a high responder. Since I was having decent appetite suppression as well. I’ve been splitting the .75mg dose Sunday and Thursday started at .5 though I think I’ll stick here as I did notice very slight side effects that were undesirable. Plus two pounds down is reasonable. I have played around a little with diet ate a bit of carbs one day and didn’t really notice a difference in length of elevated glucose. The one thing I was thinking is the slow motility spreads the insulin/glucose activity and that might be what I’m seeing. Without the peps I was working on insulin resistance and meal timing to reduce time of active insulin. So for me, that could be why it’s higher longer. I mean like I notice it’s about 5/6 hours and I get that little stomach empty iron that tastes ever so slightly like the beef patties I ate. But I’m going to stick with it and let the numbers tell the weekly story.

 

[Calm Logic]

I suspect that some form of protein restriction might actually be advisable, as insane as I know that sounds.

Reminds me of the rice diet from way back:

Lin Lab | Duke Department of Medicine

medicine.duke.edu

 

[tubby]

Reminds me of the rice diet from way back:

Lin Lab | Duke Department of Medicine

medicine.duke.edu

Yes, that style of approach is specifically what I was referring to. Not necessarily rice per se (since that implementation of a rice diet typically includes calorie reduction as well, which is pretty miserable on such a diet), but more of a mixed vegetable and starch diet, being selective in your starches to keep protein low. And yes, I know that's going to sound like a jumble of contradictions and insanity to those who haven't done the macro math on such diets before. This diet has found a recent resurgence online under the moniker HCLPLF (high carb low protein low fat).

I tried something resembling that theme for 2 months and was surprised by the results (in both good and bad ways). But if one wanted to read more about it, something like this would probably be a better starting point:

https://deniseminger.com/2015/10/06/in-defense-of-low-fat-a-call-for-some-evolution-of-thought-part-1/

 

[tubby]

True and I’m definitely coming from a background of metabolic derangement, though like mentioned im working on it. My blood sugar was well controlled on carnivore prior to taking Reta. Though no weight loss. I have had weight loss and I know the glucagon can take a little to kick in. I wasn’t sure whether I was a high responder. Since I was having decent appetite suppression as well. I’ve been splitting the .75mg dose Sunday and Thursday started at .5 though I think I’ll stick here as I did notice very slight side effects that were undesirable. Plus two pounds down is reasonable. I have played around a little with diet ate a bit of carbs one day and didn’t really notice a difference in length of elevated glucose. The one thing I was thinking is the slow motility spreads the insulin/glucose activity and that might be what I’m seeing. Without the peps I was working on insulin resistance and meal timing to reduce time of active insulin. So for me, that could be why it’s higher longer. I mean like I notice it’s about 5/6 hours and I get that little stomach empty iron that tastes ever so slightly like the beef patties I ate. But I’m going to stick with it and let the numbers tell the weekly story.

And that's ultimately where I think the problems lies for some with carnivore. While you're on it blood sugar is often well controlled (although in some people fasted morning blood sugar levels will consistently land in the pre-diabetic range, depending on protein intake). Still, at worst you'd have A1cs in the high-5s to low-6s, which beats the heck out of typical diabetic numbers.

But the only way you're going to win longer term is to bring your weight down. That's (in my opinion) because weight is highly correlated to fasting insulin levels. You'd think zerocarb (another name for strict carnivore) would be the ultimate diet for that, but what a lot of people miss is that carbohydrate isn't the only thing that spikes insulin levels. Protein actually spikes insulin too (although gram for gram, only about half as much as carbohydrate). Many are unaware of the protein-insulin connection (google "insulin index" if you're in doubt) because it doesn't immediately impact blood sugar levels, since your pancreas is clever and releases a matching amount of glucagon to avoid blood sugar deviating significantly from a protein meal.

One technique I read about from a carnivore was to fast one or two days a week, which seemed to be enough to balance things out where fasting blood sugar came back down to normal levels. Others will make an effort to eat more fat (to get full on that rather than protein), but that never really worked for me and my hunger and satiety seemed more related to how much protein I would eat.

Of course, since you're now here, GLP1 is probably the past of least resistance to get your body weight down, and as that drops over time you'll also see your fasted insulin (and fasted blood sugar levels) come down further. Again, in the short-term GLP1s will probably slightly increase fasted insulin levels, but longer term the weight loss effect will win out against that effect.