Gymnema, Jiaogulan and Berberine: Can herbs replace metformin?
We all lose insulin sensitivity with age, and this is is a primary mechanism by which we become more vulnerable to all the diseases of old age. But there is much that we can do to retain insulin sensitivity: diet, exercise, drugs and herbs. Because these act differently on the metabolism, there is reason to hope that combining treatments will yield combined benefits (this is theoretical–there is no data available on combinations.)
While emerging anti-aging technologies are still emerging, the best-tested treatments we have for the present all rely on the insulin metabolism. Our bodies are evolved to sense stress–especially food scarcity–and adjust our rate of aging to compensate for those around us who may be starving to death. (This is the demographic theory of aging, and though the theory may still be controversial, the fact that we can address the rate of aging through the insulin metabolism is undisputed.)
Insulin manipulation works much better in mice than in larger animals like us, but it’s the best-studied, surest way to improve your odds for a long and healthy life, and there are vitality, alertness, productivity, freedom from infectious disease–almost every aspect of your quality of life is improved with more exercise and less food.
The best measure of diabetes risk is glucose tolerance. The body is challenged by swallowing a dose of sugar, and glucose levels in the blood rise immediately. Over several hours, follow-up blood tests measure how quickly the blood levels come back to normal.
Fasting glucose is a secondary predictor, not so robust as glucose tolerance [ref].
For anyone who doesn’t choose to maintain the most rigorous program of exercise and caloric restriction, metformin can make up the difference. Metformin is a fifty-year-old drug, long out of patent and cheap. Mice fed metformin live longer. We have a great deal of epidemiological data on metformin, because tens of millions of people have been taking it for decades. Diabetics who take metformin have much lower rates of cancer, heart disease, and AD. Arguably, their survival statistics may even be better than non-diabetics who don’t take metformin. There are researchers who are proposing that Alzheimer’s Disease should be regarded as type 3 diabetes. (FightAging! led me to this article.)
The numbers look so good that Nir Barzilai (Einstein Hospital, New York) has banked the future of FDA policy on a clinical trial to demonstrate that aging is a risk factor that can be mitigated, and that aging should be recognized as a treatable condition. Last month, there was a major article in Science Magazine about his program. It is hardly a radical claim, from a scientific perspective. But government policy lags science, and what Barzilai is doing will be a boon for us all, if it works.
Metformin is a safe drug, without serious side-effects except rarely among people taking high doses. I have recommended it to anyone over 40 who is overweight, or over 60 even if you’re not overweight.
Many people prefer a natural alternative, and I’m witing today about three good ones. The reasons for preferring “natural” may transcend science. There is a general feeling that natural products are safer, though in this case we know a heck of a lot about the safety of metformin. There are decades of epidemiological data for metformin, vs centuries of traditional wisdom for the herbal products. Readers of this column are accustomed to my periodic rants about the fact that capitalism has distorted funding priorities for medical research, hence we know a lot less about natural products than about patentable ones.
Thanks to Bill Sardi for introducing me to Gymnema. Here is a review of limited evidence for Gymnema and diabetes that was available as of 2007. Gymnema has a long pedigree through the Indian ayurvedic tradition of life extension, in which it is called mesasrngi [sic]. Gymnema reduces uptake of sugar from the small intestine, and also increases generation of insulin in the pancreas. The former is definitely beneficial; the latter is helpful for diabetes type 1, but not for type 2 which is associated with aging. In this study, Gymnema improved cholesterol profiles, fasting glucose, and also results from the (most predictive) glucose tolerance test. This study found similar benefits in obese mice.
Berberine is a chemical, not a plant, though it is extracted from several different plant sources. The best source is goldenseal. Berberine has a 5,000-year legacy in Chinese medicine–even longer than Gymnema has in Indian medicine.
Metformin reduces blood glucose by shutting off the source (in the liver), while berberine reduces blood glucose by augmenting the sink (glucose uptake in muscle and nerve cells). Berberine affects cells in much the same way as insulin, increasing the uptake of glucose from the blood into the cell. This means that if you take berberine before exercise, it might (theoretically) enhance your performance, while taking metformin before exercise might (theoretically) reduce your performance.
This study compared metabolic benefits from berberine with metformin head-on in a three-month trial. 500 mg berberine had benefits equal to 500 mg metformin, with fewer reported stomach upsets and better triglyceride control for berberine.
This column by Frank Shallenberger raves about the advantages of berberine.
“Berberine has low rates of absorption when taken orally due to both being subject to P-Glycoprotein (ejects Berberine back into the intestines) and increasing the activity of P-Glycoprotein (augmenting its own ejection), but absorption is greatly increased when taken with P-Glycoprotein inhibitors such as Silymarin from Milk Thistle.” [Examine.com]
This traditional Chinese herb (绞股蓝) has recently been marketed by LEF under the name “AMPK Activator”. The latin name of the plant is Gynostemma pentaphyllum. It is sometimes known as “southern ginseng” because it contains some of the same active ingredients as ginseng, deemed the king of all Oriental medicines. But the anti-diabetic benefits of jiaogulan derive from constituents that are not found in ginseng. In parts of Southeast Asia, jiaogulan has a reputation as an “immortality herb”.
Like Gymnema, jiaogulan shows promise, both theoretically and in limited human trials, but there isn’t yet enough data to know how well it works. In one study, it improved both fasting glucose levels and (more important) tolerance.
In promoting its new product, LEF has made a case that low AMPK is part of a keystone aging pathway. We have less AMPK as we get older. Both fasting and vigorous exercise increase AMPK levels. Less body fat leads to more AMPK expression, and, even better, more AMPK leads to burning more fuel, storing less as fat. This is a positive feedback loop that can work in either direction. AMPK → faster metabolism → less fat → more AMPK or low AMPK → slower metabolism → more fat → less AMPK. By adding AMPK, they claim, we can be sure to go around the circle in the right direction. Like many LEF reports, I find this one to be well-rooted in truth but a bit breathless in presentation and overstated in its significance.
Weight control is still your first line defense against the creeping insulin resistance that affects all of us as we get older, and only is diagnosed as diabetes in its more severe form. There’s a school that says low protein diet offers best protection, and another that favors low carbs. (I have favored carb restriction, but I may be tipping toward low protein.) You can’t do both without raising fat intake, and there is good agreement that dietary fat shouldn’t be more than 40% of your calories.
Exercise prodigiously. Exercise right before eating can change your body’s insulin response to the sugar challenge. Even a minute of high-intensity exercise can make a difference [ref, ref].
Vegan diets are associated with much lower incidence of diabetes. In this study, vegans had half the incidence of diabetes, even after controlling for the fact that they had lower BMI. Non-vegan vegetarian diets were not far behind.
Almost all of us can benefit from magnesium supplements. Zinc [ref, ref] and tiny quantities of chromium might also help. Resveratrol extends life span in fat mice. There is some evidence for thiamin (vit B1). Large quantities of cinnamon may or may not be helpful. One small study showed a substantial benefit from boswellia=frankincense.
The Bottom Line
Loss of insulin sensitivity is so closely intertwined with all the diseases of old age that it is hardly distinguishable from “normal aging”. It’s an issue that we all face, and there is a whole Chinese menu of measures you can take to better your odds for health, vitality and a long life.
The mechanisms of metformin, berberine, jiaogulan and Gymnema are quite different, and there is reason to think that combining them offers more benefit than any treatment separately; but there is as yet no data on combined therapies.
I was talking to Dr. Ward Dean recently about metformin and he mentioned he had a company that used to sell Goat’s Rue aka French Lilac from which metformin is derived.
Metformin is an amino (contains nitorgen) guanidine (contains guanine- the G in GCAT)
The other herbs listed above I don’t think are. ……..so might act a little differently..However if they all stimulate AMPK they might all have the same effect regardless of their makeup.
Check out metformin’s chemical structure….it is unlike most other chemicals/herbs/ supplements that are good for you.
OOPS actually metformin does not contain a fully formed G…..as in guanidine but it can collapase into a guanidine if you add a =o and some carbons.
Adding berberine to metformin did not change my fasting glucose at all. I assumed similar, if not identical, mechanisms of action. I wouldn’t be too quick to assume accumulative benefits until good studies are done.
When you first started Metformin, did it lower your fasting blood sugar. And does it still lower FBS. I used berberine for a couple of months increasing 4 per day (500 mg per capsule) and it did not lower FBS at all.
I have fasted twice a week for 24 hours (for a few months) last fall and that first day my BS went down into the 60’s. But every time I fasted after that my FBS remained the same as always, in the lower or upper 90’s, low 100. Same with going low carb. At first FBS lowers down into the 70’s-80’s. After a while my FBS goes back to 90’s low 100’s. I remember reading about how the body adapts to these changes and goes back to what it thinks you need regarding glucose for brain function. I am very athletic and absolutely not overweight. But I am 63. Although going low carb reduced inflammation greatly and I lost 4 inches around my waist, It seems like my body or maybe its my liver that adapts to going back to glucose production.
Lezlee, check out this post:
“Well, the first thing is that LC eating rapidly induces insulin resistance. This is a completely and utterly normal physiological response to carbohydrate restriction. Carbohydrate restriction drops insulin levels. Low insulin levels activate hormone sensitive lipase. Fatty tissue breaks down and releases non esterified fatty acids. These are mostly taken up by muscle cells as fuel and automatically induce insulin resistance in those muscles. There are a couple of nice summaries by Brand Miller (from back in the days when she used her brain for thinking) here and here and Wolever has some grasp of the problem too”
What about aminoguanidine?
Resistant starch significantly improves insulin sensitivity and is a wonderful natural solution. It is the subject of a health claim petition before the FDA now. The data is very impressive with improvements seen within a hour or two and improvements ranging from 20% in women to 70% in men. I believe that insulin resistance is directly due to the lack of fermentable fiber. See http://www.resistantstarch.us for details.
Don’t forget to mention that one possible side effect of metformin to par particular attention to is vitamin B12 deficiency. See: http://www.ncbi.nlm.nih.gov/pubmed/20134380
Great article as always, I can’t wait to introduce berberine into my supplement regime.
I have a question related to one of your statements though:
” You can’t do both without raising fat intake, and there is good agreement that dietary fat shouldn’t be more than 40% of your calories. ”
How did you arrive at that conclusion? Why 40%? Why is it bad if you’d have more than that?
I am a bit confused as I thought both protein and carb restriction were pro longevity and that 80%+ fats would be a good thing.
I hope you find five minutes to answer my inquiry even though your blog seems to become more popular every month :-).
Have a great day,
I’m and currently becoming a Ray Peat acolyte and trying to reconcile the low calorie/healthy high calorie longevity paradoxes (both reduce unstable fatty acids and allergenic proteins and increase nutrient density). My guess is that the AMPK activators (Berberine maybe others) in the cell would be the best alternatives…and questions about how metformin work should stay flexible. I personally like the ease of access, lack of stomach problems, bright color and known anti inflammation (other pro-health heuristics), and lack of absorption problems of Berberine over metformin, so for me the choice is clear.
The beauty about calroic restriction and intermittent fasting is that they both release a whole cascade of health benefits. It is natures own gene therapy 100% free of charge.
Josh, I am still wondering how you construct your diet if your fat is at 40% (which i assume is mostly monos (and from oils), if you only get like 15% protein, what is going to comprise your 45% of carb? If you don’t eat grains because of issues, how much of those carbs are going to come from fruit or root veggies and what is that going to look like?
I find if I get my protein from vegetarian or vegan sources, there are plenty of carb calories that come along with the protein. Look at the percentages in beans and even in milk.
Have you seen the FMD recipes at
I am interested in berberine and was wondering if there has been any real research done concerning it’s safety. I have read that muscle atrophy, DNA damage and liver tumors are possible side affects.
Two links sent to me by George Goldsmith, one pro-berberine the other anti-berberine.
(My take is that berberine looks promising, but we don’t know as much as we know about metformin which has been prescribed to tens of millions of diabetics over 50 years.)
Why is there so little research done with Epitalon? I never see or hear any interest in it at these conferences or on blogs. It seems to have incredibly promising potential. Has anyone thought of combing Epitalon and Rapamycin?
I agree. See http://joshmitteldorf.scienceblog.com/2015/09/15/untested-treatments-for-longevity-and-how-to-test-them/
There seems to be some distrust of Russian research in the West. But whether or not you take Anisimov’s results as absolute truth, there is more than enough reason to test epitalon in Western labs.
I’m 64 m, watch blood sugar before but no serious problem before. Tried berberine and notice a drop. What amazes me is after trying some Ray peat stuff. I cut out 100% all grains, vegetable oils and keep under 15% fat derived mainly from egg, milk, coconut. The amount of sugar I take blows my mind. For example, in morning I drink 18 oz of OJ with 4 raw eggs while eating a cup of chocolate covered dried mangoes, lunch 16oz black coffee with 5 tbs of raw sugar, 2 tbs coconut oil 10 oz milk, afternoon then 24oz milk with 4 tbs raw sugar, 2 tbs chocolate, cup protein(whey) powder, 1 tbs creatine, 2 raw eggs then in the evening a cooked Japanese yam, bedtime 8 oz OJ with vitamins and herb supplements. I sleep solid thru the night. Next morning blood sugar test at 90. Various test thru out the day after 1 1/2 hour of eating I still test under 100. Sometime I’ll add to this a lb of organic grapes or more to snack on. Occasionally a salad.
The result is I have seen more improvement in my skin and my health than I have seen on any of my 100% raw vegan food diets. Although they were quit helpful and healthy and healed problems I had. But now my wrinkles have decreased, skin gotten plumber, a small basel cell cancer slowly disappearing, my body seems to be regenerating. My eye glasses strength dropped some. I feel good.
I guess Ray is right that the glucose is speeding up my cells metabolism and they are operating at a more peak level, so maybe with the protein, repairs are being made including maybe the pancreas. My insulin levels are high in my last lab test at 14; Glucose 103; estimated average glucose 116; Anti-GAD <5, 6 weeks ago and I just took another and will be watching closely to try not to damage myself. I will back off it it stays too high over a year.
People say that I could damage my beta cells of the pancreas but maybe all body parts work better when exercised. I'll push my heart rate while exercising and it then gets stronger. Maybe by not eating what interferes with and/or damages the body this is what can happen? I usually test diets for 9 months or more. Any comments from others that experimented like this let me know.
Step… you should look into zero carb diet too. It’s not really well known but most of the research we have supports the idea that either VERY low carb (below 10g/day) or VERY low fat (below 10%) is the healthiest way to eat.
I don’t know what Josh thinks about this but to me it feels like this somehow interacts with the Demographic Theory Of Aging. Could it be that in our primitive ancestors lifes times of STARVATION – and therefor better health – were triggered when either no fat / animals were available (natural disaster / low fat) or all that was available were animals (low carb / “ice age”).
There is this guy, I forgot his name, who cured people from all kinds of diseases by putting them on a rice, sugar and fruit diet. You were not allowed to eat anything else. Most of them lived long, healthy life’s.
I would really, really, really love if Josh would tell us his take on low carb / low fat and how that interacts with his theories on aging.
Why no mention of DHEA? It isn’t coincidence that as DHEA levels plummet with age that insulin sensitivity decreases.
Thanks, Patrick – this connection is new to me, and it seems well-documented. On the other hand, metformin increases life span in mice, while DHEA does not http://www.ncbi.nlm.nih.gov/pubmed/10197641 .
Any thoughts on the Scripps Research Institute’s study finding the overactivation of AMPK implicated in Alzheimer’s disease?
FYI: I’ve had good luck with jiaogulan for weight loss (myself and 3 others all over 40) and an abstract supports this:
Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial.
Park SH1, Huh TL, Kim SY, Oh MR, Tirupathi Pichiah PB, Chae SW, Cha YS.
Erratum: Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): A randomized, double-blind, placebo-controlled trial. [Obesity (Silver Spring). 2015]
The effects of actiponin was investigated, a heat-processed Gynostemma pentaphyllum extract, on body weight, fat loss, and metabolic markers of Korean participants in a 12-week, randomized, double-blind, placebo-controlled clinical trial.
DESIGN AND METHODS:
Obese participants (BMI ≥ 25 kg m(-2) and WHR ≥ 0.90 for male or WHR ≥ 0.85 for female) who had not been diagnosed with any disease and met the inclusion criteria were recruited for this study. The 80 subjects were randomly divided into actiponin (n = 40, 450 mg day(-1) ) and placebo (n = 40) groups. Outcomes included measurement of efficacy (abdominal fat distribution, anthropometric parameters, and blood lipid profiles) and safety (adverse events, laboratory test results, electrocardiogram data, and vital signs).
During 12-week of actiponin supplementation, total abdominal fat area, body weight, body fat mass, percent body fat, and BMI were significantly decreased (P = 0.044, P < 0.05, P < 0.0001, P < 0.0001, and P < 0.05, respectively) in the actiponin group compared to the placebo group. No clinically significant changes in any safety parameter were observed.
Our study revealed that actiponin is a potent antiobesity reagent that does not produce any significant adverse effects. These results suggest that actiponin supplementation may be effective for treating obese individuals.
Copyright © 2013 The Obesity Society.
PMID: 23804546 DOI: 10.1002/oby.20539
I can not take metformin. Gives me spontaneous diarrhea.
Any ideas on adverse reactions to Mefformin? I was prescribed 5 years ago and the side effect was diarrhea, so I quit. Then recently tried it again, and after two weeks, broke out with an allergic, very itchy rash that took 3 weeks to go away after stopping the Metformin. So last night I took one 500 mg tab, and today the itching started again.
Metformin has interfered with my sleep patterns extremely vivid and strange dreams,my blood pressure increased and felt dizziness after first week taking 500mg 1/day.First 3 days saw blood sugars and appetite drop, and then they went back to old higher sugar levels. I am type 1 for 68 years now. Does anyone have long term experience with natural herbal alternatives?
Regarding Metformin: Many people can not tolerate it due to a MTHFR gene defect.
This lack of tolerance may show up immediately or after a few years of usage. Many people immediately report fatigue and muscle weakness after beginning Metformin and others report this only after longer term usage.
This is thought to be due to the fact the Metformin depletes B12 and methylfolate.
MTHFR is: MTHFR is a gene . We all carry two copies of MTHFR. MTHFR tells our body how to create an enzyme involved in breaking down the amino acid homocysteine. As is true for any gene, the DNA code of the MTHFR gene can vary.
There are, many are medications which help stabilize blood sugar levels via various mechanisms.
These medications, especially when combined with the C677T MTHFR defect, may increase homocysteine levels due to the decreased amounts of methylcobalamin and methylfolate.
However I personally know at least one non-diabetic person taking Metformin for reported anti-aging benefits who told me that after four years of 500 mgs per day, split into am/pm dose of 250 mgs, that they started to experience profound weakness in their legs and could not work out as heavily.
This person was supplementing with B12 and Methylfolate at the time, but they still experienced the side effect of weakness.
They stopped the Metformin and those issues resolved.
If you research this, there or many similar reports on the internet.
I also have talked to type 2 diabetics who absolutely can not tolerate Metformin.
A published case study provides evidence of this significant interaction:
Vitamin B12 deficiency may be induced by long-term use of metformin, which may in turn lead to hyperhomocysteinemia. Thus, hyperhomocysteinemia may increase the risk of vascular thrombosis in diabetic patients, when metformin is used and a homozygous methylenetetrahydrofolate reductase (MTHFR) C677T mutation is present.
We report a 65-year-old Taiwanese diabetic woman who was treated with metformin for 6 years and who had suffered from swelling of the left lower extremity for 3 months. Ascending venography confirmed the diagnosis of proximal deep vein thrombosis, while hyperhomocysteinemia, megaloblastic anemia caused by vitamin B12 deficiency, and a homozygous C677T mutation of the MTHFR gene were also found.
She had no identifiable venous thrombotic risk factors other than hyperhomocysteinemia, which seemed to be caused by both MTHFR C677T homozygous mutation and vitamin B12 deficiency.
With the substitution of insulin injection for metformin, short-term supplement of vitamin B12, and anticoagulant therapy for the deep vein thrombosis, her anemia and hyperhomocysteinemia recovered rapidly.
The deep vein thrombosis also responded well. Our findings highly suggested the role of Metformin in causing vitamin B12 deficiency, which may serve as an additional risk factor for venous thrombosis in diabetic patients. Our report also highlights the need to check vitamin B12 levels during metformin treatment.
While this individual responded well to vitamin B12 alone, it is recommended to also supplement with methylfolate due to the C677T MTHFR mutation.
Again, even some people who are savvy enough to supplement with B12 and methylfolate while taking Metformin still report side effects.
My interest in metformin is longevity evidence. Is there any evidence with these alternatives that they act in the same way?
The evidence is only biochemical, not epidemiological. There is no lifespan or mortality data for any of these substances in humans.
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Not Goat’s Rue? Isn’t French Lilac a good herbal alternative to Metformin too?
Goat’s rue is the same as Galega officinalis, also known as French lilac.
“Galega officinalis, commonly known as galega, goat’s-rue, French lilac, Italian fitch, or professor-weed, is an herbaceous plant in the Faboideae subfamily. It is native to the Middle East, but has been naturalized in Europe and western Asia.” Wikipedia