Bigaunide derivatives such as Metformin structurally resemble to 5-HT3-receptor

agonist, which leads to the activation of 5-HT3 receptors  and induce nausea, vomiting, and diarrhea.  Additionally, these biguanides are also known to interfere with intestinal functions and reduce glucose absorption, which leads to osmotic diarrhoea due to increasing concentrations of intestinal glucose levels.

Suhasini, many thanks for your prompt answer.

Challenging!

So, apparently Metformin induced diarrhea has a complex but at the same time simple mechanism. It resembles, on a small scale, what we gastroenterologists know as "after bypass surgery dumping syndrome", in which you have a simultaneous osmotic/hipermotility condition.

Would it be too much to ask you to provide me w/a reference list in which I could read up on this topic as much as possible? It would be greatly appreciated. As a researcher and clinical gastroenterologist I work w/Metmorfin tolerability, especially diarhrea, that is present between 5-10% of the cases in patients beginning Metformin treatment or in those who are increasing their daily dose.

There are also some susceptible ethnic populations such as the mestizo group, which are highly prevalent in most Latin American countries, (Mexico, CA and Pacific Andean Region) who are relatively intolerant to Metformin. As clinicians we usually deal w/this problem by progressively escalating the dose on a weekly basis and in more severe cases by adding on loperamide/psyllum as rescue medication.

Now, in order to provide a better and tolerable metformin, first we need to understand what we are dealing with, and second, to work on a different improved delivery system such as NERF "novel extended release fotrmulations" and/or drug combinations.

Looking forward to hear from you soon.

My best rgds.  

http://www.springerlink.com/app/home/contribution.asp?wasp=9f8f0aba6b224f108f96bc1157f5a473&referrer=parent&backto=issue,13,15;journal,71,143;linkingpublicationresults,1:100530,1

The above site might be helpful Jose

Dear Dr. Vargas,

I am not into diabetes, but your question has definitely intrigued me. It is sad to see people having diabetes with so many complications with or without treatment. Even in diabetes, patients are presented with diarrhea in which 5-HT3 receptors have been clearly implicated (http://care.diabetesjournals.org/content/33/3/e38.full).  Administration of metformin also leads to many gastrointestinal side effects such as diarrhea and again 5-HT3 secretion by duodenal mucosa has been implicated in this (http://www.ncbi.nlm.nih.gov/pubmed/10651152). It is due to structural resemblance between metformin and 5-HT3 receptor which makes metformin an agonist. Though in early 1994, serotonin 5-HT3 receptor antagonist ondansetron has shown beneficial effects on diabetic patients having diarrhea (Bossi A,  Baresi A, Ballini A, Bindelli C : Ondasentron in the treatment of diabetic diarrhea. Diabetes Care 1994;17:453–454 ), but its effect in combination with metformin on metformin-induced diarrhea and other GI side effects has not been yet performed.

Besides 5-HT3 neurotransmitter, Glucagon like peptide- 1 (GLP-1) has also been implicated in metformin-induced diabetes.  Here is the irony, GLP-1 itself leads to increase production of insulin and clinical trials using GLP-1 agonists and DPP inhibitors (DPP degrades GLP-1) have shown good anti-diabetic effects on patients. However, GLP-1 itself leads to the GI sideeffects which also includes diarrhea and has been well established. Metformin induced the secretion of GLP-1 which is great to increase insulin secretion, but bad at the same time due to increasing glucose content in intestine which leads to osmotic diarrhea (http://www.hindawi.com/journals/jdr/2012/230624/).

These are the only two mechanism that have been little bit studied in terms of metformin-induced diarrhea. In order to know the exact reasons behind this, we need to know about diarrhea causing molecular mechanisms. There are different types of diarrhea: Osmotic, secretory, and inflammatory (infectious). There could be other plausible mechanisms as well. For example, activation of adenylyl cyclase, which leads to prolonged increase in intracellular concentration of cyclic AMP within crypt enterocytes. It will in turn leads to  prolonged opening of the chloride channels causing uncontrolled secretion of water. Lastly, we need to first know what kind of diarrhea these patients have and why do they have this kind of diarrhea (mechanistic aspect), to specifically treat these patients.

Dear Prosper,

Many thanks for your recommendation. Great site. I will thoroughly explore it.

Rgds

You are welcome Antonio.

Best

Dear Suhasani,

I greatly appreciate the extensive and profound input. I fully agree with your comments.

There are some relatively recent publications which strongly suggest molecular AMPK involvement in down regulating the cholera toxin (CTX) mechanism in the enterotoxin mediated secretory diarrhea. The whole CTX-GM1-Adenylate Cyclase-cAMP-CFTR system seems to be modulated by AMPK activation in the presence of secretagoges CTX or forskolin via AICAR and metformin administration (www.plosone.org: Rogers AC et a. (2013) "Activation of AMPK inhibits Cholera Toxin Stimulated Chloride Secretion in Human and Murine Intestine". PloS ONE 8(7): e69050. doi:10.1371/journal.pone.0069050). As you mentioned before, cAMP activation could be part of the equation, but apparently, metformin AMPK activation seems to have an opposite response. So, the answer is still very complex.

Apparently there is not enough research concerning standard-high dose metformin oral tolerability due to the GI symptoms. I am wondering if there is any ongoing protocol or published article concerning oral administration of 1gr t.i.d. either for DM2 or cancer co-treatment. Please let me know if you know of any.

One of your 2012 publications, as co-author,  especially caught my attention (Graviola: A Novel Promising Natural-Derived Drug That Inhibits Tumorigenicity and Metastasis of Pancreatic Cancer Cells in vitro and in vivo Through Altering Cell Metabolism).Apparently, both Annonaceous acetogenins as well as metformin act by inducing cytotoxicity by inhibiting the mitochondrial complex I. Also, as mentioned in your article, there are a couple of publications showing that A. muricata activity regenerates pancreatic islet beta cells in diabetic rats.

I would love to hear your comments concerning the afore mentioned topics.

Rgds

Very interesting correspondence. Is anything known about the distribution of possible receptors for 5HT3, or GLP-1, in colon?  There are CFTR channels involved in secretion in the colon. In my experience the diarrhea due to metformin is quite dose-dependent and could be due to a spillover from small into large intestine increasing with dosage. Metformin diarrhea also appears to be worse in those with fast intestinal transit. I have no scientific data on these points, but I have heard that pancreatitis  due to metformin is due to inhibition of CFTR channels in pancreas, so it may happen also in colon, inhibiting reabsorption of fluid.

Very interesting chain of discussion!

While I agree with many of the comments above, I've been persuaded myself more and more toward the metformin-induced gut biota dynamic hypothesis. Metformin is very well uploaded into the gut lining where it seems to reside longer than expected (animal studies). This leads to a microenvironment that triggers an immediate response from existing flora and facilitates recollonization of short-chain fatty acids producing biota. Bile acids recirculation may also play a role.

Thanks for sharing your insight Alice.

I too would like to know more about the methodology of the diarrhea from Metformin for personal reasons, but can provide some person thoughts about how it might be causing the problem.

I have been on it since March 2018 with a gradual dose increase to 500 mg in the morning and 1000 mg in the evening. I found that by taking lomotil with it, I did not have as much diarrhea. Subsequently, I held the metformin for 7 days and developed significant constipation, so it seemed to me that the diarrhea was due to increase intestinal secretion and without it, constipation developed.

I restarted the metformin and added lomotil at the same time along with extra fiber, and the diarrhea is more manageable. Since I am following a very low carb diet, I doubt this is an osmotic diarrhea due to excess glucose.

50 year old patient with fatty liver. Non-diabetic. Abnormal LFT’s (ALP, GGT, ALT AND AST all worsened at onset of diarrhoea that persisted till 2 days after withdrawal of Metformin 500mgs nocte only. LFT’s improved after this too.

To treat metformin induced diarrhea...consider using

ondasetron (5HT3 antagonist)....fairly benign drug.

Loperamide ( Imodium*) is also an option ( as mentioned)

and Imodium is also fairly benign.

Following up on John W's case: intensified glucose uptake (ie increased by metformin) likely occurs on the background of limited oxygen availability, thus lactic acid levels increase as a consequence. Even though not "lactic acidosis", this is expected to put a strain on the liver, hence elevated LFTs. Depending on the extent of fatty liver condition, the LFTs may normalize. I expect metformin to prevent or delay insulin resistance in that case. If CRP is over 1.5, a statin may be warranted and it may very well synergize metformin's benefit

One thought is that metformin impedes mitochondrial function of the local intestinal cells reducing activities such as absorbing of nutrients.

Microvilli are hairs that aid in absorption of nutrients. ... In the small intestine, these cells contain microvilli, which are tiny hair-like projections that increase nutrient absorption. with low levels of ATP...this process can not occur

properly.

Metformin accumulates within mitochondria to concentrations up to 1000-fold higher than in the extracellular medium, because metformin carries a positive charge and the membrane potentials across the plasma membrane and mitochondrial inner membrane (positive outside) drive metformin into the cell and subsequently into the mitochondria (Fig. ​(Fig.2)2) [14, 15]. The most intensively studied mitochondrial action of metformin is the inhibition of Complex I of the respiratory chain [14, 16], which suppresses ATP production. .

Source:

"The mechanisms of action of metformin"

Graham Rena,1 D. Grahame Hardie,📷2 and Ewan R. Pearson📷1\Diabetologia. 2017; 60(9): 1577–1585.Published online 2017 Aug 3. doi:  10.1007/s00125-017-4342-zPMCID: PMC5552828PMID: 28776086

Lester Mandelker DVM

Fellow Anmerican Academy of Veterinary Pharmacology and Therapeutics

The interference with mithocondria physiology is very intriguing and it might explain why metformin resides longer in the intestinal wall. Food for thought - thank you!

Our team is currently looking into the influence of "inactive" ingredients on metformin induced diarrhea. I noticed that the same patients develop diarrhea when taking from certain manufacturers, but not others. If you are interested in joining us in this research, please let me know.