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Mechanism of action of Metformin is

Ultimately, it decreases gluconeogenesis (glucose production) in the liver

Gluconeogenesis results from breaking up of fat. Metformin also inhibits cellular lipolysis and increases glucagon storage.

But Insulin resistance, which is the cause for Pre-Diabetes and Type 2 Diabetes is itself caused by excess accumulation of fat in muscle cells and liver. Reference

Insulin resistance occurs when your muscles and liver have an impaired response to the action of insulin. This is caused by the accumulation of excess fat in tissues that are not designed to store large quantities of fat, resulting in a reduced ability of insulin to promote glucose uptake in both muscle and liver cells.


If this is true, then even though, in short term, Metformin reduces blood glucose levels by reducing the hepatic contribution, it simply is working for the disease on long term by progressively making a person more and more insulin resistant by making sure the fat accumulated in the cells and liver is not broken down. This may explain why people on Metformin for Pre-diabetes will almost always progress into Type 2 Diabetes and need insulin secretagogues.

So, what is the rationale of using Metformin in Pre-Diabetes and Type 2 Diabetes?

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  • I am not sure and will need to do some reading on it. But surely, as you are pointing out, Metformin is there to prevent more glucose production when glucose uptake is required by the liver but the insulin resistance is blocking that function. May 15 at 9:01
  • As for excess fat in tissues, that can be dealt with through exercise and better diet. The muscles can use the fat in the tissues for energy. May 15 at 9:03
  • @ChrisRogers the muscle can't use fat in tissues for energy because of metformin. Metformin inhibits lipolysis. Metformin basically inhibits any kind of fat utilization. So the cellupar fat tend to stay the same. May 15 at 13:57
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Metformin has effects on many body systems and its many effects are not completely understood, as explained in this 2019 review article discussing use of metformin to treat Type II diabetes mellitus.

Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15, 569–589 (2019). https://doi.org/10.1038/s41574-019-0242

This article can be accessed through Google Scholar at a site that is an open-access site and is not paywalled.

According to this article,

“…..several actions have been attributed to its ability to lower blood glucose. For example, metformin acts primarily by the suppression of enhanced basal endogenous glucose production in individuals with T2DM through a 25–40% decrease in the hepatic gluconeogenesis rate…..”

“Moreover, in some euglycaemic-hyperinsulinaemic clamp studies, a beneficial effect of metformin on insulin sensitivity has been reported in skeletal muscle.”

“……the drug increases peripheral glucose utilization by the intestine, primarily via non‐oxidative metabolism…..”

That is, according to this article, citing references, metformin does not increase insulin resistance. It increases insulin sensitivity. That is one reason it is given both in people with Type 2 diabetes and in people with pre-diabetes.

The question states that

“people on metformin for pre-diabetes will almost always progress into Type 2 Diabetes and need insulin secretagogues.”

This is not a correct statement. Metformin decreases the chances that a person with pre-diabetes will progress to Type 2 diabetes. The most convincing evidence for this statement comes from a 2019 Cochrane Systematic Review of randomized trials of metformin compared with placebo or diet/exercise in people with pre-diabetes reported that the:

“incidence of T2DM was 324/1751 versus 529/1881 participants (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 3632 participants, 12 trials; moderate‐quality evidence.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889926/

The detail of the trials that compared progression to Type 2 diabetes comparing metformin with placebo or diet/exercise can be found on page 102 of this publication—Analysis 1.2 and 1.3.

EDIT. The Diabetes Prevention Program trial, which is the largest trial of metformin in people with pre-diabetes, showed an effect of metformin in decreasing the chances of progression from pre-diabetes to Type 2 diabetes at 3 years. The percentages of people with pre-diabetes who had progressed to Type 2 diabetes were 28.9% in the placebo group, 21.7% in the metformin group, and 14.4% in the lifestyle group.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370926/

The authors estimated that metformin delayed onset of Type 2 diabetes by 3 years.

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  • @DianaPeetitti thank you for the answer. I have two queries. 1. You said metformin increases insulin sensitivity? How is this measured? It increases peripheral glucose uptake, because it inhibits lipolysis there, so the tissues have no other enefry source but accept glucose where fat goes on depositing. This temporarily seems like increased insulin sensitivity but ffaat goes on accumulating. 2. Regarding the claim metformin decreases the chance, it would be correct to say metformin postpones but doesn't decrease the chance. All the studies are done for a limited period, so its postponed. May 18 at 13:51
  • @DianaPeetitti if Metformin really workerd we wouldn't need sulfonyl ureas. More over unfortunately the answer doesn't answer the key issue that if insulin sensitivity is raised by fatr accumulation and metformin increases fat accumulation then how does metformin help in long term. May 18 at 13:53
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    @ Mr Green Gold A detailed description of the various methods for assessing insulin sensitivity and resistance, updated in 2018, is available online at: ncbi.nlm.nih.gov/books/NBK278954 Ranganath Muniyappa, M.D., Ph.D. and Ritu Madan, MBBS, MD. Assessing Insulin Sensitivity and Resistance in Humans. The answer is careful to use the term "progression" when referring to the effect of metformin in people with pre-diabetes. May 18 at 20:39
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    @ Mr Green Gold Here is a 2021 review article that describes, in section 3.1, the mechanisms whereby metformin is believed to affect glucose metabolism and insulin sensitivity and resistance. ncbi.nlm.nih.gov/pmc/articles/PMC7915435 May 18 at 21:27
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    @Mr Green Gold I think you're vastly overestimating how much metformin increases fat accumulation. If we say that without metformin a person has blood glucose of 200 mg/dL (the cutoff to diagnose diabetes), and with metformin has blood glucose of 140 mg/dL (upper limit of "normal), and has 5 liters of blood (average for a person), that's a difference of 3 g (3,000 mg) of glucose. How much fat is going to be broken down to make up that difference? Probably not enough to significantly change the cell size of enough fat cells to decrease insulin sensitivity.
    – Katie
    May 20 at 21:05

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