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Thursday 28 November 2013

Metformin's unusual mechanisms - Lower Carb and Pro-Prebiotic

Metformin is generally considered to be a drug with few vices, so I was intrigued to read some tweets a while back that mentioned GI upsets in patients. Wikipedia lists these:

"The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs. Gastrointestinal upset is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common."

These are side effects one associates with fibre, especially of the FODMAPs type. It occurred to me that if metformin was inhibiting the uptake of dietary carbohydrate this could account for the effect, as sugars would then became more available to gut bacteria, the population of which would tend to regain balance over time (as potato experimenters have recently reported on the resistant starch kick).
The science is conflicting on this, but most papers seem to find some reduction in glucose absorption, e.g.  "
The results suggest that metformin decreases intestinal glucose absorption in a dose-dependent manner by effects on mucosal and serosal glucose transfer."This raises the possibility that some of Metformin's effects are produced through carbohydrate restriction, and others through increased butyrate production, as well as any localised effects on cells. Both Metformin and butyrate activate AMPK and protein-kinase A.

This is a simple explanation; I ran it past Silvia Price, who unlike me has extensive clinical experience with Metformin, and she turned up a stunning twist on the theory.
Metformin isn't feeding glucose to the microbiotia directly; it is stimulating the intestinal goblet cells to increase and to produce more mucus. Microbiota, specifically Akkermansia Muciniphila, then harvest sugars from the mucus.

An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice


Background Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents.
Objective To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition.
Design C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT).
Results Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p 0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT.
Conclusions Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.

Comment on another "high-fat diet-induced obese mouse" study:

i. Obesity is associated with a decrease in the abundance of Akkermansia muciniphila in gut microbiota.
ii. Akkermansia muciniphila is able to cross-talk with the intestinal epithelium to control gut barrier functions in the pathophysiology of obesity. We show for the first time that obesity is associated with a decrease in the mucus layer thickness recovering epithelial cells. Interestingly, Akkermansia muciniphila is the dominant human bacterium that abundantly colonizes this nutrient-rich environment. We found that living Akkermansia muciniphila was able to control mucus layer production by the host and restore mucus layer thickness in high-fat diet-induced obese mice thereby reducing gut permeability.
iii. Akkermansia muciniphila decreases lipid storage and increases lipid oxidation in high-fat diet obese mice.
iv. Akkermansia muciniphila counteracts inflammation associated to obesity.
v. Akkermansia muciniphila controls high-fat diet-induced obesity and type-2 diabetes. 

Goblet cells. Not at all clear what's going on here, chosen for the nice colours.

I wonder if the missing glucose, when and if it does go missing, is being used as the substrate for mucopolysaccharide synthesis by the enhanced goblet cells. I also wonder if it is wise to give Metformin with antibiotics, and whether this increases the risk of Clostridium or Salmonella infection - or indeed, decreases it.

[Goblet] cells that line the gut extrude long chains consisting of exotic and familiar sugars linked together and known by a catch-all term: mucus. This homely product serves two valuable functions. First, by coating the inside intestinal wall, mucus forms a reasonably impervious protective barrier to keep the resident microbes, which serve useful purposes inside the gastrointestinal tract, from getting out of the gut and into the bloodstream, where they could be lethal. But the mucus has a second function as well: It gives our resident microbes a guaranteed source of various sugars, like sialic acid and fucose, that they can snap off and use in a number of ways. They can, for example, break these sugar molecules down and derive energy from them."We believe that bacterial pathogens in the gut cause disease in two steps," he continued. "Others have shown that once these pathogens attain sufficient numbers, they use inflammation-triggering tricks to wipe out our resident friendly microbes ― at no cost to the pathogens themselves, because they've evolved ways to deal with it. But first, they have to surmount a critical hurdle: In the absence of the inflammation they're trying to induce, they have to somehow reach that critical mass. Our work shows how they go about it after a dose of antibiotics. They take advantage of a temporary spike in available sugars liberated from intestinal mucus left behind by slain commensal microbes." (From Scicasts).

Note that pretreatment with Metformin lowered HCV viral load by 0.52 log in insulin-resistant patients in this small study.

On a personal note, I have started an 8-week trial of Sofosbuvir and GS-5816 (Vulcan). It is day 11 and it seems tolerable so far.
A pre-trial blood test on 22nd October was normal except for these counts:
AST 74
ALT 174

and viral load was 600,419 (log 5.78), counts consistent with the tests I've had done this last year.

But the day the trial started, 18th November, before my first dose, things were different:
AST 21

ALT 32
Viral load 27,167 (log 4.43)

The low viral load is easy to explain; I get a consistent 1 log drop (to 14,000-60,000) when I try to eat very low carb (50g/day or lower) and an elevation to 400-600,000 when my carbohydrate intake is over 50g/day. When I ate very high carb (but took antioxidant supps) it was as high as it was on 22nd October. So for me the tipping point seems to be where ketosis begins, and other variations don't have much effect; it's an on/off switch, not a dial (and the name of that switch is PPAR-alpha).
(I do however, according to CAPSCAN elastography, have zero excess fat in my liver, which is an effect of low carb in general, as well as avoiding vegetable seed oils).

The perfect AST and ALT are harder to explain. They have never been so good, not since 1991 when they were first measured. Is it the 30mg/day zinc (as gluconate) I started over a month ago? That would be cool. It's already fixed any lingering fatigue and helped me sleep better.


lissjeanrosa said...

So your jumped on the 5816 wagon! The data looks very promising. Have the trials extended to compensated yet? I'm logged to start 3a SOC 48 weeks in Feb but somehow this 5816 looks sooooo much sweeter. I am amazed at the log drop with the low carb approach. I have been doing same and have seen good drops in AST ALT & half log viral load drop.

Puddleg said...

After 1 week, my VL is <15
ALT and AST both 18
Minimal SFX so far.
I think some in my trial have cirrhosis from their comments and state of health, but not sure.

lissjeanrosa said...

That's an awesome result!
Ask around for me. I am keen to try to push my specialist into seeking a compassionate trial.

Puddleg said...

If you're in Auckland, ring Auckland Clinical Studies 0800 788 3437 to ask about/volunteer for places in trials.

Puddleg said...

Silvia Price informs me that there is one other diabetes drug with the same side-effects profile as Metformin - Acarbose (Precose/Prandase/Glucobay), which is an alpha glucosidase inhibitor blocking starch digestion.
This supports the idea that Metformin exerts some of its effects through restricting the uptake of glucose.

Silvia Price said...

Told you it was connected to endocannabinoids..."A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion."

Would it be wise to use metformin and antibiotics together? No, because antibiotics can change the bacterial community. The paper on metformin's gutsy role says, "The antidiabetic effect of metformin can be abrogated by an antibiotic treatment reinforcing the importance of gut microbiota as a target of metformin."

BTW, Samir just obtained a 90% success rate at EOT with Peg+Riba+Metformin (pretreated for 3 months), which should embarrass all those who screwed up all the other metformin studies. I'm sending them a coipy as soon as it's published.

Silvia Price said...

That's one way of having lots of comments.