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

Abstract

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.

Dr Richard Mackarness meets low-carb and Paleo pioneers in 1958

Dr Richard Mackarness


In Chapter 7 of his influential 1970's book on food allergies "Not All In The Mind" U.K. physician Dr Richard Mackarness describes his encounters with the pioneers of low-carb medicine when he visited the States in 1958. That same year Dr Mackarness wrote "Eat Fat and Grow Slim".
"His first book, Eat Fat and Grow Slim (1958), exposed the "calorie fallacy" and proposed a non-carbohydrate "Stone Age" diet of protein and fat with no restriction as to the amount eaten. The book was immensely popular and went through six editions."




In the US Dr Mackarness interviewed, or studied the works of, the following "anti-cereal" doctors. Those that are covered in "Good Calories/ Bad Calories" or well-referenced on the internet I will treat briefly, I am mainly interested in drawing attention to some unsung heroes and their tales.

Dr Ray Lawson was a surgeon at one of the biggest hospitals in Montreal and surgical consultant to the Canadian Arctic Medical Service. Some of his Eskimo patients in the far north were still eating their old high-fat, high-protein, non-cereal diet, which seemed to him to keep them remarkably fit and give them great powers of endurance. He decided to try to lose some unnecessary weight by following an Eskimo diet himself, an enterprise in which he was completely succesful. just before I visited him, he had confounded his personal physician by curing himself of an attack of jaundice. His doctor had been treating him with orthodox methods, including a low-fat diet, without much success.Dr Lawson switched to large doses of double cream, and promptly got well. An article about him and his high-fat eating was published in the popular Canadian magazine Maclean's, and caused quite a stir.

After seeing Dr Lawson I visited the late Dr Alfred Pennington of New Jersey who was consultant physician to Du Pont, the vast chemical company...he was asked to develop a reducing plan for the company's overweight executives... most of them had high blood pressure and were potential stroke- and heart-attack victims.
The diet he prescribed completely eliminated foods of cereal origin, i.e. everything containing starches or sugars; it was virtually an all-meat diet with the fat left in. When I lunched with him at his house I found he practised what he preached; we had an all-meat meal. He told me that he gave the duPont executives about 3000 calories per day in the formof fat meat and on this regime they lost at the rate of two to three pounds per week. They liked the diet, nd by the time their weight had returned to normal, their blood pressure had returned to normal too.
The relationship between obesity and high blood pressure is recognised by doctors all over the world, and the type of high blood pressure known as 'idiopathic' (of unknown cause) is one of the commonest stress disorders of twentieth-century civilised countries, crippling millions every year. It is a forerunner of strokes and coronary thrombosis. I believe that it and its associated obesity are both diseases of maladaptation to certain foods and chemicals we have been eating in increasing quantities over the past sixty to seventy years.

From Pennington I went on to Minneapolis to talk to Dr. George L. Thorpe, a general practitioner from Wichita in Kansas, who was attending the 1958 annual meeting of the American Medical Association. At the previous annual general meeting in New York in 1957, Thorpe had been chairman of the section of General Practice and had made the cereal-elimination approach to overweight the subject of his address .
Thorpe told me that he hated to call his method a diet. "Proper eating is the normal and complete answer to the problem of excess weight," he said. "The words diet and dieting should be avoided.

"Several years ago," Thorpe went on, "while I was considering a personal problem of excess weight, it became evident that huge numbers of calories in my daily total came from three to four large glasses of milk, two to three bottles of soft drinks, numerous slices of bread, and an educated taste for cookies, candy and sweets in general, all of which are concentrated carbohydrates. Cereal grains, historically, were cultivated in order that limited agricultural areas might supply food to support population densities not otherwise possible. They are concentrated forms of food, readily assimilated in the body, containing small residue of bulk, and so may be eaten in quantities far in excess.of the calorie needs, without sensation of fullness. All carbohydrate foods and most drinks fall into this category, either by virtue of their origin or the reaction of the body to them. Milk is actually a liquid infantile food, the use of which man has carried over into his adult life and which, in general, satisfies the definition of concentrated carbohydrate.
  "The simplest to prepare and most easily obtainable high-protein, high-fat, low-carbohydrate diet and the one that will produce the most rapid loss of weight without hunger, weakness, lethargy or constipation is made up of meat, fat, and water. The total quantity eaten is not important, but the ratio of three parts lean to one part fat must be maintained, as any decrease in the fat portion will reduce the weight loss..
   "Black coffee, clear tea and water are used without restriction. reduction of salt, while not required, will increase the speed of weight loss"

The last doctor I met was the late Blake Donaldson (he died in 1963). When I saw him at his clinic in New York I found that not only was he slimming his fat patients on a cereal-elimination diet, but he was using this diet and a graduated system of simple exercises to clear up a whole variety of chronic disorders in a most remarkable manner. I saw elderly rheumatic patients made supple and pain-free, martyrs to migraine relieved of their headaches and asthmatics helped to breathe freely again. In an interview in 1962, when he came to London to visit a patient Donaldson told me how he did it.

Dr MACKARNESS: When and how did you first come on the ideas which caused you to write Strong Medicine?

Dr DONALDSON: About 1919. I was faced with the problem of people with heart disease, fat people who were short of breath, had swollen feet (oedema) and could not lose weight. I tried them for a year on a low-calorie diet with a very bad result. At the end of the year practically none had lost weight, they were still breathless and had not lost their oedema.

[I wish I could copy all of this interview but it is far too long for my single-fingered typing skills. Dr Donaldson followed an investigative route similar to that of Weston A Price, except he looked at teeth in museum specimens. I think those heads have since had to be returned. The story is told in Strong Medicine beginning on page 32. Dr Donaldson talks of an "allergy" to flour, which is a terminology and concept Dr Mackarness later adopted. Its use means that the response to these foods is maladaptive and stressful, without always implying an immunological basis for this, which the scientists of the day were in no position to determine with certainty.]

Dr DONALDSON: We found out the patients could live on just fresh meat and a cup of coffee three times a day, and lose weight at the rate of three pounds a month. (You don't want to lose weight much faster than that, otherwise the skin becomes wrinkled.)
...
When you reduce their weight to normal you have to prove their weight can stay normal; that's very important...They have to be able to eat fat meat with salt, potato with butter, raw fruit and a full cup of coffee three times a day and show no gain in weight...there is no restriction on the amount.

Dr MACKARNESS: How many patients over the last forty years have you treated on this basis?

Dr DONALDSON: About seventeen thousand. I now have a group of about fifteen hundred patients over the age of seventy, who have avoided flour for between five and forty years,.and have kept primitive food as their basic way of maintaining health.

Dr MACKARNESS: This is what I call a Stone-Age diet. Would you agree with that description? It is a pre-cereal diet.

Dr DONALDSON: Well, I should say that it is perhaps six thousand years old and twenty years ahead of its time. I think this will be a popular idea in twenty years, that flour is a bad thing for about eighty percent of the population.

Dr MACKARNESS: And do you also ban all carbohydrate derivatives - sugar, chocolate, etc?

Dr DONALDSON: Once you have an allergic fat person under control you reduce that person's weight to normal. I find that I am unable to feed them sugar in any form, and unable to feed them flour, without bringing back their obesity and their allergic symptoms.

Dr Mackarness goes on to discuss F. Curtis Dohan and his 1969 work on schizophrenia and coeliac disease. He then describes the work of Andresen (1942) that ulcerative colitis is a result of food allergy "in 66% of cases" and that of Professor S. C. Truelove of Oxford who wrote in 1961 about improvement of ulcerative colitis upon removal of milk from the diet. These are both early descriptions of a disease due to lactose (or FODMAP) intolerance.

Mackarness returned to the UK and wrote the highly successful diet book Eat Fat To Grow Slim. Dr John Yudkin, a far more conservative academic nutritionist, also wrote a low-carb book, This Slimming Business, with similar recommendations to those of Mackarness, as can be seen in this 1970 paper. I wish I knew something about the relationship between these two great men. It cannot have been an easy one, as Yudkin was a cautious sceptic and Mackarness a speculative innovator. Mackarness bears responsibility for the popularising of elimination diets; these were harmless when meat was the default food, as it was in Not All In The Mind, but are more problematic now that the idea has been adopted by Naturopaths with eating disorders and strange ideas about animal foods.

The biggest difference between the British and American low carb doctors is, that Yudkin and Mackarness were respected members of the British medical establishment, and their ideas were given common currency by a country with a then-progressive approach to preventive medicine. You can see it in this 1967 video, where an overweight child is told to eat meat and green vegetables, and avoid sweet and starchy foods. Stodge, not grease, was the enemy and the cause of Overweight and Shortness of Breath.



Regardless of whether the consumption of starch and sugar has changed during the obesity epidemic, we can be quite sure that the advice given to the most vulnerable people - the newly overweight or pre-diabetic - has. In my opinion this is what we should be looking at - whether alterations in the primary diet and exercise advice given to individuals in at-risk groups by the most authoritative agencies has been associated with any particular outcome.
But really, I think we all know the answer to that.

[EDIT: The major difference between Yudkin and Mackarness's approach to weightloss was that Yudkin as serious nutritionist emphasised the need to cut calories (carbohydrate calories being easiest and most profitable to cut), whereas Mackarness was more of the ad libitum "calories don't count" persuasion.
But in practice Yudkin believed that calories should be automatically reduced on a low-carbohydrate diet and that there was no need to count them, as you can read here (PDF) in the introduction to his recipe book Eat Well, Slim Well (1982) which summarises the argument of This Slimming Business (1958, the same year as Eat Fat and Grow Slim).Here is a list of “unrestricted” foods: those, that is, which you don’t have to limit but which limit themselves. They are meat, poultry, fish, eggs, butter, margarine, cream, leafy vegetables. In addition, you should take between half and one pint of milk a day, up to half a pound of fruit, and up to two ounces of cheese.
John Yudkin's obituary from 1995]