The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 7 • August 2013

For Those Using Metformin, Good News

Better Results When Metformin Is Combined With the Prebiotic Oligofructose Than When Either Is Used Alone in the Treatment of Obesity—a Rat Study

A defect in glucagon-like peptide 1 (GLP-1) secretion, a hormone that increases insulin secretion and induces satiety, is believed to be one of the causes of obesity. Overeating is known to blunt the GLP-1 response to food ingestion, whereas prebiotics can improve the response to the hormone. Both oligofructose (a form of the prebiotic inulin) and metformin are known to improve GLP-1 sensitivity. Researchers decided to test whether a combination of these two treatments would result in a greater improvement in obese rats on a high fat high sucrose diet as compared to the result of treatment by metformin or oligofructose alone. They assessed the results by measuring peripheral glucose clearance through the phosphorylation (activation) of AMPK, decreasing gluconeogenesis (glucose release by the liver, which is supposed to be inhibited by insulin but in diabetics is not effectively suppressed) and increasing peripheral glucose uptake in liver and skeletal tissue.

The researchers observed a decrease in energy intake, percent body fat, and blood glucose with both oligofructose and metformin. The combination resulted in improvement as compared to the individual treatments.

“The interaction between OFS [oligofructose] and MET [metformin] affected fat mass, hepatic TG [liver triglycerides], secretion of glucose-dependent insulinotropic polypeptide (GIP) [a satiation hormone] and leptin, and AMPKalpha2mRNA and phosphorylated acetyl CoA carboxylase (pACC*) levels (p<0.05). “The rats in the OFS group had lower fat mass than the control rats, and rats in the MET group and the OFS+MET group had lower fat mass than those in the control and OFS groups. Thus, MET or the combination of OFS + MET resulted in a superior outcome by reducing fat mass as compared to that of OFS alone, while OFS alone reduced fat mass as compared to controls.

Thus, the authors conclude, metformin (already the most utilized treatment for type 2 diabetes) when combined with oligofructose has “the potential to improve metabolic outcomes associated with obesity.”

This is very good news for those taking metformin for diabetes, obesity, or obesity-related metabolic defects (such as insulin resistance), assuming that the metformin-oligofructose combination works similarly in people as it did in the obese rats. (Current data imply that it does.) Simply take supplemental oligofructose (we use long chain inulin) 2 or 3 times a day along with your usual dose of metformin.

* “ACC, the downstream target of AMPK … once phosphorylated, increases oxidation and suppresses fatty acid synthesis … The hepatic [liver] pACC [phosphorylated ACC] level was higher in rats in the OFS + MET group compared to all other groups.”


  1. Pyra et al. Prebiotic fiber increases hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose-dependent insulinotropic polypeptide secretion more effectively when used with metformin in obese rats. J Nutr. 142:213-220 (2012).

Metformin Increases Lifespan of C. elegans Via Its Effects on the C. elegans Resident Bacterium

We may be on the verge of a new expanded analysis of life extension that includes the effects of the microbiota living within us starting with a new paper1 in Cell. There, the researchers found that metformin, said to be the most commonly used treatment for diabetes worldwide, extended lifespan in the nematode Caenorhabditis elegans by acting as an antibiotic that altered the metabolism of the E. coli that are the worm’s resident bacterium. The E. coli, the primary food source of the worm, had a decreased production of nutrients such as folate and methionine as a result of the antibiotic effect of metformin, resulting in nutritional restriction in the worm and THAT was what increased the lifespan of the worm. If this analysis is correct, then the lifespan effects of metformin on C. elegans have to be considered from the point of view of both C. elegans and its microbiome.

The implications of this finding (assuming that it is verified) could be enormous when considering the human-microbiota system as a whole. Germ-free rodents weigh less than rodents with a normal gut microbiota, which is believed to be due to decreased extraction of nutrients from food, a form of dietary restriction. Also, rodents with a normal microbiota given a microbiota transplant from fat rodents themselves become obese on a high fat diet. The implication is that, just as the C. elegans gets less nutrients from its E. coli microbiome as a result of metformin’s antibiotic effect on the E. coli, metformin might (by a similar antibiotic effect) reduce the nutrients derived from food (and thus made available to us) by our normal gut microbiota. Indeed, metformin induces weight reduction, among other things, in diabetics that receive it as a treatment.

Interestingly. “[i]t was recently discovered that C. elegans live longer on an E. coli mutant with reduced folate levels (aroD). Moreover, metformin can decrease folate levels in patients.”1 The authors draw no conclusions from these curious facts, which may or may not be relevant to the effect of metformin in humans. We know of no studies in humans that have provided evidence for a life extending effect of metformin. Humans have such a long lifespan that such studies would be impractical. However, studies of the gene modulating effects of metformin in humans as compared to gene microarrays showing changes of gene expression with age that occur in the absence of metformin supplementation can be used to infer anti-aging gene expression changes with metformin.

It was noted by the authors of the C. elegans-metformin paper in Cell1 that, while metformin activates AMPK (one of its antidiabetic effects), it does not increase lifespan in Drosophila and suggest that this might reflect the presence of metformin-resistant microbiota in Drosophila. This prediction shouldn’t be difficult to test.

A recent paper2 reported that, using a sophisticated analysis of 184,094 sequences of the microbial rRNA genes from 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery, they “detected significantly higher numbers of H2 [hydrogen]-utilizing methanogenic Archaea in obese individuals than in normal weight or post-gastric-bypass individuals.” These researchers therefore propose that “interspecies H2 transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons.”2 One implication of this paper’s results would be that reducing the number of methanogens in the gut would be a way to decrease energy uptake for the purpose of reducing weight.

In another paper,3 researchers tested the hypothesis that modification of the gut microbiota with two antibiotics could cause antidiabetic effects, e.g., improvement in whole body glucose tolerance. They thought that this might be the case because of prior work that showed that (for example) an infusion of a low dose of lipopolysaccharide, a component of gram-negative cell wall, leads to excessive weight gain and insulin resistance in mice concommitant with the production of low-grade inflammation. In their study,3 they found that treatment of the ob/ob diabetic mouse and diet-induced obese mice with a combination of two antibiotics, norfloxacin and ampicillin, improved whole body glucose tolerance and reduced liver accumulation of fat.


  1. Cabreiro et al. Metformin retards aging in C. elegans by altering micorbial folate and methionine metabolism. Cell. 153:228-39 (2013).
  2. Zhang et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA. 106(7):2365-70 (2009).
  3. Membrez et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22:2416-2426 (2008).

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