"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- Metformin -

General Information:

Names:  Metformin,
Wikipedia entry:
Dr. Ray Shahelien entry:



See also Tau Busters

Diabetes Drug Metformin Headed to Dementia Trials1,2,3

Metformin acts on tau phosphorylation.

The "cocktail"3 is metformin and resveratrol[How much of each???]

[No mention of resveratrol in the press release, but there is for the article printed the same day: http://www.dailymail.co.uk/health/article-1332185/Alzheimers-prevented-cocktail-cheap-drugs-including-metformin-resveratrol.html?printingPage=true

The news articles I found imply that Professor Susann Schweiger also mentioned resveratrol, but I can only find research or a press release relating to her work on metformin.]

It had been thought that cognitive improvements were the result of better control of diabetes and sugar metabolism, but perhaps metformin actually improves Alzheimer's disease symptoms by promoting brain self-repair. Metformin activates the "CBP pathway"  in the liver, and it is theorized that it could also do that in neural stem cells of the brain to encourage brain repair.7,8

Some caution that metformin may cause kidney damage in some individuals, but I have not found documentation for this yet.

Metformin may also interfere with dietary absorption vitamin B12.6 Low B-12 levels could lead to small strokes, and therefore, cognitive impairment in the form of vascular dementia or "multi-infarct dementia" (cerebrovascular disease).9,10 There should be a way to work around this side effect, perhaps by monitoring vitamin B12 levels and supplementing as necessary.

Known sources:

Natural sources:


1. Diabetes Drug Could Work Against Alzheimer's, Animal Study Suggests
Published: Week of November 28 - December 5, 2010

2. ScienceDaily (Nov. 24, 2010)
Metformin, a drug used in type 2-diabetes might have the potential to also act against Alzheimer's disease... The researchers have found out that the diabetes drug metformin counteracts alterations of the cell structure protein Tau in mice nerve cells. These alterations are a main cause of the Alzheimer's disease. Moreover, they uncovered the molecular mechanism of metformin in this process...  results have been published in the Proceedings of the National Academy of Sciences (Nov. 22, 2010)...

3. Cocktail of cheap drugs 'can prevent Alzheimer's' and keep the brain healthy into old age
By Fiona Macrae
Last updated at 8:38 AM on 23rd November 2010

A cheap diabetes drug taken with a red wine ‘miracle pill’ could prevent millions from suffering the agony of Alzheimer’s. Costing only pennies a day, the two-in-one cocktail could keep the brain healthy into old age, stopping dementia developing in some cases and halting it in others, British doctors believe. With the pills already credited with a host of health-boosting qualities, including potentially extending life, the Dundee University breakthrough brings hope of a brighter future for millions... The latest breakthrough centres on drugs called metformin and resveratrol. Metformin has been safely used for more than 50 years to control blood sugar levels in age and obesity-related diabetes. Recent research suggests it has other benefits, including the ability to extend life. Resveratrol, the ‘miracle ingredient’ behind many of red wine’s health-boosting qualities, has also been hailed as an elixir of life, with experiments crediting it with warding off a host of ills, from old age to cancer.

4.Diabetes Drug May Treat Alzheimer's Disease
November 25, 2010
David Goodhue - AHN News Reporter

Germany (AHN) - German scientists say a drug taken to treat type-2 diabetes may be effective against Alzheimer’s disease.

The researchers said the drug metformin counteracts alterations of the cell structure protein known as Tau in mice models. These cell structure changes are a significant cause of the development of Alzheimer’s, the researchers said in a statement.

The scientists were from the German Center for Neurodegenerative Disease, the University of Dundee and the Max-Planck-Institute for Molecular Genetices...

5.Metformin in Amnestic Mild Cognitive Impairment (MCI)
This study is currently recruiting participants.
Verified by Columbia University, October 2010
First Received:          February 7, 2008   Last Updated: October 13, 2010   History of Changes
Sponsor:                 Columbia University
Collaborators:           Institute for the Study of Aging (ISOA)
                         National Institute on Aging (NIA)
Information provided by: Columbia University
ClinicalTrials.gov Identifier: NCT00620191

6. Risk factors of vitamin B(12) deficiency in patients receiving metformin.
Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM.
Arch Intern Med. 2006 Oct 9;166(18):1975-9.
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong.


BACKGROUND: Identification of risk factors for metformin-related vitamin B(12) deficiency has major potential implications regarding the management of diabetes mellitus.

METHODS: We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B(12) and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B(12) deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B(12) deficiency while taking metformin.

RESULTS: A total of 155 patients with metformin-related vitamin B(12) deficiency (mean +/- SD serum vitamin B(12) concentration, 148.6 +/- 40.4 pg/mL [110 +/- 30 pmol/L]) were compared with 310 matched controls (466.1 +/- 330.4 pg/mL [344 +/- 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B(12) deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B(12) deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B(12) concentration, dose of metformin remained the strongest independent predictor of vitamin B(12) deficiency.

CONCLUSIONS: Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.

PMID: 17030830 [PubMed]
Free full article: http://archinte.ama-assn.org/cgi/content/full/166/18/1975

7. Diabetes Drug Makes Brain Cells Grow
ScienceDaily (July 5, 2012) — The widely used diabetes drug metformin comes with a rather unexpected and alluring side effect: it encourages the growth of new neurons in the brain. The study reported in the July 6th issue of Cell Stem Cell, a Cell Press publication, also finds that those neural effects of the drug also make mice smarter...

8. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Jing Wang, Denis Gallagher, Loren M. DeVito, Gonzalo I. Cancino, David Tsui, Ling He, Gordon M. Keller, Paul W. Frankland, David R. Kaplan, Freda D. Miller. Cell Stem Cell, 6 July 2012 DOI:

9. B-Vitamin Deficiency May Cause Vascular Cognitive Impairment
ScienceDaily (Sep. 2, 2008) — A deficiency of B-vitamins may cause vascular cognitive impairment, according to a new study. Researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University used an experimental model to examine the metabolic, cognitive, and microvascular effects of dietary B-vitamin deficiency. "Metabolic impairments induced by a diet deficient in three B-vitamins -folate, B12 and B6- caused cognitive dysfunction and reductions in brain capillary length and density in our mouse model," says Aron Troen, PhD, the study's lead author. "The vascular changes occurred in the absence of neurotoxic or degenerative changes."...

10. B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice
Aron M. Troen*, Melissa Shea-Budgell, Barbara Shukitt-Hale, Donald E. Smith, Jacob Selhub, and Irwin H. Rosenberg
Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111-1524
Communicated by Leon E. Rosenberg, Princeton University, Princeton, NJ, June 5, 2008 (received for review July 20, 2007)


In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r = −0.757, P < 0.001), and with plasma total homocysteine (r = −0.631, P = 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline...

Diabetes drug breakthrough to ease heart failure impact

[Where do they get the following from???]

But some types of medication — metformin (Glucophage), metformin and sitagliptin (Janumet), glipizide (Glibenese, Minodiab) — also reduce levels of haemoglobin, which can lead to low levels of vitamin B12, says one study. The drugs also appear to reduce levels of succinate dehydrogenase, and in turn, CoQ10.
RISK: Anaemia, muscle cramps, fatigue, memory loss, irregular heartbeat.
PROTECTION PLAN: CoQ10, 50mg to 200mg once or twice a day; Vitamin B12, 500 mcg to 1,000 mcg a day.

Dundee researchers and European collaborators find that anti-diabetes drug fights Alzheimer's
23 November 2010

Diabetes drug could work against Alzheimer’s
Bonn, 24th November 2010. Metformin, a drug used in type 2-diabetes might have the potential to also act against Alzheimer’s disease.

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling.
Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, Williamson R, Fuchs M, Köhler A, Glossmann H, Schneider R, Sutherland C, Schweiger S.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21830-5. Epub 2010 Nov 22.
Source: Max-Planck Institute for Molecular Genetics,14195 Berlin, Germany.
Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.
PMID: 21098287 [PubMed - indexed for MEDLINE] PMCID: PMC3003072
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003072/?tool=pubmed

Life span extension by resveratrol, rapamycin, and metformin: The promise of dietary restriction mimetics for an healthy aging.
Mouchiroud L, Molin L, Dallière N, Solari F.
Biofactors. 2010 Sep;36(5):377-82.
Source: UMR, CNRS Université Lyon, Centre Léon Bérard, France.
Life expectancy at the turn of the 20th century was 46 years on average worldwide and it is around 65 years today. The correlative increase in age-associated diseases incidence has a profound public health impact and is an important matter of concern for our societies. Aging is a complex, heterogeneous, and multifactorial phenomenon, which is the consequence of multiple interactions between genes and environment. In this review, we survey animals models that have been of great help for both investigating mechanism of aging and identifying molecules, which slow down the onset of age-related diseases. Resveratrol (RSV) is one of those. We will report evidences supporting RSV as a molecule that acts by mimicking the beneficial effects of dietary restriction, and may share common downstream targets with rapamycin and metformin. Although those molecules do not reveal all the secrets of the fountain of youth, they may help us maintaining the quality of life in the old age.
PMID: 20848587 [PubMed]




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