44 replies to this topic

[goku]

Just like people's opinion -- thinking of adding this -- what's the general consensus? As I feel like the opinions are mixed and there are disadvantages such as it can lower testosterone levels -- I use exogenous so I don't care all that much -- but just curious.

[tintinet]

Dunno- maybe worth low dose. Might be helpful to check yer blood glucose, and, if feasible, insulin levels before and after starting it.

[asnufu]

Might be a good idea to monitor test levels periodically, and monitor glucose & insulin while cycling metformin. On & off periods would allow you both determine efficacy and see if gluconeogenesis is affected at all, as shepard speculated in "the metformin club" thread.
If resv was guaranteed to actually work = become bioavailable, it would be the first choice, but until then, metf appears to be the only substance that consistently effects changes in gene expression similar to CR (of course, you have to believe that's worthwhile, but everyone here seems to do so [glasses]).

[Brainbox]

Merged goku's question and various answers into this one.

[ilanso]

I've been on metformin (2 * 500) for about two years (not a diabetic) and dropped it cold turkey 3 weeks ago. My August blood works showed signs of incipient anemia (for the first time, out of range RDW (H) and MPV (L) values, MCV and MCH normal but borderline high, hematocrit and RBC down) without specifically pointing to a B12 or folate shortage (of which I am taking 1 and 0.8 g/d respectively). My homocysteine was also abnormally high (16.1).
There are no physical symptoms. On the positive side, my fasting glucose had reached 54, down from 98 in '05. Yesterday, after the 3 week non-metf. break, the FBG returned to the old 98 value.
Some research pointed me to a relatively uncommon side effect regarding the intrinsic factor, without which no matter how much B12 one takes, the absorption is impaired.
Here are a few references:

Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy.
Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS.

In a survey of 46 randomly selected diabetic patients on biguanide therapy, 30% had malabsorption of vitamin B12. Withdrawal of the drug resulted in normal absorption in only half of those with malabsorption. In most patients with persistent malabsorption, the results of absorption tests with exogenous intrinsic factor suggested the diagnosis of coincidental intrinsic factor deficiency. Further considerations, however, led to the concept that biguanides can induce malabsorption by two different mechanisms. One of these is temporary and unrelated to intrinsic factor secretion and the other is permanent and mediated by depression of intrinsic factor secretion.

PMID: 6825978 [PubMed - indexed for MEDLINE]

Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides.
Caspary WF, Zavada I, Reimold W, Deuticke U, Emrich D, Willms B.

Since vitamin B12malabsorption has been described in diabetics on biguanides and inhibition of bile acid absorption found in rat ileum the effect of treatment with different biguanides (phenformin, buformin, metformin) on bile acid metabolism and vitamin B12 absorption was assessed in maturity onset diabetics. Biguanides did not alter faecal weight or faecal fat excretion, but they decreased faecal bile acid excretion. All biguanides tested increased deconjugation of glycocholic acid, as determined by a simple breath test technique. Vitamin B12 malabsorption was most prominent in patients on metformin. Discontinuation of biguanide treatment, or administration of antibiotics, normalized or improved the increased deconjugation of bile acids and the Schilling test. Decreased faecal bile acid excretion, positive 14C-glycocholate breath tests, pathological Schilling tests and the reversal of pathological tests by antibiotic treatment suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic-factor-vitamin B12-complex to bacteria, is responsible for the previously observed pathological Schilling tests in diabetics on biguanides. Bile acid malabsorption, possibly responsible for the cholesterol-lowering effect of biguanides, does not occur in diabetics on biguanides. Whether qualitative changes in small intestinal bile acid composition might affect cholesterol metabolism remains to be determined.

PMID: 873086 [PubMed - indexed for MEDLINE]

Risk factors of vitamin B(12) deficiency in patients receiving metformin.
Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM.

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 - indexed for MEDLINE]

VITAMIN B12 MALABSORPTION. Of patients who take this drug, 10%-30% show evidence of reduced vitamin B12 absorption. A substance formed in the stomach called "intrinsic factor" combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of your cells to absorb this intrinsic factor-vitamin B12 complex.(12)

Over the long term, vitamin B12 insufficiency is a significant health risk. B12 is essential to the proper growth and function of every cell in your body. It's required for synthesis of DNA and for many crucial biochemical functions. There is also a link between B12 insufficiency and cardiovascular disease.

At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people.(13) The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.

ELEVATED HOMOCYSTEINE. People who take Glucophage tend to have higher homocysteine levels.(14) Women with PCOS also tend to have elevated homocysteine.(15)

Homocysteine is an amino acid in the blood. A normal amount is OK. But an elevated level means that your metabolic processes are not working properly. Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia,(16) cognitive impairment.(17), and cervical cancer. (18)

Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances (19). Therefore, when metformin reduces absorption of vitamin B12, you lose one of the nutrients needed to reduce homocysteine and thus reduce your risk of cardiovascular disease.

I am anxious to be persuaded (see quote below) to resume taking it, probably at half the dose I used to, depending on the outcome of my next CBC panel sometime next week. Supposedly, the condition is reversible with massive B12 and calcium. Will see. Then again, the anemia-ish state could be caused by some recent CR.



http://www.topcancer...man-tumor-cells

A new study reported in Cancer Research shows that a common diabetes drug, metformin, kills human tumor cells in mice that lack p53, a key regulatory gene.

In more than half of all human cancers, the p53 gene has been lost. However, scientists have not been able to figure out how to compensate for this loss yet. Unlike a genetic mutation that changes the function of gene that can then be targeted with a drug, the loss of a gene also means the loss of a target.

Metformin activates AMP-activated protein kinase which affects p53 function. Two earlier observational studies have shown that diabetics who take metformin have a lower rate of cancer incidence and mortality than other diabetics. According to the researchers, if preclinical trials continue to be promising, metformin could be used as a cancer therapy quickly as it is already approved by the FDA for use in humans.

Edited by ilanso, 17 September 2007 - 06:29 AM.

[asnufu]

Ilanso, that's disturbing; I supplement 2*850mg myself, and was aware of the B12 deficiency risk which is why I supplement heavily with extra B12, but I wasn't aware that the condition might be irreversible. From what I gather, only a certain percentile of chronic users are affected, though ? The homocysteine count is not pleasant to look at, either.

Have you been supplementing with B12 and calcium while on metf, and if so, how much ?

[Fredrik]

Some research pointed me to a relatively uncommon side effect regarding the intrinsic factor, without which no matter how much B12 one takes, the absorption is impaired.

You don´t need intrinsic factor to absorb B12. If you take large enough amount at least 1% will get absorbed by passive diffusion. No intrinsic factor needed. That´s why oral vitamin B12 still can treat elderly with malabsorption (to little stomach acid).

[asnufu]

Fredrik, that's good to know. Also, I see from research that calcium + b12 supplementation should offset any deficiency that may occur

http://care.diabetes...tract/23/9/1227

ostensibly, this would also hold if one suffers a permanent deficiency due to old age, as you suggest, or metf use...

[ilanso]

I was already taking 1g a day (2 * 500, time release).
After the blood test, I started with an additional 1g sublingually, aiming to restore the deficit.
The RDA is 6 mcg and optimum intake 25-300 mcg. On a 1% sublingual absorption rate, for optimum I would need 2.5-30g a day, which seems like a lot. Of course, I ignore the percentage, however reduced, that still gets converted in the gut via whatever's left of my the intrinsic factor.
Again, my test endpoint is not B12 itself, but the effects down the line (RDW, hematocrit, etc). I wonder how many feedback cycles I need to be able to adjust my B12 intake toward normal lab test values, and once there, how many more when I resume taking 500mg metformin.

[bgwowk]

You must surely mean mg of B12, not grams. 1 mg (milligram) = 1000 mcg (micrograms)

[ilanso]

You must surely mean mg of B12, not grams. 1 mg (milligram) = 1000 mcg (micrograms)

Yes, mg, I stand corrected (This thing happens for the lack of the greek mu character). So to get 300 absorbed micrograms a day at 1% rate, I would need 30 mg, or a whole 30 1000mcg pill bottle.

[tintinet]

Ya could always go for the fun of B12 injections!

[krillin]

You must surely mean mg of B12, not grams. 1 mg (milligram) = 1000 mcg (micrograms)

Yes, mg, I stand corrected (This thing happens for the lack of the greek mu character). So to get 300 absorbed micrograms a day at 1% rate, I would need 30 mg, or a whole 30 1000mcg pill bottle.

Even with intact intrinsic factor, you don't absorb all 300 mcg of a 300 mcg dose.

http://books.nap.edu...d=6015&page=308

Adams and colleagues (1971) measured fractional absorption of radiolabeled cyanocobalamin and reported that nearly 50 percent was retained at a 1-mcg dose, 20 percent at a 5-mcg dose, and just over 5 percent at a 25-mcg dose. [. . .] Although evidence indicates that a B12 content of 1.5 to 2.5 mcg/meal saturates ileal receptors and thus limits further absorption (Scott, 1997), absorption of as much as 7 mcg in one subject (18 percent) was reported from a serving of liver paste that contained 38 mcg of B12 (average absorption was 4.1 mcg or 11 percent) (Heyssel et al., 1966).

[asnufu]

It seems to me that this is more circumstantial evidence that metf is a cr mimic, but maybe there's a not-so-rosy explanation instead. Comments ?

CONCLUSIONS: We conclude that initiation of metformin treatment in type 2 diabetic patients is associated with improved diabetes control as well as with activation of oxidative stress together with antioxidant system. The atherogenic process measured by biochemical indicators is diminished in parallel

http://www.ncbi.nlm....l=pubmed_DocSum

Edited by asnufu, 24 September 2007 - 12:07 PM.

[tintinet]

Point taken that metformin may not be unqualified beneficial agent. Nonetheless, overall beneficial outcome, for diabetics, evidently.