Dangers of metformin, Mitochondria dysregulation, Alazhimers, B12 Deficiency, Neuropathy, Blunts muscle growth, Increases metabolic disease risk.
Metformin, A drug touted in bodybuilding circles for its amazing benefits. Many suggesting its use for improved muscle building and health due to improved insulin sensitivity. But, these effects do not come without risk, nor are all said benefits true either.
So let’s start picking away at metformin’s faults one by one.
B12 deficiency associated with metformin use.
What are some issues with b12 deficiency? Constipation, loss of appetite, bloating, muscle weakness and of course required in cell division for muscular growth. All amazing features that can really hamper your bodybuilding goals right? Let’s not forget neuropathy a lovely side effect as well which can cause loss of proper contraction of muscles leading to muscle atrophy as well.
“Long-term therapy with metformin was shown to decrease the Vitamin B12 level and manifested as peripheral neuropathy.
Even short-term treatment with metformin causes a decrease in serum Cbl folic acid and increase in Hcy, which leads to peripheral neuropathy in Type 2 diabetes patients. A multicenter study with heterogeneous population would have increased the power of the study. We suggest prophylactic Vitamin B12 and folic acid supplementation or periodical assay in metformin user.”
Elevated homocysteine levels and erectile dysfunction and cardiovascular disease?
“This establishes a dose-dependent association between Hcys and ED. Furthermore, we showed that Hcys was an earlier predictor of ED than Doppler studies, as the Hcys increase was present in patients with mild ED even before abnormal Doppler values.”
“Serum Homocysteine Levels in Men with and without Erectile Dysfunction: A Systematic Review and Meta-Analysis”
Results from our meta-analysis suggest that increased levels of serum Hcy are more often observed in subjects with ED: based on existing literature on this topic, a causative role for HHCy as an independent risk factor for ED can be postulated, although confirmation would require interventional studies aimed to decrease serum Hcy levels considering erectile function as primary outcome. Actually, only in rat model of HHcy has been observed an improvement in erectile function after being treated with a demethylation agent . We also reported significantly higher levels of Hcy in subjects without diabetes, compared to diabetic men: while we can assume that this is further proof of a multifactorial pathogenesis for ED, it is also a clear indication that future research in this field should investigate the possible association with other known risk factors—such as smoking habit and obesity—in order to adequately address the possible effects of different variates.
“Association of Metformin, Elevated Homocysteine, and Methylmalonic Acid Levels and Clinically Worsened Diabetic Peripheral Neuropathy
RESULTS Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences.”
Alzheimer’s risk increased.
Well not much to talk about this one, I am sure we all know what Alzheimer’s is. Well, metformin has a direct effect on amyloid plaque and increasing Alzheimer’s risk.
“Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription.
Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.”
“Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation.
Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.”
Blunts muscle growth due to inhibiting mTOR pathway.
“Maintenance of skeletal muscle mass is regulated by the balance between anabolic and catabolic processes. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, and is known to play vital roles in protein synthesis. Recent findings have continued to refine our understanding of the function of mTOR in maintaining skeletal muscle mass. mTOR controls the anabolic and catabolic signaling of skeletal muscle mass, resulting in the modulation of muscle hypertrophy and muscle wastage.”
Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial
Mitochondria dysregulation and metabolic diseases?
Another great feature of metformin is its ability to lower mitochondria respiration. Mitochondria respiration being, “Mitochondrial respiration is the set of metabolic reactions and processes requiring oxygen that takes place in mitochondria to convert the energy stored in macronutrients to adenosine triphosphate (ATP), the universal energy donor in the cell.”. Your whole body cellular energy as a whole. Lowered mitochondria respiration is linked to a whole host of metabolic diseases such as the ones listed in the said study below, heart failure and obesity. But lastly, we cannot forget the shortened life span/aging effects of mitochondria respiration being lowered.
“Nevertheless, these diminutive mitochondria may have a strong influence on cellular metabolism and susceptibility to metabolic diseases like heart failure or obesity, according to preliminary research by Scott Ballinger, Ph.D., professor of pathology at the University of Alabama at Birmingham.
“For 50 years, researchers have tried to find disease susceptibility using Mendelian genetics,” Ballinger said, speaking about studies of the chromosomal genes in the cell nucleus. “But this explains only 10 percent of the reasons for susceptibility to disease.”
Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.”
“Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.
Late life metformin treatment limits cell survival and shortens lifespan.
Metformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion.
Old cells fail to upregulate glycolysis as a compensatory response to metformin.
The dietary restriction (DR) mimetic response to metformin is abrogated in old animals.
PKA and not AMPK pathway instigates the early life DR response to metformin.
Stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo.
The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented.”
“Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin’s effect.”
Metformin’s effects on insulin sensitivity were equal to that of antibiotics showing its effects are mainly mediated via the gut.
“Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.”
“Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice.
In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin.
Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.”