Top diabetes drug Metformin causes muscle atrophy by activating AMPK/myostatin

[haidut]

The drug metformin probably needs no introduction here. It is one of the oldest and most widely used drugs for diabetes II worldwide. It is often a so-called first line of therapy for many/most diabetes patients and its mechanism of actions and side effects are fairly well-known. As one of the study quotes below states, up 90% of diabetes II patients are taking metformin. While medicine prefers to ignore/downplay the serious side effects of metformin – lactic acidosis due to metformin being an inhibitor of Complex I of the electron transport chain (ETC) – the “beneficial” effects of metformin are touted non-stop and the general consensus is that metformin works mostly by activating the enzyme AMPK. That enzyme also happens to be activated by “endurance” exercise, fasting / caloric restriction (CR), and/or low-carb diets. The pro-AMPK effects of metformin are the main reason the drug is being promoted as an exercise- or CR-mimetic, which is why metformin is currently a very hot topic in anti-aging and obesity research. It is worth noting that one of the main effects of AMPK activation is increased fatty acid oxidation (FAO), which is another reason metformin is being promoted for diabetes II – i.e. the idea is that burning a lot of fat will lead to leanness and thus reversal of diabetes. Yet, if one looks at metformin from the bioenergetic point of view the drug looks like pure poison. Aside from being able to kill a person through lactic acidosis (30%+ lethal even with emergency medical treatment), massively increasing FAO hardly sounds like something a person would want to induce on a regular basis. Unsurprisingly, several studies have come out in recent years demonstrating that metformin promotes cancer growth by increasing lactate and FAO, while anti-lactate measures such as baking soda are therapeutic. Since AMPK is what drives most of these negative effects of metformin, one would expect that inhibiting AMPK would be therapeutic. Well, see the study below:-)

https://pubmed.ncbi.nlm.nih.gov/24419061/

In further corroboration, using metformin in diabetic patients does not improve the course of the disease. It does lower blood sugar, but that was recently discovered to be due to its inhibitory effects on gluconeogenesis and not due to AMPK activation or increased FAO. Worse, the increased FAO due to metformin would be expected to worsen insulin sensitivity, and multiple studies have confirmed that stopping metformin after taking it for a while results in exacerbation of the diabetes pathology compared to other diabetic patients who did not take metformin at all. So, it is definitely starting to look like metformin is not only not the miracle drug we are being told it is, but is a very dangerous “Trojan Horse”- i.e. masking the symptoms of diabetes, while ruining systemic health and all but ensuring not only worsening diabetes in the future, but possibly even getting cancer in the process. If all that was not enough to change people’s mind on metformin, the study below may add more fuel to the fire. It looks like that not only is metformin potentially detrimental to metabolic health, but its primary target – AMPK activation – seems to lead to muscle atrophy by increasing the expression of myostatin (the primary negative regulator of muscle growth). As most of my readers know, lean muscle mass is the primary regulator of the resting metabolic rate (RMR) and losing muscle mass is just about the worse outcome a person can hope for from a drug, diet or exercise regimen as it would tank their RMR. This has already been corroborated by the (in)famous studies that looked at participants in the “Biggest Loser” (what an apt name) contests. All those people lost a lot of weight through fasting and “endurance” exercise (i.e. AMPK activation), but it turned out that most of their weight loss was from muscle, which resulted in those people’s metabolic rate essentially halving (due to the grueling weight loss regimen) and thus regaining ALL of the weight they lost even while maintaining a reduced calorie diet. Well, it looks like metformin is a great mimetic of the “Biggest Loser” regimen and the muscle loss it induces probably explains a good deal of the lack of long-term benefit from using the drug. Wait, what about fat loss, considering metformin increases drastically FAO by increasing AMPK? Well, it turns our increasing FAO does not result in leanness, so in effect all the mechanisms of action of metformin (except potentially inhibition of gluconeogenesis) are directly disease- and disability-promoting.

https://pubmed.ncbi.nlm.nih.gov/20522000/

“…One mechanism by which AMPK regulates lipid metabolism is phosphorylation and inactivation of acetyl CoA carboxylase (ACC), an important rate-controlling enzyme for the synthesis of malonyl-CoA. ACC is both a critical precursor for biosynthesis of fatty acids and a potent inhibitor of long-chain fatty acyl-CoA transport to mitochondria for β-oxidation. Knockdown/knockout of ACC1 and ACC2 (predominantly expressed in liver and skeletal muscle, respectively), has been reported to cause continuous fatty acid oxidation, increased energy expenditure and reduced fat mass (Abu-Elheiga et al., 2001; Choi et al., 2007; Savage et al., 2006). But recent studies have reported limited effects of ACC2 deletion on fatty acid oxidation in skeletal muscle and overall energy expenditure or adiposity (Hoehn et al., 2010; Olson et al., 2010). These recent reports indicate that increased fatty acid oxidation in skeletal muscle does not cause leanness and raises questions regarding the use of ACC2 inhibitors in the treatment of obesity.”

https://pubmed.ncbi.nlm.nih.gov/34725961/

“…Our findings reveal the role of metformin in the regulation of muscle wasting at the transcriptional level. Although first‐line biguanide metformin is often administered to patients with T2DM, its long‐term administration can cause several side effects, including those that affect muscle function. Currently, the effect of metformin on the muscles is controversial. Blood glucose levels and other conditions can also induce muscle atrophy. Metformin is known to produce a glucose‐lowering effect that is accompanied by improvements in insulin sensitivity; however, it is also known to increase the levels of p‐AMPK and myostatin, a muscle atrophy‐related molecule. Thus, three different arguments arise. A recent study revealed that metformin negatively affects the hypertrophic response to resistance training in healthy older individuals. Because metformin reduces inflammation, the researcher of the study hypothesized that metformin would augment the muscle response; however, the placebo group had more gains in lean body and thigh muscle mass than the metformin‐treated group. 33 Another study suggested that leg lean mass and appendicular skeletal muscle mass were significantly lower in older men with T2DM than in controls. Notably, 87% of patients in the T2DM group received metformin. 30 …”

“…On the other hand, our results support the negative effects of metformin on muscle hypertrophy. Furthermore, our in vivo findings from GC muscles after metformin treatment correlated with our in vitro findings….First, db/db mice administered metformin did not differ significantly from the control group in the grip strength test, but the wild‐type mice administered metformin had a significant decrease in muscle grip strength. Second, the myoglobin level of metformin‐treated wild‐type mice decreased in the serum analysis. Therefore, metformin has a complicated effect on the muscle regulation mechanisms. In db/db mice, the glucose‐lowering effect of metformin may partially offset its muscle‐wasting effect.”

“…Based on our in vitro results, the up‐regulation of myostatin in response to metformin is controlled by activated p‐AMPK, which regulates subcellular localization and ultimately enables binding between FoxO3a and myostatin. In the myostatin promoter region, FoxO3a binds to the putative binding site of myostatin by directly activating its expression. Therefore, it can cause muscle wasting. Because HDAC6 also binds to FoxO3a in this molecular process, we hypothesized that HDAC6‐mediated myostatin up‐regulation might be related to its deacetylation activity. In other words, HDAC6 might regulate acetylated FoxO3a and increase FoxO3a expression. HDAC6 may also regulate muscle atrophy. This study is the first to provide a clear molecular mechanism for the effect of metformin on muscle function. Moreover, we identified the novel muscle atrophy effects of the AMPK‐ and HDAC6‐FoxO3a‐myostatin axis at the transcriptional level. We also identified that the transcriptional and epigenetic pathways induced by metformin could cause muscle wasting and induce negative effects in T2DM patients treated with metformin. To date, a broad range of metformin has been used in experiments. 35 …In the present study, we used 2 mM in vitro and 250 mg/kg in vivo. These doses are slightly higher than the therapeutic concentrations of metformin in patients, but within the ranges of other studies used metformin. In the future, more studies are necessary to define the relationship between dose‐dependent efficacy and the corresponding plasma concentration of metformin.”

Via: http://haidut.me/?p=2724

[cedric]

@haidut
Metformin lowers iron, copper (could be good) ,influences zinc, magnesium, B9, B12, B1, chromium but restores Randle cycle to burn glucose
zinc could lower demand on metformin

metals and gallstones

https://www.sciencedirect.com/science/article/pii/S1015958424011527
The roles of metal ions in gallstones formation
Author links open overlay panelKuinan Tong 1, Chao Jing 1, Tingting Wang, Kun Liu, Wei Guo, Zhongtao Zhang
https://doi.org/10.1016/j.asjsur.2024.05.243

https://ars.els-cdn.com/content/image/1-s2.0-S1015958424011527-gr1.jpg

https://ars.els-cdn.com/content/image/1-s2.0-S1015958424011527-gr2.jpg

AI Metformin disrupts the Randle cycle (glucose-fatty acid cycle) by inhibiting fatty acid oxidation and reducing free fatty acid (FFA) levels, thereby promoting glucose utilization over fats. By inhibiting this cycle, metformin reduces insulin resistance, decreases hepatic glucose production, and restores the body’s ability to utilize glucose efficiently.

Key Aspects of Metformin and the Randle Cycle:Randle Cycle

Overview: The Randle cycle is the competition between glucose and fatty acids for energy oxidation, where high fat levels inhibit glucose uptake and oxidation, promoting insulin resistance.

Mechanism of Action: Metformin reduces the oxidation of long-chain fatty acids, specifically in red muscle, which restores glucose oxidation and reduces the reliance on fat as a primary fuel source.

Impact on Diabetes: By inhibiting this cycle, metformin helps lower elevated blood glucose levels and reduces hypertriglyceridemia, which are common in type 2 diabetes.

Insulin Sensitivity: Metformin-induced inhibition of the Randle cycle improves overall metabolic flexibility and improves insulin sensitivity, enhancing muscle and peripheral uptake of glucose.

Energy Balance: The drug helps reverse the overactive Randle cycle that occurs in obese or diabetic patients, improving the balance between glucose and fat utilization.

Both metformin and zinc appear to have protective effects against gallstones, often through improving metabolic health and reducing gallbladder inflammation. While they are frequently used together for diabetes management, their individual roles in gallbladder health are distinct.

Metformin and Gallstones

**Reduced Risk: Long-term use of metformin is associated with a significantly lower risk of developing gallstones in diabetic patients.

Mechanism: Metformin helps by improving insulin sensitivity and gallbladder motility, which prevents the "stasis" of bile that leads to stone formation.**

Animal Research Warning: In some mouse studies, while metformin prevented stones, it was also linked to porcelain gallbladder (mucosal calcification), though it is unclear if this occurs in humans.

Zinc and Gallstones

Zinc Deficiency Connection: Patients with gallstone disease often have significantly lower serum zinc levels.

Protective Properties: Zinc may help prevent gallstones by reducing free radical formation and protecting against oxidative stress in the liver and gallbladder.

Bile Flow: Supplementation has been shown in animal models to suppress liver fibrosis and improve the composition of bile, potentially aiding in stone prevention.

Taking Zinc and Metformin TogetherSynergy: For diabetic patients, combining zinc and metformin can be more effective than metformin alone for overall metabolic health.

Safety: There are no known direct drug interactions between zinc supplements and metformin.

Metabolic Benefit: Both substances help lower HbA1c levels and improve lipid profiles (cholesterol/triglycerides), both of which are key risk factors for gallstone formation.

Zinc deficiency causes significant muscle loss (muscle atrophy), reduced muscle strength, and impaired muscle repair, as zinc is essential for protein synthesis, cell growth, and tissue regeneration. Severe deficiency increases muscle protein breakdown (catabolism), reduces muscle mass, and is an independent factor for sarcopenia.

Zinc Deficiency and Muscle Loss Mechanisms:Reduced Protein Synthesis & Regeneration: Low zinc levels restrict muscle regeneration by slowing down myogenesis (muscle cell formation) and impairing muscle cell activation.

Increased Breakdown: Deficiency disrupts skeletal muscle proteostasis, activating the ubiquitin-proteasome system, which breaks down muscle proteins.

Mitochondrial Dysfunction: Zinc is crucial for mitochondrial health; its lack can lead to impaired mitochondrial function, reducing energy supply (ATP) for muscle cells.

Hormonal Imbalance: Zinc deficiency can lead to lower levels of testosterone and growth hormone, which are essential for maintaining muscle mass

.Chronic Diseases & Aging: In patients with chronic liver disease, zinc deficiency is an independent predictor of sarcopenia (age-dependent loss of muscle).

Zinc acts as a modulator of AMPK (AMP-activated protein kinase), a key cellular energy sensor, influencing its activity in ways that can be beneficial or harmful depending on the context. It helps maintain metabolic homeostasis and is crucial for muscle protein synthesis, with zinc deficiency often increasing susceptibility to muscle atrophy via AMPK.

Key Aspects of Zinc-AMPK Interaction:Muscle Metabolism: AICAR (an AMPK activator) increases intracellular zinc levels, and zinc-depleted conditions lead to greater muscle atrophy under stress.

Neural Protection: Zinc can regulate glucose metabolism in spinal cord neurons via the AMPK signaling pathway. It has been shown to induce autophagy and protect against neuronal apoptosis following injury.

Neurotoxicity Mechanism: Excessive free zinc (zinc excitotoxicity) can trigger neuronal death by overactivating the LKB1-AMPK-Bim cascade, leading to ATP depletion.

Metabolic Regulation: Zinc affects the AMPK pathway by modifying the Thr172 phosphorylation of AMPK, which in turn regulates downstream targets like ACC (acetyl-CoA carboxylase).Cellular Energy: Studies suggest zinc exposure can influence energy metabolism by activating the AMPK pathway.

In summary, zinc helps regulate AMPK activity, with appropriate levels aiding in energy management and tissue health, while excessive free zinc can trigger toxic, AMPK-dependent cell death.

Signs of Zinc-Related Muscle Issues: Difficulty gaining or maintaining muscle mass.Reduced endurance and increased muscle fatigue.Slow recovery after exercise.Slow wound healing.

Important Context:Athletes: Athletes are susceptible to zinc loss through excessive sweating and elevated metabolic demand, necessitating adequate intake to avoid muscle performance decline.

Cancer Cachexia: Interestingly, excess zinc accumulation in muscles—driven by a protein called ZIP14 during severe illnesses like cancer—can also lead to severe muscle wasting, not just deficiency.

Ensuring adequate zinc intake through diet (meat, shellfish, legumes, nuts) is key to preventing this type of muscle loss.

Insulin-degrading enzyme (IDE), or insulinase, is a zinc-dependent metalloproteinase (~110 kDa) that breaks down insulin, amylin, and other small polypeptides. It plays a crucial role in regulating insulin levels and is a key target in diabetes research. It is often found in the cytoplasm of human cells and acts with a unique (HXXEH) zinc-binding motif.

Key Details About Zinc Insulinase (IDE):Function: Degrades insulin, amylin, glucagon, and amyloid (\beta ) (A(\beta )).

Structure: It belongs to the M16 metalloprotease family and requires zinc as a cofactor for activity.

Location: Found in mammalian cytosol, peroxisomes, and endosomes.

Alternative Names: Insulysin, insulin protease, or bacterial protease III (in E. coli).

Medical Relevance: Because it degrades insulin, IDE is studied for its impact on insulin resistance and type 2 diabetes.

Key Characteristics:Active Site: Unlike many zinc proteases, it uses an "inverted" (HXXEH) motif to bind zinc.

pH Stability: The enzyme has an optimal pH around (7.0).Inhibitors: Its activity can be inhibited by endogenous factors or specific compounds.