Essay: Metformin

Besides eating, one must consume water. There is a reason why people could survive 40 days without food but only a couple without water. Hydration is a key point to your success. Your body is made up to 60% water. Water is extremely important, especially for blood. 92% of your plasma is made up of water and the plasma is 55% of your blood. That means water is 50.6% of your blood. Blood is extremely important for delivering your red blood cells (RBC) around your body and delivering O₂ to the tissues, such as your muscles. When you sweat, you lose water, the total blood volume decreases, and the ratio between RBC: total blood volume increases. When that ratio increases, the blood flow decreases and there is less blood flow that goes to your tissue. How do we fix that? By drinking water. When you exercise, the metabolic heat production increases by 15-20 times than at rest.11 Because of the increase in heat production, your body sweats to limit the increase in body temperature. However, yo lose water and electrolytes, such as sodium, potassium, and magnesium, because of sweating. According to Maughan, fatigue accrues more quickly when a person is dehydrated, as the dehydrated person will have an increase core temperature and higher heart rate.11 The increase in core temperature is because the body has less water to release. The increase in heart rate is because the body has to work harder in order to maintain the same cardiac output when there is less stroke volume.4 The recommended intake should be about the amount that you are sweating.5 However, water should not be consumed more than what you are sweating during exercise. I recommend that you should have CHOs in your water, like Gatorade, to have extra CHO fuel for your body during exercise and to decrease the settling of fatigue.
Another important factor to fluid intake are electrolytes. Electrolytes play an important role in maintaining osmolarity, as well as nerve impulse conductivity. Sodium and chloride are usually well consumed, but with the amount of training and sweating you will encounter, consuming them in the fluids will be beneficial. Maughan states that consuming these essential electrolytes are crucial to athletes who sweat a lot.11 The replenishing of sodium and chloride helps with kidney mechanisms, osmolarity of the blood, and better blood volume as the sodium and chloride helps retain the water intake. Another important electrolyte is potassium. Potassium is a cation that assists with muscle contractions, nerve impulse conductions, and the growth and repair of muscles. Potassium, unlike sodium and chloride, does not sweat out easily, but it can especially in hot conditions. If you lost that electrolyte, Schauss states that it could affect blood flow, energy stores, and muscle functionability.13 Without potassium, your training performance (if you lost it) would decline. Lastly, magnesium is another important cation. It’s usually found in bones, but the rest is found intracellularly with potassium.9 Magnesium has a lot of jobs that include blood sugar maintenance, protein synthesis, energy metabolism, and the transportation of potassium and calcium.9 Like potassium, magnesium does not really get excreted during sweat, however there are two problems: 1) the average diet does not consume enough magnesium and 2) magnesium levels go to suboptimal levels during high levels of physical activity.12 Magnesium is mainly found in whole-grain foods and leafy green vegetables, so consuming these foods will be important, plus they offer good complex CHOs to add to your CHO calories and will help you feel good when you eat well. As for benefits of magnesium, the levels of magnesium decrease during exercise and the reason is unknown as of now. For now, you should consume as much water as you are sweating during exercise. If you are thirsty, drink water. It is your body telling you that you need water. As for the electrolytes and minerals, you should eat more vegetables and add electrolytes to your water while you train to replenish your body for when you sweat.
Vitamins
Vitamins are essential for your body’s function. They assist with metabolism, nerve impulses and a ton more. I will discuss a couple of vitamins that could help, and some that will help. First is Vitamin D, with the help of calcium.12 The point of calcium is that it helps with the mineralization and promotion of bone. However, vitamin D improves calcium absorption.12 There have been conflicting reports for whether it actually helps with exercise performance, but the point of it for you is to reduce the risks of bone fractures. The best way to consume vitamin D is through the sun, which you will get in sunny San Diego, but calcium could be obtained through milk. If you do not consume enough calcium, your body will start to breakdown the bone to obtain the calcium. With vitamin D and calcium, vitamin K has been shown to enhance performance. The job of vitamin K is to prevent blood clotting, but also to help synthesize proteins for bone growth. In a study by Craciun et al., participants who took vitamin K had greater levels of osteocalcin and a higher ratio of osteoblastic biomarkers to osteoclastic biomarkers.7 Vitamin K was shown to improve bone density in athletes, which in turn provides better bone strength. The last two vitamins are vitamin E and vitamin C. They are both antioxidants that are important for the immune system. Vitamin E’s main job is to neutralize electron-scavenging molecules, such as free radicals, and to give one of vitamin E’s electron to the free radical. This is crucial to you because exercise induces a lot of free radicals. In a study by Viña et al. discussed the extra production of free radicals induced by high-intensity exercise could cause serious damage to DNA, protein structures, and fats.14 Even though he showed that vitamin E, nor C, enhance performance, he discussed the idea that these antioxidants that could improve your immune system and reduce your oxidative stress levels.14 These vitamins are important, but not crucial, to your success. I would recommend these vitamins to you and these could all be obtained straight from your diet.12
“More than 30 million Americans have diabetes.”1 That is about a ratio of 1:10. Imagine if this room represented the population of the U.S., 10% of this room would have diabetes.1 According to the National Institute of Diabetes and Digestive and Kidney Failures, some of the problems type II diabetes (T2D) could cause include heart disease, stroke, hypoglycemia, kidney disease, and diabetic neuropathy.8 To treat diabetes, people could give themselves insulin shots, an insulin pump that gives you small doses throughout the day, or even orally through a pill. The most common type of T2D pill, according to the NIDDK, is metformin.8 The purpose of metformin is to lower the production of glucose by the liver and help the body better utilize insulin. This discussion will hopefully help explain the molecular pathways of this process and how metformin affects exercise.
The reason why metformin is the most commonly prescribed drug is due to its ability to decrease glucose production by the liver and also its ability to lower insulin resistance, but how? According to Foretz, metformin is a hydrophilic drug that has properties to make passive and rapid diffusion very unlikely to occur.2 The intestines uptake metformin through the molecular transporter of plasma membrane monoamine transporter (PMAT). This transporter is located on the lumen side. The basolateral side contains another transporter, Organic cation transporter 1 (Oct1), to transport metformin into the interstitial fluid.3
Metformin-induced AMPK activation is important for understanding the molecular mechanism behind inhibiting glucose production. Hepatocytes are what produce glucose in the liver. In a study done by Shaw in 2005, liver kinase B1 (LKB1) was found to be an important factor in lowering blood glucose levels.9 The purpose of LKB1 is that it phosphorylates and activates AMPK and its location is upstream of AMPK. Shaw et al. found that metformin reduced blood glucose in the ob/ob mice by 40%, however when LKB1 was removed from the liver, there was not a decrease in the amount of blood glucose in the mice.9 LKB1 regulates AMPK and SIK. AMPK and SIK phosphorylate TORC2 (a transcriptional coactivator) and downregulate transcriptional events that would inhibit gluconeogenesis. However, gluconeogenesis can occur when SIK and AMPK are not active to phosphorylate TORC2 when LKB1 is absent.9
Metformin also has another molecular mechanism to decrease gluconeogenesis. In an article by He, metformin was shown to phosphorylate CBP via PKCι/λ at serine 436.4 CBP is a transcriptional co-activator that sets off a cascade of events for dissociating CREB, CBP, and then TORC2. The phosphorylation of TORC2 reduces gluconeogenesis by downregulating transcriptional events.4
Another mechanism was published by Miller et al. who discussed the idea that metformin suppress hepatic glucagon signalling by decreasing production of cyclic AMP.7 Here, the article discussed how the fasting glucose levels decreased because metformin counteracted the effects of glucagon. Normally, glucagon binds to its receptor which stimulates PKA, produces cAMP, and activates adenylate cyclase. These three help with gluconeogenesis. Miller’s study examined the hepatocytes of mice and how metformin increased the amount of AMP and ADP (Figure 1)7. The increase of AMP and ADP led to the inhibition of adenylate cyclase. The increase of AMP and ADP meant that there was a decrease in ATP levels. Less ATP causes the amount of cAMP to be lower and the activity of PKA to decrease. The decrease in ATP also limits the amount of glucose that can be produced through gluconeogenesis as ATP is required to make glucose. The increase in AMP levels inhibited one of the major enzymes in gluconeogenesis, 1,6-bisphosphatase. As cAMP was reduced, AMPK was upregulated. In one of the studies, diabetic mice were fed a high fat diet for 10 weeks. Half were given metformin while the other half were control. The mice all had elevated liver AMP and fasting blood glucose levels. After metformin was administered, the mice that received metformin had higher AMP levels and lower blood glucose levels. Ultimately, metformin led to an increase in AMPK phosphorylation due to the upregulation of AMP and ADP. Since AMPK was phosphorylated, ACC was upregulated, which inhibits lipogenesis and upregulates fatty acid oxidation.
The inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD) could also be a mechanism for metformin to decrease hepatic gluconeogenesis. mGPD is a redox shuttle enzyme that was found by Midaraju et al. alter redox state of the liver cells and decrease the conversion of glycerol and lactate to glucose.6 According to Madiraju et al., the other mechanisms discussed earlier suggest “that metformin suppresses gluconeogenesis independently of AMPK.”6 Rather, it changes the energy charge of the liver and provokes inhibition of either glucagon-induced upregulated transcription of glucose and adenylate cyclase or the inhibition of glycolytic enzymes. The problem according to Madiraju is that the adenine-nucleotide levels of the liver do not change because of metformin. This demonstrates the above hypotheses to be inconsistent.6 Madiraju examined the effects of metformin on endogenous glucose production (EGP) and found that metformin decreased the production of EGP. They also found that metformin increased the redox rates of the cytosol and decreased the redox rates within the mitochondria. Due to the increase of the redox state of the cytosol, the amount of lactate in the plasma also increased. They measured this by using an EPG inhibitor. Another interesting examination was that the ratios of [NADH]:[NAD+], [NADPH]:[NADP+], [ATP]:[ADP], [ATP]:[AMP], or liver [cAMP] all remained the same before and after metformin treatment. Due to the increase of the redox state in the cytosol, and decrease in the mitochondria, Madiraju et al. examined the effect of metformin on the glycerophosphate shuttle. In Figure 2, we can see the inhibition of the mGPD would not allow glycerol of glycerol-3-phosphate (G3P) to be phosphorylated and converted to dihydroxyacetone phosphate.6 The glycerophosphate shuttle is necessary for gluconeogenesis, but the inhibition of mGPD blocks the shuttle and inhibits gluconeogenesis from glycerol. The inhibition of mGPD also leads to an increase in the amount of NADH in the cytosol. This accumulation creates an environment that is unfavourable for LDH so lactate can be converted back to pyruvate. Metformin inhibited glucose production from glycerol and lactate. However, the gluconeogenesis that derived from alanine, dihydroxyacetone, or pyruvate entered was normal because those substrates are able to undergo gluconeogenesis without increasing the ratio of [NADH]:[NAD+].
All of these mechanisms had the same end goal: to stop the liver from creating more glucose so that there would be less glucose in the blood. It is successful, but how does metformin affect exercise performance of a person with diabetes when glucose is critical.
To find out what happens to exercise when a person takes metformin, we need to know what happens to exercise performance when gluconeogenesis is inhibited. John-Adler et al. examined what would happen running endurance when gluconeogenesis was inhibited.5 He used 3-mercaptopicolinic (3MPA), a gluconeogenic inhibitor, for half the rats while a placebo was used for the other half. As shown in Figure 3, blood glucose and lactate are shown at rest, 90 minutes and a third point.5 For the placebo group, the time was 130 minutes, but for the 3MPA group, it was until expiration because the rats of the 3MPA exhausted before the 130 minute mark. At rest, that blood glucose and lactate levels were not significantly different. The interesting finding of this study was blood glucose levels increased during exercise as time prolonged for the placebo group, but decreased for the 3MPA. The rats became hyperglycemic under placebo during exercise, while the rats became hypoglycemic under the 3MPA. Another important finding was in the blood lactate levels and how they increased throughout exercise for both groups. The metabolic profile of lactate concentrations, free fatty acid and glycerol were the same between both groups, however the difference came with the amount of blood glucose during exercise that caused the difference in exercise performance.
The inhibition of gluconeogenesis decreased the amount of blood glucose. During exercise, your muscles uses the energy that is closest to its myocytes. That storage contains muscle glycogen. However, that storage of glycogen depleted during exercise and constantly needs to obtain glucose from the blood to maintain energy output. However, the blood glucose levels are sensitive and gather glucose from the liver, via gluconeogenesis, to maintain homeostatic balance as it delivers glucose to the muscles. When a person takes metformin, gluconeogenesis is inhibited, and thus less glucose is being delivered to the muscle for energy during exercise. Therefore, exercise performance is inhibited when a person takes metformin.5
Even though the molecular mechanism for how metformin works is in question, the function of what metformin does is not. The function of metformin is to inhibit gluconeogenesis. This is great for a person with T2D because less glucose will be inputted into the blood because of the downregulation of making glucose in the liver. Therefore, a person with T2D does not have to release as much insulin to extract the glucose from the blood when the blood does not even become as hyperglycemic. However, metformin has a big negative. It hurts exercise performance. By inhibiting the production of glucose, the body does not create as much fuel and cannot expend the energy it does not have. Since there is an inhibition of gluconeogenesis, exercise could cause hypoglycemia, glycogen depletion, lactacidemia and fatigue. Overall, metformin is good for type 2 diabetics, but not for type 2 diabetics who exercise.