Metformin - Fountain of Youth or Muscle Destroyer?

Metformin is one of the most effective drugs for the treatment of type 2 diabetes. This type of diabetes is the form where the body does not respond effectively to insulin, primarily because the insulin receptor has become desensitized. Since one of insulin’s primary functions is to shuttle sugar from the blood into the cell, the loss of insulin function seen in type 2 diabetics usually causes problematic increases in blood sugar. Metformin is able to combat this elevation in blood sugar by suppressing the production of glucose by the liver while also restoring the insulin response.

Interestingly, metformin has also been shown to increase the life span in many different species such as worms and mice.^1,2 Additional epidemiological data has shown that humans with type 2 diabetes who took metformin for an extensive period of time to treat their diabetes had a lower occurrence of many other life-threatening diseases, including heart disease and cancer.³ In fact, this data is so compelling that other scientific groups are going to see if metformin intake by individuals who don’t have diabetes but have other health conditions, including cancer and heart disease, can forestall the progress of the diseases they already have. Of course, prevention of these diseases would likely increase the life span of each subject, giving metformin the remarkable capacity to function as a molecular “Fountain of Youth.”

Increasing Insulin Action and Life Expectancy by Activating AMPK

So, what is it about metformin that gives it the remarkable capacity to reestablish insulin signaling and increase life span? Well, this capability most certainly stems, in large part, from the ability of metformin to activate the enzyme AMPK.⁴ The AMPK enzyme is the cell’s energy regulator that is normally activated when cellular energy is depleted, such as when you exercise or reduce caloric intake while dieting. Upon activation, AMPK turns on processes that produce cellular energy, such as fatty acid oxidation, which burns body fat and ultimately recharges cellular energy levels. The activated form of AMPK also turns off biochemical pathways that consume energy, such as cholesterol biosynthesis. Of course, the loss of body fat and reduced cholesterol levels caused by AMPK activation will positively contribute to one’s life span. Consequently, the ability of metformin to activate AMPK and lower body fat and cholesterol levels most certainly promotes the life extension seen with metformin use. In addition, the activated form of AMPK also boosts insulin signaling by directly restoring the insulin receptor’s response to insulin, while also increasing the amount of glucose transporters on the cell surface. As a result, the activation of AMPK by exercise, dieting or metformin enhances insulin function.

Combating Insulin Resistance

Because of the fat-burning qualities associated with metformin, the unprescribed use of this drug to boost fat loss has increased. In addition, the insulin-sensitizing effect caused by metformin has also apparently attracted attention from those using black-market growth hormone (GH) for performance enhancement, as use of GH can induce insulin resistance.⁵ Growth hormone is a protein molecule secreted by the anterior pituitary gland that functions by binding to the growth hormone receptor found on the cell surface of many different organs and tissues within the body. The binding of GH to the receptor triggers biochemical-signaling cascades that powerfully stimulate an anabolic environment, supporting greater muscle growth. One of the primary ways that GH triggers muscle growth is by binding to growth hormone receptors found on liver cells, driving the production of the insulin-like growth factor 1 (IGF-1), which stimulates muscle growth by binding to the IGF-1 and insulin receptor, increasing muscle cell protein synthesis.⁶ Of course, the extraneous amounts of GH that are typically used for performance enhancement tend to overstimulate the insulin-signaling machinery, triggering several negative feedback mechanisms within this system, inducing insulin resistance. As a result, some have used metformin to diminish insulin resistance caused from the use of too much GH.

Reducing Testosterone Production and Function

From a biochemical perspective, the use of metformin for superior fat loss, or to mitigate insulin resistance caused by GH use, may seem like a good idea at first glance. Yet the truth is, not only is it dangerous to use a prescription drug like metformin without the guidance of a physician, but side effects caused by metformin make the use of this drug for the aforementioned reasons an even worse decision. More specifically, this is because studies have shown that metformin has a negative effect on the muscle-building hormone testosterone, which would unquestionably negate most, if not all, of the muscle-building influence from GH use while also increasing the proclivity to gain body fat— thus countering any consistent reason to take metformin along with GH.

The first study investigating the negative impact of metformin on testosterone revealed that consuming 850 milligrams of metformin twice a day for two weeks had several negative influences on testosterone in healthy, young male subjects.⁷ The first adverse consequence being a reduction in total testosterone levels and the second, more deleterious, consequence being a decrease in the biologically active form of testosterone, which is the form of testosterone that stimulates muscle growth.

In addition to metformin reducing testosterone levels, a second study looked at the negative impact that metformin had on testosterone function.⁸ In this investigation, a group of scientists from China determined that metformin reduced levels of the testosterone receptor in prostate cancer cells in vitro. The loss of the testosterone receptor led to decreased testosterone function within these cells, ultimately causing the cancer cells to die, which is obviously a desirable outcome. However, the loss of testosterone function is certainly not a sought-after effect when trying to gain muscle mass, as reduced testosterone action within the muscle cell would significantly diminish muscle growth.

In summary, taking everything in consideration, despite metformin’s ability to enhance insulin signaling and encourage fat loss, its use alone or in conjunction with GH seems very counterproductive, especially when considering the remarkably negative impact that this compound has on testosterone function.

For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a research scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK— leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.

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