Insulin: How to Maximize Muscle Growth

Selective Insulin Receptor Modulators (SIRMs): New Class of Muscle-Building Compounds

 Insulin is arguably the most anabolic hormone produced in the human body, possessing the ability to drastically increase muscle protein synthesis and enhance muscle growth.¹ Insulin achieves this muscle-building effect by binding to the insulin receptor and setting off a cascade of signaling events that eventually activates the enzyme mTOR, which triggers muscle cell protein synthesis.^2,3 So, of course, someone interested in maximizing muscle size will be intrigued by this ultra muscle-building hormone. At first glance, insulin may seem like the perfect muscle-building drug. It’s relatively cheap and extremely powerful. However, the dilemma is that insulin does more than simply enhance protein synthesis within muscle cells.

When insulin binds to the insulin receptor, it also regulates carbohydrate metabolism in the body by causing cells in the liver, muscle and fat tissue to take up glucose from the blood and store it as glycogen inside these tissues. While the uptake of glucose could provide energy for muscle contraction and be very beneficial for muscle growth, too much glucose uptake could be very detrimental. Moreover, insulin also stimulates cell division by activating another signaling pathway known as the mitogen-activating protein kinase (MAPK) pathway.⁴ As a consequence of imprecisely activating either of these two aforementioned pathways, insulin use could deleteriously promote severely low blood sugar by shuttling too much glucose into the cell or cause excessive cell division, promoting the progression of certain types of cancers.

The potentially detrimental side effects associated with insulin use, along with insulin’s powerful anabolic capabilities, have generated interest in the medial community as well as the bodybuilding world for an improved version of insulin that would selectively activate the insulin receptor and only replicate the beneficial actions of insulin without any adverse effects. This interest has spawned the investigation of a unique class of molecules known as selective insulin receptor modulators (SIRMs), which are being considered for their ability to promote muscle growth while possessing minimized side effects typically associated with insulin use.⁵

The ability to selectively modulate certain cell receptors with a novel set of molecules that exclusively produces desired biochemical effects is not a novel concept. For instance, in the February 2012 issue of Muscular Development, I wrote an article about the extremely anabolic class of molecules known as selective androgen receptor modulators (SARMs) that selectively activate the androgen receptor— producing mostly anabolic muscle-building effects while generating very little unwelcome androgenic effects. SARMs achieve their largely anabolic influence by binding and regulating the steroid receptor in a different manner than either testosterone or anabolic steroids do. This unique mode of binding only turns on the sought-after muscle-building anabolism while significantly decreasing androgenicity. Therefore, the ideal SIRM will also uniquely bind and regulate its natural receptor, the insulin receptor, solely stimulating muscle protein synthesis and imparting greater muscle growth.

Selectively Stimulating Protein Synthesis

In the quest to find molecules with SIRM activity, scientists will leave no stone unturned. They will investigate all molecular types and varieties during the hunt for the ideal SIRM. This all-encompassing search includes a class of molecules known as antibodies. Antibodies are protein molecules typically produced by the immune system to bind and neutralize foreign objects such as bacteria and viruses. Because antibodies are so adept at interacting with an extremely wide array of compounds, they make fantastic drug candidates. As a result, antibody drugs represent the cutting-edge in a new wave of therapeutics being developed by the biotechnology and pharmaceutical industry.

A recent study by Bhaskar et al.⁶ discovered an antibody molecule that has SIRM-like activity. While rapidly probing several thousand potential binding partners for the insulin receptor, the authors identified an antibody molecule they called XMetA. This newly discovered antibody tightly binds the insulin receptor, yet specifically activates only protein synthesis and glucose uptake in the cell— although not as powerfully as insulin. More specifically, XMetA selectively triggers the AKT/mTOR pathway with a maximal effect that is 40 percent that of insulin but in contrast to insulin, does not induce the MAPK pathway to drive cell division. Consequently, XMetA promotes protein synthesis and glucose uptake in the muscle cell— stimulating muscle growth but not cell division.

Interestingly, XMetA was shown to bind the insulin receptor at a different site than insulin does— perhaps explaining the difference in activation by XMetA as compared to insulin. Altogether, this antibody appears to be a selective modulator of the insulin receptor that apparently reproduces some of the favorable effects of insulin without insulin’s most harmful consequence. Nonetheless, the bodybuilder or athlete interested in XMetA as a potential insulin substitute should seek alternative means— as it doesn’t appear that this antibody is a feasible option. While XMetA only partially stimulates glucose uptake, potentially providing energy for additional muscle contraction while abrogating the possibility of hypoglycemia, this lack of AKT/mTOR activity also only partially stimulates protein synthesis— which diminishes the largest anabolic quality of insulin. However, this study introduces a step in the right direction toward a purely muscle-building form of insulin.

Small-molecule SIRMs Activate Glucose Uptake

Most ergogenic aids, whether nutritional supplements or drugs, fall into the “small molecule” category— which essentially means they are much smaller in size than the protein molecules that they bind to and regulate. For example, anabolic steroids, which are small molecules, are roughly one hundred times smaller than the steroid receptor they bind to and regulate. The reason that most supplements and drugs are small molecules is because smaller molecular weights typically increase absorption into the body, thus increasing the ability to interact with its protein target— which enhances the drug’s potency. That said, the majority of SIRM molecules would also most likely be small molecules.

In order to elucidate potential small-molecule SIRM candidates, Jensen et al.⁷ explored thousands of potential small molecules for SIRM-like activity and discovered the synthetic insulin mimetic peptide S597 that selectively initiates different signaling responses as compared to insulin. In this study, the researchers showed that S597 activates the insulin receptor but not as strongly as insulin does. As a result of this lower insulin receptor activity by S597, only the AKT/mTOR signaling pathway is fully turned on while the MAPK pathway is partially stimulated. If this is the case, weaker binding molecules might potentially be the more specific SIRM-like molecules— generating more favorable anabolic end product while minimizing the likelihood of uncontrolled cell division.

Currently, our understanding regarding SIRMs is still incomplete— primarily due to the fact that selective modulation of the insulin receptor is a novel idea. However, while recent scientific investigation has shed some light on this phenomenon, further research will be needed to bolster the anabolic properties of SIRMs and achieve greater functional selectivity before they become molecules of interest for the athletic and bodybuilding world.

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.

References:

1. Hillier TA, et al. Extreme hyperinsulinemia unmasks insulin’s effect to stimulate protein synthesis in the human forearm. Am J Physiol, 1998;274(6 Pt 1): p. E1067-74.

2. Guillet C, et al. Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. Faseb J, 2004;18(13): p. 1586-7.

3. Biolo G, Declan Fleming RY, et al. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest, 1995;95(2): p. 811-9.

4. Kayali AG, Austin DA, et al. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Diabetes, 2000;49(11): p. 1783-93.

5. Vigneri R, Squatrito S, et al. Selective Insulin Receptor Modulators (SIRM): A New Class of Antidiabetes Drugs? Diabetes, 2012;61(5): p. 984-5.

6. Bhaskar V, et al. A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes, 2012;61(5): p. 1263-71.

7. Jensen M, et al. Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts. Biochem J, 2008;412(3): p. 435-45.