One of the major problems with GLP-1 drugs (in addition to their gastrointestinal problems) is the loss of lean body mass. The obvious solution to the problem might be to increase protein intake. But for the GLP-1 user, adding more protein to an already compromised gastrointestinal system may not be beneficial, as protein is the slowest and most metabolically demanding of the three macronutrients to be processed before absorption. Therefore, it is not clear that increased muscle mass will result from simply adding more protein to a meal.

However, I believe there is a more complex metabolic reason that adding more dietary protein will not be the answer to increasing lean body mass for someone using GLP-1 drugs. This reason is mTOR. Dietary protein itself doesn’t build muscle mass; mTOR does. Consider mTOR to be the master growth regulator. If mTOR isn’t stimulated, there will be no growth of new lean body mass. First, dietary protein must be broken down into small peptides (typically 1-3 amino acids) for their initial absorption (1). The dipeptides and tripeptides are further broken down into single amino acids in epithelial cells, allowing them to enter the bloodstream as individual amino acids. Now the amino acids can enter the cell through specific transporters on the cell surface (2). However, there is still a long way to go to synthesize new proteins inside the cell to maintain lean body mass (3).

Thanks for reading Dr. Barry Sears Substack! Subscribe for free to receive new posts and support my work.

Subscribed

To stimulate protein synthesis, the incoming amino acid must still interact with the insulin signaling pathway to ultimately stimulate mTOR, which causes new protein synthesis. Of all the amino acids, leucine is the most potent to stimulate new protein synthesis. So far so good.

Now here is the problem for GLP-1 users. The success of GLP-1 drugs stems from sustained suppression of appetite, which, in turn, stimulates AMPK activity throughout the body. This increased AMPK activity is why you lose excess body fat. If the GLP-1 drug is constantly stimulating AMPK activity, then mTOR is constantly inhibited. The result is very little stimulation of the formation of new lean body mass.

So how to solve this problem? The answer is the Zone diet. Harvard Medical School demonstrated in 1999 that a very small change in the macronutrient composition of isocaloric meals could have dramatic effects on insulin and glucagon levels in obese teenage boys (4). Those teenage boys consuming a single Zone meal had a significant depression of insulin and a dramatic increase in glucagon levels in their blood during the next five hours after a test meal. On the other hand, when they were given the same calorie-restricted meal but with an altered protein-to-carbohydrate ratio on a different visit, their glucagon levels decreased, and their insulin levels increased. Regardless of which meal they consumed, five hours after eating each test meal, the levels of both insulin and glucagon had returned to baseline.

At the end of each initial five-hour period, they were given the same meal again, and they were brought into a conference room filled with typical snacks and treats that obese teenagers like to eat. There was a significant difference in their food consumption over the next five hours depending on the composition of their previous meal. Specifically, those consuming a second Zone meal reduced their calorie intake by about 45 percent over the next five-hour period compared to back-to-back consumption of a higher-glycemic-load meal with the same number of calories (4). The significant increase in glucagon, coupled with a decrease in insulin, may have contributed to their reduced hunger. The implication is that a Zone meal containing 400 calories could significantly reduce hunger for approximately 5 hours compared with a meal of the same number of calories, but with a different protein-to-carbohydrate ratio.

The clinical application of this early observation was confirmed in a six-month study involving type 2 diabetics who consumed prepared meals. Those type 2 diabetics consuming the calorie-restricted prepared meals with the Zone diet composition had a complete remission of their type 2 diabetes after six months with a gain of lean body mass. In the control group consuming isocaloric meals with a slightly different macronutrient composition, only 17% had remission of their diabetes, and they all lost lean body mass (5). Why?

Calorie restriction activates AMPK and inhibits mTOR. Furthermore, if you eat during daylight hours, AMPK is activated, and mTOR is inhibited. Once you stop eating, especially after the sun goes down (both AMPK and mTOR are controlled by circadian rhythms), mTOR activity increases and AMPK activity decreases. The next day, this dynamic cycle starts again. The secret is to consume adequate protein (about 90 grams per day) evenly spread out during those daylight hours. Unfortunately, with GLP-1 therapy, AMPK is always activated, thereby constantly inhibiting mTOR.

This is why the Zone diet is the foundation of Metabolic Engineering®. However, Metabolic Engineering® can do things that GLP-1 drugs can’t do. In particular, Metabolic Engineering® also supplies adequate levels of omega-3 fatty acids to reduce inflammation and of polyphenols to reduce free-radical damage, thereby reducing oxidative stress. Both are critical for controlling inflammation, which drives the development of chronic disease and accelerates the aging process.

Bottom line: do not expect adding more protein to your current GLP-1 intake will increase lean body mass. On the other hand, following Metabolic Engineering® provides additional metabolic benefits that GLP-1 drugs alone do not. In particular, the reduction of lipid- and free-radical-based inflammation that GLP-1 drugs cannot do. You will still lose excess body fat but now maintain, if not increase, lean body mass while maximally reducing inflammation. The benefit is that you will live longer and better.

References

1. Wu G. Dietary protein intake and human health. Food Funct. 2016; 7:1251-1265. doi: 10.1039/c5fo01530h.

2. Ling, ZN., Jiang, YF., Ru, JN. et al. Amino acid metabolism in health and disease. Sig Transduct Target Ther. 2023; 8:345. doi.org/10.1038/s41392-023-01569-3

3. Meijer AJ and Dubbelhuis PF. Amino acid signaling and the integration of metabolism. Biochem Biophys Res Commun. 2004; 313:397-403. doi.org/10.1016/j.bbrc.2003.07.012.

4. Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, Roberts SB. High glycemic index foods, overeating, and obesity. Pediatrics. 1999; 103:E26. doi: 10.1542/peds.103.3.e26.

5. Stentz FB, Lawson D, Tucker S, Christman J, Sands C. Decreased cardiovascular risk factors and inflammation with remission of type 2 diabetes in adults with obesity using a high protein diet: Randomized control trial. Obes Pillars. 2022; 4:100047. doi: 10.1016/j.obpill.2022.100047.

Thanks for reading Dr. Barry Sears Substack! Subscribe for free to receive new posts and support my work.

Subscribed