Monday, May 28, 2012

Essential Amino Acids Stimulate Muscle Glucose Uptake by Exponentiating Insulin's Effect on GLUT4 Expression

Image 1: High EAA smoothies are a good, high sugar one a very bad idea
Scientists from the Exercise Physiology and Metabolism Laboratory at the Department of Kinesiology and Health of the University of University of Texas at Austin, the Abbott Laboratories in Columbus, Ohio, and the Taipei Sports University in Taipaie, Taiwan, report in one of their latest papers that the administration of an amino acid enriched perfusate, a solution that is administered by the means of a canula, into the hindlimb (from the right iliac artery and vein to the tip of the femoral artery of the rat) of 9-week old Sprague Dawley rats stimulates glucose uptake in the presence of insulin, but not by increasing insulin and/or p-Akt (Bernard. 2012).

EAAs stimulate insulin induced GLUT-4 translocation

This is interesting, as we have hitherto assumed that many of the beneficial effects of additional protein or amino acids on glucose clearance were related to BCAA or EAA induced increases in insulin. The data, Jeffrey R. Bernard and his colleagues produced, do now suggest that this process, despite its dependence on the presence of insulin, is not the result of increases in insulin, phosphatidylinositol 3-kinases (PI 3K) or p-Akt levels (cf. figure 1), but rather a consequence of an increasd expression of AS160 a relatively unknown substrate of p-Akt that mediates the effects of the former on GLUT-4 (glucose receptor) translocation to the cell membrane and subsequent glucose uptake into the muscle (and unfortunately fat cells):
Figure 1: Simplified schematic illustration of the insulin > PI3K > p-Akt > AS160 induced increase in GLUT-4 glucose transporter expression and the effects of increased serum amino acids
Practically speaking this would mean that any increase in serum EAA levels should be able to increase the insulin-mediated glucose uptake, without increasing insulin even further. This observation would, at least in part, explain the beneficial effects individual EAAs or EAA rich protein sources have been shown to have on insulin stimulated glucose uptake (Frid. 2005; Kalogeropoulou. 2008, Morifuji. 2009).
EAA solutions, perfused rat hindlimbs and the real world: I guess it is about time to put some things into perspective here. While the locally mediated increase in glucose uptake, as it occurs in a study like this, is not mediated by increases in circulating insulin (would be hard to imagine, I mean, when the pancreas in not "connected" to the "test system" ;-), the real world effect of EAA rich protein sources, above all whey protein isolates and hydrosolates on pancreatic insulin production is very pronounced.

Figure 2: Insulin levels in 16 healthy male subjects after 0-180min after the ingestion of 45g whey protein isolate (white triangle) or hydrosolate (black squares) after an overnight fast (Power. 2009)
Power, Hallihan and Jakeman, for example, observed a peak increase of +100% and +150% in plasma insulin in sixteen healthy men after the ingestion of 45g of whey isolate or whey hydrosolate after an overnight fast (Power. 2009). Now, before you get scared, think about it this way: Through its systemic effect on pancreatic insulin release, whey - you may remember originally a constituent of milk (click here to read all about milk, colostrum & co.) - does thusly facilitate the uptake of the milk sugar via two distinct mechanism: Firstly it ramps up pancreatic insulin production, which in and out of itself would have increased GLUT4 translocation and subsequent glucose uptake. And secondly, its amino acid content will exponentiate this effect via AS160, or, put simply by increasing the insulins ability to stimulate GLUT4 translocation at the tissue level.

That other EAA rich protein sources will have similar beneficial effects on glucose clearance and that those are obviously not restricted to milk sugar, but would apply for every other source of glucose in your diets should be as obvious as the unfortunate fact that  these effect are not muscle specific :-(

Faster glucose clearance, no increase in insulin, no decrease in AMPK-alpha2

In their study, the scientists had used a solution that was particularly high isoleucine and contained 5.28 mg cysteine, 3.36 mg methionine, 6.68 mg valine, 944.8 mg isoleucine and 6.68  128 mg leucine per 50 ml solution. Whether another mixture would have elicited similar, if not superior results is questionable, what can be said, however, is that this mix is already superior to isoleucine, alone (Bernard. 2011).
Figure 3: Glucose uptake, AS160 and GLUT4 expression expressed relative to baseline (no insulin, no amino acids) in the presence and absence of insulin, and an essential amino acid mixture (AA); data calculated based on Bernard. 2012
As you can see in figure 3 these changes, in particular the increase in GLUT4 receptor density, were pretty profound (+800%!), but occurred only, if 200 μU/ml insulin were added to the perfusion solution (according to Bernard, this results in high, but still physiological insulin concentrations).

The expression of AMPK-alpha2, as you remember from the Intermittent Thoughts the "good" isoform of AMPK that is expressed in response to exercise and won't hinder your gains, on the other hand, did not differ between treatments. This would have been a surprise, anyways, but I guess the scientists wanted to check, whether amino acids could induce GLUT4 translocation via AMPK activation and thus by the same mechanism as your workouts do. That the latter is not the case, makes them even more interesting to promote the already improved ability of skeletal muscle glucose uptake after a workout.

Bottom line: Take advantage of the GLUT4 amplifying effects of amino acids...

... not just after your workouts, but with every meal, by making sure that it contains an ample amount of high quality protein (~10g+ EAA content, e.g. ), or, if nothing that falls into this category is available, by adding additional BCAAs, better EAAs in capsule(=more convenient) or powder (=cheaper and in some cases even palatable ;-) to your ready-to-eat-low-protein-whatever.

And in case you are still doubting the real-world significance of this in most people's eyes probably maddish practice, let me briefly quote the results of a study by Loenecke et al. who investigated the relationship between the amount of quality protein, carbohydrate, and dietary fat consumed and the amount of times the ~10 g essential amino acid (EAA) threshold was reached at a meal, with percent central abdominal fat in 27 young and healthy men and women (Loenecke. 2012; my emphases):
Quality protein consumed in a 24-hour period was inversely related with percent CAF (r = -.420, p = 0.041). No associations were found with carbohydrate (r = -.198, p = 0.354) or dietary fat (r = -.196, p = 0.359) with percent CAF. The amount of times reaching the EAA threshold for a meal throughout the day was also inversely related with percent CAF (r = -.547, p = 0.006).
I would say this means you either buy a new fridge for all the eggs, meats, fish, crustaceans, dairy & co. or head over to the supplement vendor of your choice and get yourself a bag of whey, casein or milk protein. And if your digestive tract doesn't like those (try using isolates, first, those should be 100% lactose free), pick egg, pea or beef protein isolates - mostly they don't taste as well, but their essential amino acid content is high and at least pea is also "kosher" for vegans ;-)

References:
  1. Bernard JR, Liao YH, Hara D, Ding Z, Chen CY, Nelson JL, Ivy JL. An amino acid mixture improves glucose tolerance and insulin signaling in Sprague-Dawley rats. Am J Physiol Endocrinol Metab. 2011 Apr;300(4):E752-60. Epub 2011 Feb 8.
  2. Bernard JR, Liao YH, Doerner PG 3rd, Ding Z, Hsieh M, Wang W, Nelson JL, Ivy JL. An amino acid mixture is essential to optimize insulin-stimulated glucose uptake and GLUT4 translocation in perfused rodent hindlimb muscle. J Appl Physiol. 2012 May 17.
  3. Frid AH, Nilsson M, Holst JJ, Björck IM. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr. 2005 Jul;82(1):69-75
  4. Kalogeropoulou D, Lafave L, Schweim K, Gannon MC, Nuttall FQ. Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose. Metabolism. 2008 Dec;57(12):1747-52.
  5. Loenneke JP, Wilson JM, Manninen AH, Wray ME, Barnes JT, Pujol TJ. Quality protein intake is inversely related with abdominal fat. Nutr Metab (Lond). 2012 Jan 27;9(1):5.
  6. Morifuji M, Koga J, Kawanaka K, Higuchi M. Branched-chain amino acid-containing dipeptides, identified from whey protein hydrolysates, stimulate glucose uptake rate in L6 myotubes and isolated skeletal muscles. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):81-6.
  7. Power O, Hallihan A, Jakeman P. Human insulinotropic response to oral ingestion of native and hydrolysed whey protein. Amino Acids. 2009 Jul;37(2):333-9.