Tuesday, August 20, 2013

8g+ (HED) of Arginine Boost Glucose Clearance & Triples GLP-1 Release in Lean and Obese Mice. Plus: 14+ Studies On Things Arginine Can Do For Diabetics & Athletes

Type II diabetes and insulin resistance has long become an issue for lean individuals as well. But can you really abuse your "pump supplement" as a means to stash away your post-workout carbs at a significantly increased pace?
Statements like "XY boosts" and figures like "+30%" are real attention-grabbers. I mean 200mg/dl glucose vs. 300mg/dl glucose after a 2g/kg glucose load that must certainly be significant, right? Well, as always, there are exceptions to the rule, but I can reassure you: it's not the case with the latest study from the College of Medicine at the University of Cincinnati (Clemmensen. 2013). How I know that? Well the I wrote about the real world significance of the increased glucose clearance, as well as the brown-adipose-tissue building and white adipose tissue burning effects of arginine, previously (see "Arginine: BAT Builder and WAT Killer" & "Arginine Enriched Biscuits for Diabetics"). Thus, the most recent revelation that the conditionally essential amino acid that's notorious for its non-existent effects on the pump is able to increase the GLP-1 response to a sugary meal and thus double the glucose clearance in lean mice only adds to what SuppVersity readers knew all along:

There is way more to arginine than "the pump"

Being aware that everybody believes to know exactly that the big bad insulin is the reason for the current obesity epidemic, I guess it's better to remind you that this is not just an unwarranted over-generalization, but completely beside the point. So I suggest you (re-)read "The "Pro-Insulinogenic" Effects of Non-Nutritive Sweeteners + Mechanisms & Consequences" (just do it!), if you feel like running away, when you take a closer look at the right hand side of figure 1:
Figure 1: AUC under the glucose curve (left), actual glucose response after oral glucose tolerance test 15min after the ingestion of arginine in lean and obese mice (middle) and insulin response to arginine and subsequent ingestion of dextrose during the OGGT (right; Clemmensen. 2013)
What you are seeing here is an insulin SPIKE that deserves to be written in capital letters, but the way it ameliorates the surge in blood glucose in the diet-induced obese (~type II diabetic) mice could actually protect the rodents from developing many of the neurological and endocrine side effects of high blood glucose levels and not insulin, which has only recently been demonstrated to ameliorate the cognitive decline in dementia and Alzheimer's (Craft. 2012).

I know you are not dietary obese

Figure 2: GLP-1 response in the lean mice in the study at hand (foreground, top-right; Clemmensen. 2013) and selected effects of GLP-1 (background; from byettahcp.com)
Now, while the data on the right hand side of figure 1 may be relevant for your obese neighbor,  we are actually more interested in the data on the left, which does, by the way, make it quite clear that the problem with being obese is not an increase in insulin release, but the mere fact that even that is not going to help you clear the sugar out of the blood stream.

Compared to the obese mice, where we see a slight, but at 60min significant improvement in glucose clearance, the lean mice did not even give the 2g/kg body weight of glucose they received a chance to accumulate in their blood. Rather than that, they cleared it almost instantly.

The researchers hypothesis that this effect was mediated by the concomitant up to 3x increase in GLP-1 production was supported by a follow up experiment using a genetically modified strain of mice that lacks the GLP-1 receptor, in whom the corresponding improvements in blood glucose management were absent. In the discussion of their results, the researchers add:
Suggested read: "Glycemic Load, the GI's Complex Brother, Turns Out to Be A Good Predictor of Postprandial GLP-1 and GIP Response" | read more
"The GLP-1 incretin effect has traditionally been ascribed to effects on intestinal L cells elicited by ingested carbohydrate, but the findings reported here support the involvement of gut hormones to link protein ingestion with insulin secretion.

This has also been recently suggested in studies of humans consuming meals of specific macronutrient composition (Carrel. 2011).

Also, we have recently reported that long-term dietary supplementation with L-arginine improves glucose metabolism in mice exposed to a low-protein diet (Clemmensen. 2012)." (Clemmensen. 2013)
Despite the fact that GLP-1 analogues have been used with quite some success in the treatment of type II diabetes in the recent years, our understanding of the far-reaching effects of this "satiety hormone" is still far from being comprehensive (suggested read: "Eat More, Burn More and Lose Fat Like on Crack w/ GLP-1"). What we do know is that it occupies a central position in the control of our energy intake, though. And I am pretty sure is not the SuppVersity post about glucagon-like peptide 1 (GLP-1), you are about to read.

But does that even work for you? For (pre-)diabetics we can rely on data from Piatti et al. (2001) who found a 34% increase in insulin clearance after one months on 3g/day l-arginine and data from Lucotti (2006) who observed that the addition of 8.3g of l-arginine to a hypocaloric diet + exercise regimen boosted the loss of fat mass and and waist circumference while increasing the lean mass retention and improving daily glucose and fructosamine profiles, significantly. For the sick / obese we do also have human (H) and rodent studies (R) supporting
  • Whenever the word "vascularity" appears on one of the boards, this image pops up. Now we know that arginine alone won't make your veins pop, but could it be that we have hitherto overlooked that it could help you meet another more important criteria to look like that - namely to drop body fat? Learn more in a previous SuppVersity article on arginine's BAT building and WAT killing effects and it's use as a repartitioning Agent (read more)
    an anti-platelet effect of 8.4g arginine per day in hypercholesterolemic humans (Wolf. 1997; H)
  • indirect anti-oxidant effects of 2x3g arginine per day in in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities (Jablecka. 2012; H)
  • an ameliorative effect on diabetes induced gastrointestinal malfunction (Míguez. 2004; R)
  • improved wound healing when administered alone (Witte. 2002; R) or with proline (Raynaud-Simon. 2012; R)
  • significantly reduced body fat mass in rodent model of diet induced diabesity (Fu. 2005; R)
  • beneficial effects on the hypertensive offspring of diabetic dams (Cavanal. 2007; R) 
  • direct mechanistic effects that inhibit the storage of fat in white adipose tissue (Tan. 2012; R + H + PIG)
  • reductions in diabetes induced bone loss (Pennisi. 2009; R)
  • amelioration of the negative effects on insulin sensitivity in response to a low (no typo!) salt diet (Ruivo. 2006; R)
The benefits for lean individuals are not that clear, studies like Gater et al. (1992), for example, tested the effect of the purportedly GH boosting combination of arginine + lysine and saw no effects in their healthy young participants. Other studies did however find ...
  • Suggested read: "Post-Workout Glycogen Repletion - The Role of Protein, Leucine, Phenylalanine and Insulin." | read more
    a reduced oxidation of glucose when well-trained cyclists used a mixture of 1 g carbohydrate/kg body mass and 0.08 g arginine-hydrochloride/kg body weight to refuel their muscle glycogen after a workout (Yaspelkis. 1999)
  • significantly lowered blood pressure and improved renal function and carbohydrate metabolism in healthy volunteers (Siani. 2000)
  • significantly increased rates of glucose disposal during exercise in trained cyclists (McConell. 2006; Linden. 2011)
  • direct beneficial effects on glucose and fatty acid metabolism in muscle cells (de Castro Barbosa. 2013)
  • reduced blood lactate accumulation & oxygen consumption during submax. exercise after prolonged intake of L-arginine-L-aspartate (Burtscher. 2005)
So, if it there was not the likely possibility that many of these benefits occur only with a low(ish) protein intake,  I would say: Arginine can do a lot of interesting things for you. With a possible beneficial effect on post-workout glycogen repletion being what I consider most significant for the lean physical culturist. There is yet one thing arginine cannot do and that's worth remembering, because it tells you something about the supplement business: It won't increase the pump.

  • Burtscher M, Brunner F, Faulhaber M, Hotter B, Likar R. The prolonged intake of L-arginine-L-aspartate reduces blood lactate accumulation and oxygen consumption during submaximal exercise. J Sports Sci Med. 2005; 4(3), 314-322.
  • Carrel G, Egli L, Tran C, et al.Contributions of fat and protein to the incretin effect of a mixed meal. Am J Clin Nutr. 2011;94(4):997–1003. 
  • Cavanal Mde F, Gomes GN, Forti AL, Rocha SO, Franco Mdo C, Fortes ZB, Gil FZ. The influence of L-arginine on blood pressure, vascular nitric oxide and renal morphometry in the offspring from diabetic mothers. Pediatr Res. 2007 Aug;62(2):145-50.
  • Clemmensen C, Madsen AN, Smajilovic S, Holst B, Bräuner-Osborne H.L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances.Amino Acids. 2012;43(3):1265–1275.
  • Clemmensen C, Smajilovic S, Smith EP, Woods SC, Bräuner-Osborne H, Seeley RJ, D’Alessio DA, Ryan KK. Oral L-Arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice. Endocrinology. First published ahead of print August 19, 2013.
  • Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38.
  • de Castro Barbosa T, Jiang LQ, Zierath JR, Nunes MT. L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway. Metabolism. 2013 Jan;62(1):79-89.
  • Fu WJ, Haynes TE, Kohli R, Hu J, Shi W, Spencer TE, Carroll RJ, Meininger CJ, Wu G. Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr. 2005 Apr;135(4):714-21.
  • Gater DR, Gater DA, Uribe JM, Bunt JC. Effects of arginine/lysine supplementation and resistance training on glucose tolerance. J Appl Physiol. 1992 Apr;72(4):1279-84.
  • Jabłecka A, Bogdański P, Balcer N, Cieślewicz A, Skołuda A, Musialik K. The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities. Eur Rev Med Pharmacol Sci. 2012 Mar;16(3):342-50.
  • Linden KC, Wadley GD, Garnham AP, McConell GK. Effect of l-arginine infusion on glucose disposal during exercise in humans. Med Sci Sports Exerc. 2011 Sep;43(9):1626-34.
  • Lucotti P, Setola E, Monti LD, Galluccio E, Costa S, Sandoli EP, Fermo I, Rabaiotti G, Gatti R, Piatti P. Beneficial effects of a long-term oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E906-12. 
  • McConell GK, Huynh NN, Lee-Young RS, Canny BJ, Wadley GD. L-Arginine infusion increases glucose clearance during prolonged exercise in humans. Am J Physiol Endocrinol Metab. 2006 Jan;290(1):E60-E66.
  • Míguez I, Mariño G, Rodríguez B, Taboada C. Effects of dietary L-arginine supplementation on serum lipids and intestinal enzyme activities in diabetic rats. J Physiol Biochem. 2004 Mar;60(1):31-7.
  • Pennisi P, Clementi G, Prato A, Luca T, Martinez G, Mangiafico RA, Pulvirenti I, Muratore F, Fiore CE. L-arginine supplementation normalizes bone turnover and preserves bone mass in streptozotocin-induced diabetic rats. J Endocrinol Invest. 2009 Jun;32(6):546-51.
  • Piatti PM, Monti LD, Valsecchi G, Magni F, Setola E, Marchesi F, Galli-Kienle M, Pozza G, Alberti KG. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care. 2001 May;24(5):875-80. 
  • Raynaud-Simon A, Belabed L, Le Naour G, Marc J, Capron F, Cynober L, Darquy S. Arginine plus proline supplementation elicits metabolic adaptation that favors wound healing in diabetic rats. Am J Physiol Regul Integr Comp Physiol. 2012 Nov 15;303(10):R1053-61.
  • Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens. 2000 May;13(5 Pt 1):547-51. 
  • Tan B, Li X, Yin Y, Wu Z, Liu C, Tekwe CD, Wu G. Regulatory roles for L-arginine in reducing white adipose tissue. Front Biosci (Landmark Ed). 2012 Jun 1;17:2237-46. Review.
  • Witte MB, Thornton FJ, Tantry U, Barbul A. L-Arginine supplementation enhances diabetic wound healing: involvement of the nitric oxide synthase and arginase pathways. Metabolism. 2002 Oct;51(10):1269-73.
  • Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B, Tsao PS, Cooke JP. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997 Mar 1;29(3):479-85.
  • Yaspelkis BB 3rd, Ivy JL. The effect of a carbohydrate--arginine supplement on postexercise carbohydrate metabolism. Int J Sport Nutr. 1999 Sep;9(3):241-50.