In individuals with visceral obesity …

Arginine reduces
insulin resistance

… and prevents the pathogenesis of excess blood
coagulation in obese patients

By Will Block

T here are a lot of reasons to favor a supplement program that includes arginine, especially along with correlative amino acids (such as citrulline, glycine, and taurine), vitamins, minerals, organic fruit acids, betaine, and CoQ10. Among these reasons is that a well-designed arginine formulation can help trigger your own internal biochemical resources of mental and physical power for feeling more vital and youthful. It can do this by increasing GH release for stronger muscles, boosting sexual function, enhancing memory, and strengthening immune function, not to mention improving cardiovascular function.

Insulin resistance leads to early death

It is no small advantage in the battle to prolong healthspan and lifespan to have a strong heart, because heart disease is the leading cause of death in the U.S., with nearly 599,413 deaths in 2009. That’s about 25% of all mortalities according to the Centers for Disease Control and Prevention.* And without a doubt, one of the major problems leading to death by heart failure is insulin resistance, that silent unacknowledged epidemic that is extrapolated to have over 73 million Americans in its clutches. Insulin resistance is a deadly disease that’s makes you fat and sick and can kill you in a number of ways, but especially and eventually through heart failure. What’s worse, most people don’t even know they have it, and few doctors are trained to find it. In fact, they are not even looking for it.


* http://www.cdc.gov/nchs/fastats/lcod.htm

http://www.rightdiagnosis.com/i/insulin_resistance/stats-country.htm


The failure to facilitate glucose transport

In simple terms, insulin resistance is the decreased ability of insulin (a hormone secreted by the pancreas) to do its primary job of moving glucose (blood sugar) from our bloodstream into our cells. Since all of our cells use glucose as their primary fuel for maintaining the metabolic processes of life, an impairment of insulin’s ability to facilitate glucose transport into the cells is a very serious problem.

In people with this condition, the pancreas, over time, secretes more and more insulin in an effort to compensate for the hormone’s declining effectiveness. Often this isn’t enough, however, and blood glucose levels begin to rise and sometimes the pancreas simply “burns out” after so many years of overwork. If the chronic underlying condition becomes sufficiently severe, the result is type 2 diabetes, a devastating disease that can be controlled (with increasing difficulty as it progresses) but rarely cured. The long-term consequences include heart disease, nerve damage, kidney damage, blindness, and premature death.

Arginine’s benefits for enhanced insulin sensitivity

The role of tumor necrosis factor alpha (TNF-α), one of the adipose tissue products, as part of the mechanisms that cause insulin resistance is well documented. Along with this, many recent studies have shown a beneficial influence of L-arginine supplementation on the cardiovascular system. However, the molecular mechanisms of its positive actions have not been fully clarified.

In order to understand this more thoroughly, Polish researchers at Poznan University of Medical and Life Sciences investigated arginine to determine if it could cause a significant improvement in insulin sensitivity, and if so, by what mechanisms.1 The study aimed to evaluate the influence of arginine supplementation on TNF-α, insulin resistance, and selected anthropometric and biochemical parameters in patients with visceral obesity.

Sixty subjects with visceral obesity were randomly assigned to either receive 9 g of arginine or placebo for 3 months. 20 healthy lean subjects were used as controls. The selected anthropometrical measurements and blood biochemical analyses were taken at baseline and after 3-months. Also, TNF-α and its soluble receptor 2 were assessed in both treated groups. Insulin resistance in the participants was evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) protocol.

The research confirmed that arginine improved insulin resistance in patients with visceral obesity, with basal HOMA-IR over 4-times higher as compared to lean controls. This is not the first time that this has been found.2 (See “Low-Dose L-Arginine Improves Insulin Sensitivity” in the January 1999 issue; and “Arginine Boosts Insulin Sensitivity and Cardiovascular Function” in the October 2001 issue).


The evidence confirms the
independent contribution of
hyperinsulinemia and insulin
resistance in the development of
cardiovascular complications.


Independent contributions to heart disease

In addition, the evidence confirms the independent contribution of hyperinsulinemia and insulin resistance in the development of cardiovascular complications. An earlier undertaking, the Insulin Resistance Atherosclerosis Study, demonstrated an independent (not related to traditional risk factors for cardiovascular disease) relationship between thickness of the intima-media in the carotid artery and a decrease in insulin sensitivity.3 The Polish researchers found, as a typical consequence of obesity and insulin resistance, abnormal lipid profiled in the studied subjects. Indeed, the critical role of insulin resistance in the pathogenesis of lipid disorders is well documented, and the results of the Polish study are consistent with previous observations, showing excessive activation of TNF-α in patients with obesity. The researchers found significantly higher concentrations of both TNF-α and its soluble receptor 2. Both levels of these correlated positively to waist circumference and percentage of body fat.


Acute or chronic administration of
supplemental arginine enhances
endothelial nitric oxide production
and improves endothelial function in
the setting of atherothrombosis.


TNA-alpha necessary but not sufficient

The important role of TNF-α in the pathogenesis of insulin resistance in patients with excessive body weight has been shown in animals and in humans. This cytokine§ inhibits insulin action in fat cells, as well as in liver and muscle tissues. In fat tissue, TNF-α inhibits fat production by reducing lipoprotein lipase activity, while it stimulates the breakdown of fat by activation of hormone sensitive lipase. TNF-α also increases insulin resistance by inhibiting the phosphorylation of tyrosine and increasing serine phosphorylation in insulin receptor substrate. As a consequence, this leads to a decrease of insulin receptor activity, while TNF-α also influences the metabolism of glucose directly, reducing the expression of GLUT-4 in muscle cells. The findings—the significant correlation between TNF-α, its soluble receptor 2, insulin concentration, and HOMA-IR—confirmed the potential role of TNF-α system in the complex pathogenesis of insulin resistance in obese patients.


§ Small cell-signaling protein molecules that are secreted by numerous cells and are a category of signaling molecules used extensively in intercellular communication.


The mechanisms of arginine

As described in a paper by Loscalzo,4 arginine, the principal substrate for endothelial nitric oxide synthase, is oxidized to citrulline and nitric oxide (NO). Endothelial dysfunction is associated with decreased bioactive nitric oxide production, an abnormality observed in atherothrombosis. Acute or chronic administration of supplemental arginine enhances endothelial nitric oxide production and improves endothelial function in the setting of atherothrombosis (blood clotting).

As defined by Loscalzo, the mechanisms by which arginine improves endothelial function are: 1) increased intracellular uptake via the high-affinity cationic transporter; 2) substrate competition with asymmetric dimethylarginine; 3) direct antioxidant activity; 4) stimulated release of histamine from mast cells, which produces a vasodilator response; and 5) decreased activity of norepinephrine and increased insulin secretion, which causes vasodilation. As well, there is a growing body of evidence that confirms both anti-inflammatory and anti-oxidant properties of arginine. Based on vasoprotective arginine action, the Polish researchers also decided to evaluate its potential benefits in patients with visceral obesity, who are characterized by endothelial dysfunction and increased cardiometabolic risk.

Arginine lowers blood pressure, but only in hypertensives

After 3-months of arginine supplementation, there was no influence on anthropometric parameters or blood pressure values. This was similar to the failure of arginine to affect blood pressure in a previous study of the researchers, where healthy normotensives had been treated with arginine in a dose of 6 g or 12 g during a 4-week period. In these normotensives, arginine led to non-significant decrease of systolic and diastolic blood pressure. In contrast, however, the Polish researchers demonstrated a strong association between arginine supplementation and blood pressure reduction in patients with essential hypertension.5 The treatment of hypertensive patients with 12 g of arginine for 4 weeks led to lowering of both systolic and diastolic blood pressure in ambulatory blood pressure measurement, with stronger hypotensive effect observed during the night. Schlaich et al,6 reported impaired arginine transport in hypertensive individuals and normotensives at high risk for the development of hypertension. This data may represent the association between a defective arginine/NO pathway and the onset of essential hypertension.


Insulin resistance is associated with
an impairment in the ability of NO to
generate its messenger, leading to a
decrease in cGMP generation and a
relative decline in insulin’s ability to
produce vasodilatation.


Yes and no: the mixed results of arginine on lipids

The results showed that arginine had no effect on lipid levels, confirming similar results obtained by others. Yet, there are reports showing the positive influence of arginine on lipid metabolism and lipid profile. In these, it was found that arginine supplementation decreased serum total cholesterol, low-density lipoprotein (LDL) and triglycerides. Perhaps the hypolipemic effect of arginine is at least in part associated with the increase in NO level in the body and lower fatty acid oxidation. Or maybe arginine regulates the expression of fat-metabolic genes in skeletal muscle and white fat tissue, thus, favoring fat creation in muscle but fat breakdown in adipose tissue, and this may influence lipid levels.

Clear results of arginine’s impact on insulin resistance

The results of several previous studies that investigated the potential influence of arginine on insulin resistance are not uniform and have been fairly inconclusive. But the present findings demonstrate beneficial impact of arginine supplementation on insulin resistance in patients with visceral obesity. HOMA-IR decreased significantly, although still remained higher than in the healthy control group. The positive influence on insulin resistance was also observed by Piatti et al.7 In this study, a group of 12 lean type 2 diabetic patients supplementing with arginine in a dose of 9 g for 4 weeks resulted in improvement of peripheral and hepatic insulin sensitivity. The authors suggested that insulin resistance is associated with an impairment in the ability of NO to generate its messenger, leading to a decrease in cGMP generation and a relative decline in insulin’s ability to produce vasodilatation. The hypothesis was consistent with another study, the conclusion of which was that there is a relationship between insulin resistance and endothelial response to inhibition of NO synthesis, as well as with evidence that the vasodilatory response is decreased in insulin-resistant individuals.

Concluding: Arginine improves insulin sensitivity independent of TNF-α

The results of the Polish study were insufficient to determine a direct mechanism responsible for favorable effect arginine supplementation on insulin resistance. Body weight, BMI, waist circumference and fat percentage remained unchanged. Before undertaking the study, the researchers believed that an increase in insulin sensitivity could be related to alternations in TNF-α concentrations. But this was found to be unsubstantiated; TNF-α system activity was unrelated to insulin sensitivity. The 3-month arginine supplementation at a dose of 9 g influenced neither TNF-α nor its soluble receptor 2. While the influence of TNF-α was initially considered potentially appealing, lack of changes in the TNF-α system excluded its potential role in the insulin resistance benefit found in obese patients treated with arginine.

References

  1. Bogdanski P, Suliburska J, Grabanska K, Musialik K, Cieslewicz A, Skoluda A, Jablecka A. Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity. Eur Rev Med Pharmacol Sci 2012 Jun;16(6):816-23.
  2. Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan LM, D’Agostino RB. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 2006 Aug;91(8):2906-12.
  3. Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ, O’Leary DH, Haffner SM. Diabetes and progression of carotid atherosclerosis: the insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol 2003 Jun 1;23(6):1035-41.
  4. Loscalzo J. L-arginine and atherothrombosis. J Nutr 2004; 134: 2798-2800; discussion 2818-9.
  5. Ast J, Jablecka A, Bogdanski P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit 2010 May;16(5):CR266-71.
  6. Schlaich MP, Parnell MM, Ahlers BA, Finch S, Marshall T, Zhang WZ, Kaye DM. Impaired L-arginine transport and endothelial function in hypertensive and genetically predisposed normotensive subjects. Circulation 2004 Dec 14;110(24):3680-6.
  7. 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.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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