Insulin Mimickers and Insulin Sensitizers

It used to be that you heard a lot about insulin and a few supplements that would make it work better. Unfortunately, the supplements that were recommended were not marketed as insulin sensitizers, but instead, anabolics. When people would purchase the supplements and failed to experience astounding muscle growth, they simply wrote it off as yet another worthless supplement. Sales soon dropped and supplement companies stopped marketing them all together.

Then came the low carb craze. Now this same group of supplements popped their heads up and called themselves "carbohydrate managers". Once again the public is given slightly skewed information about what these compounds actually do. They are told that they will reduce the fattening affect of carbohydrates. After all, that is what the public wants to hear. Just as the bodybuilding public wanted to hear that they made you grow muscles. But if you think about it, there is nothing more fattening than insulin, and if you have a supplement that mimics the effects of insulin, you basically have a supplement that "helps" insulin make you fatter.

Despite the picture that I have just painted, I am still a fan of "insulin agonists", specifically, alpha lipoic acid, vanadyl, and chromium. Lets take a look at what they actually do and why I think they are valuable to anybody trying to alter their body composition.

First of all, to understand how these supplements work you have to understand how insulin works. I am going to give you the "science" answer strait from the research without watering it down too much so hold onto your thinking cap?

Insulin signaling regulates glucose uptake into fat and muscle cells through the recruitment of glucose transporters (GLUT 4) from an intracellular membrane storage pool to the plasma membrane.

The first step in the stimulation of glucose transport is activation of the insulin tyrosine kinase receptor. The activated receptor phosphorylates endogenous substrate proteins, primarily members of the insulin receptor substrate (IRS) family. Tyrosine phosphorylation within multiple YXXM and YMXM motifs on the IRS proteins provide docking sites for Src-homology 2 domain-containing proteins. This facilitates the recruitment and the modulation of the regulatory or catalytic activities of a variety of signaling proteins including the p85 regulatory subunits (p85) of type I phosphatidylinositol 3-kinase (PI3K).

Binding of p85 to IRS proteins activates the associated p110 catalytic subunit of PI3K which in turn catalyses the phosphorylation of phosphoinositides at the D3 position of the inositol ring. Activation of PI3K has been shown to be necessary for insulin-mediated GLUT4 translocation. One of the downstream effectors of PI3K is the protein serine/threonine kinase Akt/protein kinase B (PKB). Activation of Akt causes GLUT4 translocation in L6 skeletal muscle cell, 3T3-L1 adipocytes and isolated rat adipocytes. A role for Akt in the stimulation of glucose transport by insulin in L6 muscle cells has now been confirmed using a dominant negative mutant construct.

Hopefully the image below will help you visualize the whole cascade of events more clearly. It should also show that any supplement that claims to effect insulin must be shown to have an effect somewhere in this cascade of events.

Alpha-lipoic acid (ALA) directly activates lipid, tyrosine and serine/threonine kinases of the insulin signaling pathway in both muscle and fat cells,(1) which leads to the stimulation of glucose uptake. These properties are unique among all agents currently used to lower blood sugar in animals and humans with diabetes.

In-vivo studies with humans shows that there may be a limit to the effectiveness of large oral doses.(2) The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study. Seventy-four patients with type-2 diabetes were randomized to either placebo; or active treatment in various doses of 600 mg once daily, twice daily (1200 mg), or thrice daily (1800 mg) alpha-lipoic acid. When compared to placebo, significantly more subjects had an increase in

insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. The average increase in glucose disposal was 27%. Interestingly, there was no dose effect seen in the three different alpha-lipoic acid groups. In this study taking more than 600 mg did not increase the effects on glucose uptake. This may be a result of poor absorption or a real dose response curve that is relatively level.

ALA is not just known to stimulate glucose uptake, it is probably more famous as a powerful antioxidant. ALA is a potent antioxidant in both fat- and water-soluble environments. Furthermore, its antioxidant activity extends to both the oxidized form and its reduced form. DHLA is capable of regenerating ascorbic acid from dehydroascorbic acid, directly regenerating vitamin C and indirectly regenerating vitamin E.(3) Researchers have found a-lipoic acid to increase intracellular glutathione (4) and coenzyme Q10 (5) levels.

a-Lipoic acid appears capable of chelating certain metals. It forms stable complexes with copper, manganese and zinc.(6) In animal studies, it has been found to protect from arsenic poisoning;(7) and, in both animal and in vitro studies, has been found to reduce cadmium-induced hepatotoxicity.(8) In vitro, it was found to chelate mercury from renal slices.(9)

Lipoic acid has also been shown to increase respiration rates of mitochondria, principally through antioxidative mechanisms.(10) Although not entirely clear, ALA may also increase the functioning of the insulin-signaling pathway by reducing radicals that interfere with the pathways intermediates.

References:

1. Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia 2000 Mar;43(3):294-303

2. Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 1999 Aug;27(3-4):309-14

3. Scholich H, Murphy ME, Sies H. Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on a-tocopherol. Biochem Biophys Acta 1989;1001:256-261.

4. Busse E, Zimmer G, Schopohl B, et al. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittel-Forschung 1992;42:829-831.

5. Kagan V, Serbinova E, Packer L. Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling. Biochem Biophys Res Comm 1990;169:851-857.

6. Sigel H, Prijs B, McCormick DB, Shih JCH. Stability of binary and ternary complexes of a-lipoate and lipoate derivatives with Mn2+ , Cu2+, and Zn2+ in solution. Arch Biochem Biophys 1978;187:208-214.

7. Grunert RR. The effect of DL a-lipoic acid on heavy-metal intoxication in mice and dogs. Arch Biochem Biophys 1960;86:190-194.

8. Muller L, Menzel H. Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium toxicity in isolated hepatocytes. Biochem Biophys Acta 1990;1052:386-391.

9. Keith RL, Setiarahardjo I, Fernando Q, et al. Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Toxicology 1997;116:67-75.

10. Humphries KM, Szweda LI. Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate

dehydrogenase: reaction of lipoic acid with 4-hydroxy-2-nonenal. Biochemistry 1998 Nov 10;37(45):15835-41

Vanadyl sulfate (VS) is a form of the element vanadium. Vanadium exists in at least six different states with VS being only one of them. No "essential" biological function has yet been discovered for vanadium. This doesn?t mean it doesn?t have biological effects, it simply means that it is not considered an essential nutritional element.

Vanadyl acts as a phosphatase inhibitor (1). Like insulin, VS promotes the phosphorylation of tyrosyl residues in the insulin receptor, which is the first step in initiating the cascade of events normally seen when insulin binds to it (2). This happens even without insulin. In the presence of insulin however, VS will extend the duration that the insulin receptor is active. Recent research has even shown that VS can activate the insulin cascade by mechanisms besides interacting with the insulin tyrosine kinase receptor (3). These are the ways in which VS decreases blood glucose and increases glycogen synthase activity (i.e. glycogen storage). There is even some evidence that vanadium can stimulate insulin release from the pancreas (4). Keep in mind that these effects are not just happening in muscle cells, but also in fat cells.

So why use VS if it isn?t anabolic? Well, with the popularity of ketogenic diets incorporating a carb loading phase, the value of an insulin mimicker becomes obvious. Often people advocating ketogenic diets forget to tell you that going into ketosis significantly reduces insulin sensitivity. During ketosis this has the effect of decreasing glycogen usage and increasing fatty acid usage. Unfortunately during the reloading phase this leads to decreased glucose uptake leaving you feeling flat and weak. The only way to correct the problem is to increase insulin levels, decrease fatty acid levels, or better yet, both. By adding VS, whey isolate, and a little nicotinic acid (w/B6) to your initial carb drinks you can do both without messing with injectable insulin and thereby significantly increase glucose uptake during the brief reloading phase. If you do this properly you will notice a significant increase in weight (mostly water) and a satisfying feeling of fullness in the muscle bellies.

Recent research is now focused on making VS more effective. Several forms of vanadium are indeed more effective and research continues today to finally arrive at a form that is well tolerated, potent, and that can compete on some level with existing antidiabetic drugs. So far several forms of vanadium have been found to be significantly more potent and less toxic than VS (5). Bis(maltolato)oxovanadium (BMOV) is your best bet if you want to use vanadium today. It is significantly more potent than VS and is also significantly less toxic. VS has been shown to interfere with growth of young rats where as BMOV shows no such effects while producing superior insulin-like effects (6). Perhaps the top dog of vanadium insulin mimickers not yet available is vanadyl acetylacetonate. It has shown to be even more potent than bis(maltolato)oxovanadium. Other researchers are now trying to explore the possibility of transdermal vanadium and are showing some early success (7).

References:

1. Stankiewicz PJ., Gresser MJ. Inhibition of phosphatase and sulfatase by transition-state analogues. Biochemistry 27:206-212, 1988

2. Tamura S., Brown TA., Whipple JH., et al: A novel mechanism for the insulin-like effects of vanadate on glycogen synthase in rat adipocytes. J Biol Chem. 259:6650-6658, 1984

3. Pandey SK, Anand-Srivastava MB, Srivastava AK. Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. Biochemistry 12;37(19):7006-14, 1998

4. Fagin JA., Ikeliri K., Levin SR. Insulinotropic effects of vanadate. Diabetes 36:1448-1452, 1987

5. Reul BA, Amin SS, Buchet JP, Ongemba LN, Crans DC, Brichard SM. Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats. Br J Pharmacol 126(2):467-77, 1999

6. Yuen VG., Orvig C., McNeill JH. Comparison of the glucose lowering properties of vanadyl sulfate and bis(maltolato)oxovanadium (IV) following acute and chronic administration. Can J Physiol Pharmacol. 73:55-64, 1995

7. Brand RM, Hamel FG Transdermally delivered peroxovanadium can lower blood glucose levels in diabetic rats. Int J Pharm 25;183(2):117-23, 1999

Chromium is an essential mineral that participates in carbohydrate and lipid metabolism. The trivalent form of Chromium (the kind you eat) is required for maintaining normal glucose metabolism in laboratory animals by acting as a cofactor for insulin (Mertz,1969). The biological action of chromium is believed to be due to its complexing with nicotinic acid and amino acids to form the organic compound glucose tolerance factor (GTF) (Mertz, 1974). This organic complex has recently been referred to as a chromium-containing oligopeptide low molecular weight chromium-binding substance (LMWCr) and has been shown to interact with insulin-stimulated kinase receptors of isolated adipocytes (Davis, 1997). The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. Chromium exerts its effects by increasing disulfide bridging between the insulin peptide and it?s receptor.

Populations that have been shown to respond to Chromium supplementation include type-II diabetics and the elderly. However, the results are often equivocal. Some studies have shown a great number of subjects responding to Cr supplementation (Saner, 1983; Mossop, 1983; Riales, 1981; Urberg, 1987), while other obtained less promising results with about 40% - 60% responding positively (Levine, 1968; Glinsmann, 1966), still others have shown no response (Uusitupa, 1991), and even a deterioration in glucose regulation (Wise, 1978).

Martin (Marin, 1987) examined the effect of simultaneous chromium and nicotinic acid supplementation. They found a favorable response in subjects receiving both nicotinic acid and chromium together. Both chromium and niacin administered alone had no effect on the measured parameters. Nicotinic acid is probably enhancing insulin sensitivity by decreasing FFAs. This is the same mechanism by which nicotinic acid enhances GH release in response to exercise.

Diets high in simple sugars have been shown to increase Cr excretion by 300% (Anderson, 1990). This becomes significant whenever you are trying to load carbs with high glycemic carb drinks. The now common cyclic ketogenic diets are a good example. Some advocates of this diet recommend extremely high quantities of glucose drinks for at least 24 hours during the "reloading" phase. This not only puts a strain on the ol? digestive track but also may push the limits of your chromium levels. In addition, the limited variety of foods that are allowed on such diets makes mild deficiencies of several vitamins and minerals, including chromium, possible over time.

Bottom line, chromium is critical for normal insulin activity. If you are not chromium deficient you will not notice any noticeable increase in muscle mass or decrease in body fat while supplementing with chromium. If you are using insulin I would highly suggest supplementing with chromium in the form of GTF or chromium picolinate, other than that, just take a multi vitamin with a little chromium in it for good measure.

References:

Glinsmann WH, Mertz W: 1966. Effect of trivalent chromium on glucose tolerance. Metabolism 15:510-520.

Levine RA, Streeten DHP, Doisy RJ: 1968. Effects of oral supplementation on glucose tolerance of elderly subjects. Metabolism 17:114-125.

Anderson RA, Polansky MM, Bryden NA, et al: 1983. Chromium supplementation of human subjects: Effects on glucose, insulin and lipid variables. Metabolism 32:894-899

Anderson, 1990) RA; Bryden NA; Polansky MM; Reiser S Urinary chromium excretion and insulinogenic properties of carbohydrates. Am J Clin Nutr, 51:864-8, 1990 May

Anderson RA, 1993. Recent advances in the clinical and biochemical effects of chromium deficiency. In: Prasad AS, ed. Essential and toxic trace elements in human health and disease: An update. New York: Wiley-Liss; 221-234.

Clancy S., et al: Effects of chromium picolinate supplementation on body composition, strength, and urinary chromium loss in football players. International Journal of Sport Nutrition 4:142-153, 1994

Davis, CM; Vincent, JB., 1997. Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry; 36(15): 4382-5

Evans G., The effect of chromium picolinate on insulin controlled parameters in humans. International Journal of Biosocial and Medical Research 11:163-180, 1989.

Hallmark M., et al: Effects of chromium and resistive training on muscle strength and body composition. Med Sci Sports Exerc. 28:139-144, 1996

Mertz, W., 1969. Chromium occurrence and function in biological systems. Physiol. Rev. 49:163-239.

Mertz, W., Toepfer E.W., Roginski, E.E., et al. 1974. Present knowledge of the role of chromium. Fed Proc 33:2275-2280.

Mossop RT: 1983. Effects of chromium III on fasting blood glucose, cholesterol and cholesterol HDL levels in diabetics. Cent Afr J Med 29:80-82.

Offenbacher EG, Pi-Sunyer FX: 1980. Beneficial effect of chromium rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes 29:919-925

Riales R, Albrink MJ: 1981. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high density lipoprotein of adult men. Am J Clin Nutr 34:2670-2678.

Saner G, Yuzbasiyan V, Olcay N, et al: 1983. Alterations of chromium metabolism and the effect of chromium supplementation in Turner?s syndrome patients. Am J Clin Nutr 38:574-578.

Schroeder, H.A., 1966. Chromium deficiency in rats: a syndrome simulating diabetes mellitus with retarded growth. J. Nutr. 88:439-445.

Uusitupa-MI; Mykkanen-L; Siitonen-O; et al: 1991. Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels. Br-J-Nutr. 68(1): 209-16.

Wise A; 1978. Chromium supplementation and diabetes. JAMA 240: 2045-2046.

World Health Organization (1985). Diabetes Mellitus. Report of a WHO Study Group. Technical Report Series no. 727. Geneva: WHO.

Many people may knock the use of chromium, vanadyl or even ALA. Most of these people however, do not understand anything about these compounds or how insulin itself works for that matter. With the right expectations, conditions, and consistency I really believe that a person can shift nutrient partitioning over time to favor muscle gain and fat loss.