The present invention relates to a composition of vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine to augment or normalize cellular tyrosine phosphorylation responses to insulin, thereby normalizing insulin activity, decreasing catabolic activity in the diabetic state, decreasing serum lipoproteins and maintaining normal body weight in healthy humans and animals.
The actions of insulin are initiated by its binding to insulin receptor, a disulfide-bonded heterotetrameric membrane protein (FIG. 1). Insulin binding causes conformational changes in insulin receptor that lead to autophosphorylation of the receptor and activation of the receptor""s intrinsic tyrosine kinase activity. The function of the tyrosine kinase of insulin receptor is essential for the biological effects of insulin. After autophosphorylation, the insulin receptor can phosphorylate the tyrosine residues of several substrates, including the insulin receptor substrate (IRS) proteins, which in turn can activate downstream signaling molecules in hepatic, muscle and fat cells.
A protein tyrosine phosphatase termed PTP-1B can terminate the signaling cascade initiated by insulin by removing the phosphate from the insulin receptor. Studies indicate that increased expression of PTP-1B in mice gives rise to a form of insulin resistance termed type 2 non-insulin dependent diabetes mellitus (NIDDM). NIDDM is a complex disease characterized by progressive development of insulin resistance and defects in insulin secretion, which often leads to overt hyperglycemia. On the other hand, some data indicate that mice lacking the PTP-1 B gene are more sensitive to insulin""s blood glucose-lowering effects than are control animals, and, these PTP-1B defective mice appear to be more resistant to weight gain when consuming a high-fat diet {Elchebly et al., 238 SCIENCE 1544-1548 (1999)].
Vanadate is known to be an inhibitor of many phosphatases. Some researchers have proposed that vanadate administration may mimic the activity of insulin. For example, U.S. Pat. No. 5,550,113 and U.S. Pat. No. 5,888,993 disclose vanadium salts for blood sugar regulation. U.S. Pat. No. 5,885,980 and U.S. Pat. No. 5,614,224 disclose vanadium salts for the treatment of diabetes.
However, vanadyl sulfate is not widely used to mimic the activity of insulin because chronic administration of vanadate can be toxic. Vanadyl sulfate has been shown to induce chromosomal damage and mitotic recombination in the fruit fly. Vanadyl sulfate can induce pulmonary inflammation in rats when inhaled. In vitro studies of bovine papilloma virus DNA-tranfected C3H/10T1/2 cells have demonstrated that vanadyl sulfate possess tumor promotion activity.
To avoid the toxic build-up of vanadate, some researchers suggest administering it intermittently. For example, U.S. Pat. No. 5,730,988 to Womack (Mar. 24, 1998) discloses administration of nutritional supplements containing a source of vanadate in a xe2x80x9cPhase Ixe2x80x9d supplementation program and lipoic acid and Gymnema sylvesire in a xe2x80x9cPhase IIxe2x80x9d supplementation cycle.
Given the potential usefulness of vanadyl sulfate in the treatment of diabetes, it would be desirable to administer compositions containing vanadyl sulfate to diabetic patients, and to normal individuals wishing to minimize their risk of developing NIDDM, if the undesirable side effects of vanadate could be avoided.
Alpha-lipoic acid has been studied as a potential treatment for improving glucose metabolism. U.S. Pat. No. 5,693,664 to Wessel et al. (Dec. 2, 1997) discloses the R-(+) enantiomer of alpha-lipoic acid and its metabolites for the treatment of diabetes. A formulation of DL-lipoic acid is described in U.S. Pat. No. 5,599,835 to Fischer (Feb. 4, 1997) for treatment of a metabolic aberration of the multi-enzyme complex of pyruvate dehydrogenase, which is symptomatic of diabetes mellitus.
Taurine is a conditionally essential amino acid that is found in the tissues of most animal species. It is not incorporated into proteins, but is found free in many tissues. Taurine is involved in a number of physiological processes including bile acid conjugation, osmoregulation, detoxification of xenobiotics, cell membrane stabilization, modulation of cellular calcium flux, and modulation of neuronal excitability. Low levels of taurine have been associated with retinal degeneration, growth retardation, and cardiomyopathy. Taurine has been used clinically in the treatment of cardiovascular diseases, hypercholesterolemia, seizure disorders, ocular disorders, diabetes, Alzheimer""s disease, hepatic disorders, cystic fibrosis, and alcoholism. Animal and human studies indicate that taurine supplementation is effective in alleviating some of the complications of insulin-dependant diabetes. Taurine has been found to influence blood glucose and insulin levels, as well as increasing glycogen synthesis, and it may also be involved in the functioning and integrity of pancreatic beta cells.
Trivalent chromium is an essential trace element for normal carbohydrate metabolism and insulin sensitivity. Because of this biological activity, chromium supplementation has been studied as a potential therapy of insulin resistant states and dyslipidemias, and has been promoted as a health aid to the general population. Chromium has principally been studied for its possible benefits in improving blood sugar control in diabetic patients.
Chromium improves the glucose/insulin system in subjects with hypoglycemia, hyperglycemia, diabetes and hyperlipemia with no detectable effects on control subjects. Chromium improves insulin binding, insulin receptor number, insulin internalization, beta cell sensitivity and insulin receptor enzymes with overall increases in insulin sensitivity. There have been several studies involving chromium supplementation of subjects with NIDDM and/or lipemia and most have reported beneficial effects of chromium on the glucose/insulin system. In summary, chromium is involved in the control of the glucose/insulin system and the form of chromium is critical when evaluating the role of chromium in this system.
Several forms of chromium have been studied with respect to glucose metabolism and impact on insulin resistance. Controversy exists as to which supplemental form of chromium is preferable; and, regarding insulin resistance, this controversy is likely to continue. The present invention provides a novel composition of chromium (+3) as chromium carnitine. This chelated form of chromium, administered in combination with vanadyl sulfate, lipoic acid, and taurine, functions coordinately to normalizes insulin signaling in liver, muscle and fat cells.
Hence, while certain compounds are thought to separately mimic some of the activities of insulin, a single non-toxic composition that provides a more complete range of insulin-like activities would be desirable. The ideal formulation would (i) increase cell sensitivity to insulin, (ii) maintain normal serum glucose, (iii) decrease hypertriglyceridemia and/or lipoproteins, and (iv) maintain normal body weight even with consumption of a high fat diet. These objects and other are achieved in the present invention.
In accordance with the present invention, an oral formulation is provided that comprises vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine. The present supplement; (a) increases cell sensitivity to insulin, (b) maintains normal serum glucose, (c) decreases serum triglycerides and/or serum lipoproteins, and (d) maintains normal body weight even with consumption of a high fat diet. The supplement can be used by normal, healthy individuals as well as diabetics.
The present invention also provides a method of oral supplementation in animals that includes administering to an animal suffering symptoms of diabetes a composition including therapeutically effective amounts of vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine and continuing administration of the composition until the symptoms are reduced.
The present invention further provides a method of oral supplementation in animals that includes administering to an animal a composition, which includes therapeutically effective amounts of vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine, and continuing administration of the composition until normalization of serum glucose is achieved.
The present invention still further provides a method of oral supplementation in animals that includes administering to an animal a composition, which includes therapeutically effective amounts of vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine, and continuing administration of the composition until normalization of serum triglycerides or lipoproteins is achieved.
The present invention additionally provides a method of treating obesity in an animal that includes administering to an animal a composition including therapeutically effective amounts of vanadyl sulfate, alpha-lipoic acid, taurine and chromium carnitine.
According to the present invention, the animal is a mammal selected from the group consisting of humans, nonhuman primates, dogs, cats, horses or cattle.
A pharmaceutically acceptable carrier may also be used in the present compositions and formulations. The formulations can be manufactured in any form known to the skilled artisan, for example as solid capsules, caplets, softgels, liquids, bars, or functional foods.
Other features and advantages of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the features of the invention.