Type II diabetes mellitus is a clinically and genetically heterogeneous group of syndromes characterized by elevated blood glucose levels. It occurs because the insulin produced by the .beta. (beta) cells of the pancreas is either insufficient or ineffectively utilized by target tissues. The body is unable to metabolize macronutrients in foods in the normal manner. When high levels of glucose remain in the blood and spill into urine, microvascular and macrovascular complications arise.
It is well known that optimal blood glucose control delays the onset and progression of diabetes complications, and that medical nutrition therapy is essential to obtain such optimal control. In the past, in the belief that the higher the level of insulin in the blood, the better the metabolization of glucose, great effort has been devoted to pharmaceuticals which stimulate insulin secretion. Among numerous drugs stated to be effective to stimulate secretion of insulin, sulfonamides (sulfonylureas) are preferred. However, to avoid potential side effects and complications associated with medications, it is preferred to treat a diabetic with naturally occurring compounds which are generally regarded as safe to ingest. While diet can be effective to improve glycemic control, post-prandial glucose levels may still be significantly higher for a prolonged period of time in those diabetics following a recommended or approved diabetic diet with adverse effects on glycemic control.
It is well known that L-arginine infused intravenously (IV) functions as a non-glucose insulin secretogogue. Of all the amino acids, L-arginine is known to be the most effective insulin secretogouge, stimulating insulin release as much as 30-fold when administered parenterally. The peak insulin response to an IV arginine dose is typically within two (2) minutes but falls rapidly thereafter, and for this reason is not a useful means of improving glycemic control in diabetics. In diabetics, IV arginine is used exclusively for research and diagnostic purposes. Whichever path is chosen, whether through drugs or naturally occurring food ingredients, to achieve glycemic control, blood glucose levels must be monitored, adjustments to medications must be made, and attention must be paid to the interactions of insulin, food and physical activity.
It has been disclosed that an arginine-enriched medical food having about 180 cals, one-third (33.3%) of which is contributed by 15 g of sugar (58% of the carbohydrate which is an undesirably high quantity of one or more simple sugars in a meal for a diabetic), is marketed as a "fruit bar" referred to as a HeartBar, to enhance the body's production of nitric oxide. Such a sugar-rich fruit bar is contraindicated as a food for a diabetic, and there is no suggestion that enhanced NO production, if it does occur, may have any beneficial effect on a diabetic, irrespective of when the food is eaten. U.S. Pat. No. 5,428,070 to Cooke et al. teaches a method of inhibiting the development of atherosclerosis or restenosis in the vascular system of a human host susceptible to atherosclerosis or restenosis, by administering L-arginine, its physiologically acceptable salts or a biologically equivalent compound thereof, to the host, in accordance with a predetermined regimen, to enhance NO production by NO synthase in an amount sufficient to enhance the level of endogenous NO in the vascular system. For example, it is known that endothilium-derived relaxing factor has been identified as nitric oxide, and is derived from the guanidino group of L-arginine. (see "The generation of L-arginine in endothelial cells is linked to the release of endothelium-derived relaxing factor" by Mitchell, Jane A. et al European Journal of Pharmacology 176 (1990), 253-254). The advantages attained by methods using L-arginine are unrelated to the problem of glycemic control in a diabetic. Since the source of such a problem is unrelated to NO production, as is the solution to the problem, there is no motivation to use arginine or a biologically equivalent compound, or a physiologically acceptable salt of arginine to modify glycemic control in a diabetic.
More specifically, oral ingestion of L-arginine in an essentially sugar-free food supplement, consumed in combination with an approved meal (for a compliant diabetic) having less than about 1000 Kcal, preferably less than 500 Kcal, is unconcerned with either the enhancement or the diminution of NO generated as a direct result of the meal. The actual caloric values in "Kcal" are stated herein, rather than reference being made to "calories", as is popular. By "approved meal" is meant a meal approved by a national nutritional organization for the health of a diabetic, for example, the American Diabetes Association Inc. ("ADA") as set forth, for example in "Maximizing the Role of Nutrition in Diabetes Management" published 1994 by the American Diabetes Association, Inc., the disclosures relating thereto being incorporated by reference thereto as if fully set forth herein, or an equivalent approval. Other Western organizations which recommend or approve a meal for a diabetic are The International Diabetes Federation; the European Association For the Study of Diabetes; and the European and Canadian Dietetic Association. Other Eastern and Far Eastern organizations are the Chinese Diabetes Federation; the Japanese Diabetes Federation; and the Indian Diabetes Federation. It will be appreciated that an "approved meal" will vary depending upon the culture and geography of the diabetic, it being understood that, irrespective of either, a compliant diabetic will eat a meal which makes no more than a reasonable demand upon his/her system. By "essentially sugar-free" is meant that a single serving of the food supplement contains less than 10 Kcal of sugar, that is, fructose and/or glucose and/or sucrose. There is no data suggesting that the concentration of NO in the blood is directly related to the degree of glucose intolerance in a diabetic. Further, there is no known relation between the reduction of insulin caused by ingestion of L-arginine in combination with the meal, and the concentration of NO in the blood soon after ingestion of the meal. By "in combination with a meal" is meant that the L-arginine or a physiologically acceptable salt thereof, is ingested either concurrently with, or immediately prior to ingesting the meal, that is, no more than 30 min. prior to ingesting the meal. Physiologically acceptable salts of L-arginine include arginine phosphate, arginine hydrochloride, arginine nicotinate, and arginine related amino acids including di- and tri-peptides of arginine.
Assuming there is an enhancement of NO concentration due to ingestion of L-arginine, there is no motivation to combine L-arginine with low-calorie, essentially sugar free food ingredients to provide a food supplement with the expectation that the resultant increase in NO concentration would benefit a diabetic over a long period of time, from 1 month to 1 year or more, during which period such a meal in combination with the food supplement, was ingested at least once a day.
It is also alleged that L-arginine but not D-arginine, administered parenterally, stimulates insulin-mediated glucose uptake, presumably because nitric oxide, the metabolic mediator for L-arginine, potentiates insulin-mediated glucose uptake through the increase in blood flow. An independent effect of intracellular cyclic guanosine monophosphate (cGMP) on whole body glucose disposal was not ruled out. See Metabolism Vol. 46, No. 9, pg 1068-73, September 1997.
Prior to the aforesaid disclosure relating to parenterally administered L-arginine, in an article titled "Beneficial effect of L-arginine in non-insulin dependent diabetes mellitus: a potential role for nitric oxide", U. N. Das, I. Krishna Mohan et al., concluded that oral supplementation of L-arginine administered to a Type II diabetic having non-insulin-dependent diabetes mellitus (NIDDM), increased insulin secretion, which in turn may decrease hyperglycemia. None of the test subjects, all but one of whom were long-standing diabetics on either oral hypoglycemic agents or insulin (the title of the article notwithstanding), showed either insulin resistance or insensitivity to oral hypoglycemic agents. There is no indication as to which lone patient, of the 8 patients tested, had his/her condition controlled by diet alone; and there is a clear indication that all patients had their insulin secretion stimulated.
In the study referenced above, after a stabilization period of two weeks to determine base line parameters (pre-arginine), each patient took a 500 mg capsule of pure L-arginine three times a day (a total of 1.5 g each day) for 10 days, in addition to their normal medication, and before measurements were made with blood samples drawn to determine the effects of the treatment. Only one fasting and one post-prandial sample was evaluated for each subject rather than a series of samples over time. This minimal data, makes it premature to conclude that oral arginine stimulates insulin production. In addition, the nutritional components of the lunch, or its characteristics defining the content of carbohydrates, proteins, lipids, etc. was not specified. The level of L-arginine in the blood at any particular time was not stated. Also not stated was the time at which the blood sugar levels were measured (that is, how long after lunch). Comparing post-lunch blood sugar levels of the 8 patients, it is seen that an equal number have their sugar level raised as have their sugar level lowered. It is assumed that the interaction of the medication and L-arginine was responsible for enhancement of insulin secretion, and the variation in sugar levels. We have determined that such enhancement is not found in tests on diabetics who are not on medication administered particularly for enhancement of insulin secretion.
More recently, Nutall J. A. et al have confirmed that ingested protein results in an increase in circulating insulin concentration, and a decrease in glucose concentration in people with type II diabetes, and attributed it at least in part, to the absorbed amino acids given intravenously; IV arginine stimulated the greatest increase in circulating insulin concentration, but also resulted in a small rise in glucose concentration. However, oral arginine was found not to stimulate insulin secretion, in contrast to arginine given intravenously, and there is no report as to the effect of time at which the arginine was given, or what effects of such oral administration on the level of glucose may have been. See The Effects of Arginine Ingestion, With or Without Glucose, on the Glucose and Insulin Response in Normal Subjects, a talk delivered at the Meeting of the American College of Nutrition on Oct. 11, 1998.
USPTO Backgrounds
USPTO Backgrounds