Diabetes refers to a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion or action. When abnormally high blood glucose levels are continued for a long period time, various complications occur due to chronic metabolic disorders and the result chronic vascular injuries.
Diabetes, a typical adult metabolic disease, is suffered by about 5% of the population in the world and causes a huge loss of lives and properties. Most diabetic patients take oral therapeutic agents, but a safe therapeutic agent has not yet been developed. Insulin resistance is known to be the most important cause of diabetes, but the exact mechanism of diabetes is still unknown, and it is known that diabetes is caused by genetic predisposition and environmental factors. Diabetes is the third leading cause of death in the world, and the number of diabetic patients in 2010 is estimated to be about 250 millions. In Korea, the number of diabetic patients is expected to increase continuously in the future. Non-insulin dependent diabetes (NIDDM) is the seventh leading cause of death in Korea and accounts for more than 90% of diabetic patients. It is called “adult diabetes”, because it occurs mainly in persons who are over 40 years old. It is a metabolic disorder which is caused by the insufficient production or inappropriate use of insulin (DeFronzo R A et al., Diabetes Care, 15:318, 1992). Although the cause of onset of NIDDM is not yet clearly known, it is believes that NIDDM is caused by environmental factors, including westernized eating habits and life styles, as well as genetic factors such as obesity and lack of exercise. For treatment of NIDDM, dietary therapy and exercise therapy are first attempted, and if the therapeutic effects of such therapies are insufficient, drugs are used, and in many cases, insulin is used. Insulin is required for patients whose blood glucose levels are not regulated by dietary therapy and oral blood glucose lowering drugs. However, because insulin is a protein, it is inactivated by hydrolysis in the stomach. For this reason, it cannot be administered orally and should be injected intravenously or subcutaneously.
Oral blood glucose lowering drugs improve the sensitivity of insulin receptor of a cell and stimulate the pancreases to promote secretion of insulin, and thus they are used to regulate blood glucose levels in NIDDM patients. However, oral therapy for treatment of NIDDM can cause hypoglycemia, nausea, vomiting, diarrhea, eruption and the like. Particularly, it can cause serious adverse effects such as fatal lactic acidosis. In addition, oral blood glucose lowering agents, when used for a long time, cause cardiovascular disorders or gastrointestinal and hepatic disorders. For this reason, the long-term use thereof is not recommended. Due to such shortcomings and adverse effects, among current therapeutic drugs, there are little or no drugs, which show satisfactory effects, have high safety without adverse effects and can be applied to all diabetic patients. Thus, there is an urgent need to develop a more efficient drug for treating diabetes, particularly NIDDM.
About 10 years after the onset of diabetes, almost all the organs of the body are damaged, causing complications. Such complications include acute diseases, such as hypoglycemia, ketoacidosis, hyperosmolar nonketotic hyperglycemia, hyperglycemic coma, and diabetic ketoacidosis; and chronic diseases, such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, cardiovascular complications, and viral infections. Chronic diabetic nephropathy is the most important cause of hemodialysis and end-stage renal failure, and diabetic cataract causes blindness, and eventually leading to death.
The mechanisms causing diabetes are generally described by nonenzymatic glycation of proteins, polyol pathways, and the like. The non-enzymatic glycation of protein is caused by condensation of amino acid group such as lysine residue of protein with reduced sugar without enzymatic action, that is, the Maillard reaction. As a result of the reaction, glycation end products are produced. The non-enzymatic glycation of protein includes two steps. In the first step, an amino acid group (such as lysine of protein) and aldehyde or ketone of reduced sugar are subjected to a nucleophilic addition reaction without enzymatic action to form a Schiff base, a product of the early stage, and the Schiff base is condensed with the adjacent ketoamine adduct to produce a reversible Amadori-type early glycation product. In the second step, as the high blood glucose level is kept, the reversible Amadori type early glycation product is rearranged without degradation and is cross-linked with a protein to form irreversible advanced glycation end products.
Unlike the reversible Amadori type early glycation product, the advanced glycation end products are irreversible products. Therefore, the advanced glycation end products are not degraded, even when the blood glucose level is returned to the normal level, but they are accumulated in tissue to abnormally change the structure and function of the tissue for the survival period of the protein, thus causing complications in the tissue (Vinson, J. A. et al., J. Nutritinal Biochemistry, 7: 559, 1996; Smith, P. R. et al., Eur. J. Biochem., 210:729, 1992). For example, glycated albumin which is one of the advanced glycation end products produced by the reaction of glucose with various proteins acts as the major cause of chronic diabetic nephropathy. The glycated albumin is more easily introduced into glomerular cells compared to normal albumin, and a high concentration of glucose stimulates mesangial cells to increase the synthesis of extracellular matrix. The excessively introduced glycated albumin and the increased extracellular matrix cause the fibrosis of glomeruli. By these mechanisms, the glomeruli are continuously damaged, so that extreme treatments such as hemodialysis and organ transplantation are necessarily required. In addition, it was reported that, in the case of chronic diabetes, the collagen in arterial walls and the basement membrane protein in glomeruli bind to the advanced glycation end products and are accumulated in tissue (Brownlee, M. et al., Sciences, 232:1629:1986).
Due to the non-enzymatic protein glycation as described above, proteins such as the basement membrane, plasma albumin, the crystalline lens protein, fibrin, collagen and the like are glycated. The advanced glycation end products abnormally change the structure and function of the tissue to cause chronic diabetic complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy and the like (Yokozawa, T. et al., J. of Trad. Med., 18:107, 2001). Thus, it was found that inhibiting the formation of advanced glycation end products is very important in delaying the onset of diabetic complications or preventing or treating diabetic complications (Brownlee, M. et al., N. Engl. Med., 318:1315, 1988).
In addition, advanced glycation end products overexpress vascular endothelial growth factor (VEGF) mRNA and protein to cause non-proproliferative or proliferative diabetic retinopathy. Aberrant angiogenesis or the pathogenic growth of new blood vessels is involved in a number of conditions. Such conditions include diabetic retinopathy, psoriasis, exudative or wet age-related macular degeneration (ARMD), rheumatoid arthritis and other inflammatory diseases, and most cancers (Aiello et al., New Engl. J. Med, 331:1480, 1994; Peer et al. Lab. Invest., 72:638, 1995). The VEGF in tumors or tissues suffering from diseases associated with these conditions expresses at an aberrantly high level, and has increased angiogenesis or vascular permeability. ARMD in particular is a clinically important angiogenic disease. This condition is characterized by choroidal neovascularization in one or both eyes in aging individuals, and is the major cause of blindness in industrialized countries. Anti-angiogenic agents used in various therapies can produce only a stoichiometric reduction in VEGF or VEGF receptor, and the agents are typically overwhelmed by the abnormally high production of VEGF by the diseased tissue (Lopez et al., Invest. Opththalmol. Vis. Sci., 37:855, 1996).
Accordingly, the present inventors have made extensive efforts to find a natural herbal substance for treating diabetes and its complications, which has less adverse effects. As a result, the present inventors have found that a novel compound isolated from Quamoclit sp. functions to improve diabetic indexes such as blood sugar, glycated hemoglobin, urine protein, etc. in diabetes mice, thereby completing the present invention.
USPTO Backgrounds
USPTO Backgrounds