1. Field of the Invention
The present invention is in the field of pharmaceutical compositions and methods for the treatment of insulin related disorders in individuals.
2. Description of the Related Art
Diabetes is a chronic disease that has no cure. Currently, about 18.2 million people or 6.3% of the population in the United States have diabetes. While roughly 13 million have been diagnosed, it is estimated that 5.2 million people are not aware that they have the disease. As the sixth leading cause of death by disease in 2000, diabetes is costing the U.S. health care system an estimated $132 billion annually. See National Diabetes Information Clearinghouse, NIH Publication No. 04-3892, November 2003. More serious than the economic costs associated with diabetes is the decrease in the quality of life, serious health complications/consequences, and deaths associated with diabetes.
Diabetes is a group of diseases characterized by high blood glucose levels, which result from defects in insulin production, insulin action, or both. Because diabetes can remain undiagnosed for years, many people become aware that they have diabetes only after the development of one of its life-threatening complications. It is well-accepted that both genetics and environmental factors, such as obesity and lack of exercise, are important factors in the onset of diabetes.
One group of diabetes, Type 1 (or insulin-dependent diabetes mellitus or juvenile-onset diabetes), develops when the body's immune system destroys pancreatic cells that make the hormone insulin, which regulates blood glucose levels. Type 1 diabetes usually occurs in children and young adults, although disease onset can occur at any age. Type 1 diabetes accounts for about 5 to 10 percent of all diagnosed cases of diabetes. Risk factors for Type 1 diabetes include autoimmune, genetic, and environmental factors. Individuals diagnosed with Type 1 diabetes require daily delivery of insulin via injections or pumps.
Another group of diabetes, Type 2 (or Type II) diabetes (non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes), is a metabolic disorder involving dysregulation of glucose metabolism and insulin resistance, which can result in long-term complications involving the eyes, kidneys, nerves, and blood vessels. Type 2 diabetes results from the body's inability to make either sufficient insulin (abnormal insulin secretion) or its inability to effectively use insulin (resistance to insulin action in target organs and tissues). This disease usually begins as insulin resistance, a disorder in which the cells do not use insulin properly, and as the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Patients suffering from Type 2 diabetes have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in absolute terms, although they are lower than predicted for the level of plasma glucose that is present. Type 2 diabetes is the most common form of the disease accounting for 90-95% of diabetes. Type 2 diabetes is nearing epidemic proportions, due to an increased number of older Americans and a greater prevalence of obesity and a sedentary lifestyle.
Type II diabetes mellitus is characterized by the following clinical signs or symptoms: persistently elevated plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or polyphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension. These micro- and macro-vascular complications can lead to blindness, end-stage renal disease, limb amputation and myocardial infarction
Gestational diabetes refers to a form of glucose intolerance that is diagnosed in pregnant women. During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. A percentage (5-10 percent) of women with gestational diabetes have Type 2 diabetes after pregnancy. Women who have had gestational diabetes also have a 20-50 percent chance of developing diabetes in the next 5-10 years.
Many pharmaceutical compositions and methods have been proposed to treat and/or cure diabetes. For example, one approach to reducing hyperglycemia in diabetes involves increasing liver glucokinase (GK) activity (Van Schaftingen, E. et al., Adv. Enzyme Regul. 32:133-148, 1992). Studies involving transgenic diabetic mice have shown that increased GK copy number results in increased hepatic glucose metabolism and decreased plasma glucose levels (Ferre, T. et al., Proc. Natl. Acad. Sci. USA, 93:7225-7230, 1996; FASEB J., 10:1213-1218, 1996; Niswender, K. D. et al., J. Biol. Chem., 272:22570-22575, 1997), demonstrating that increasing liver GK may be effective in reducing hyperglycemia in diabetes.
U.S. Pat. No. 5,714,519 (hereinafter the '519 patent) discloses methods for controlling either hyperinsulinemia or insulin resistance by administering panthethine (see claims 1-18; col. 5, lines 6-15) or cysteamine (see claims 19-27; col. 5, lines 16-22) at predetermined intervals during the day. Unfortunately, some of the dosages of panthethine or cysteamine (for example, 500 mg of cysteamine) disclosed in the '519 patent are toxic to humans. In fact, such dosage amounts of cysteamine or panthethine can also cause undesirable gastrointestinal symptoms, such as increased acid output or even ulcers (Srivastava, P. K. & L. Field, J. Med. Chem., 18(8):798-802, 1975). U.S. Pat. No. 6,686,337 discloses methods for treating Type II diabetes using a combination of a specified sulfamate and an antidiabetic agent.
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