Oral Hypoglycemic Agents

   Diabetes Mellitus

        Diabetes mellitus is a disease arising from the inability of the body to metabolize glucose resulting in high blood glucose level, the development of ketoacidosis and the problems thereof. It is divided into two classes : Insulin-dependent (Type I) and Noninsulin-dependent (Type II). Both types have been recognized as genetic diseases for centuries and yet the contribution of genetic factors to the development of the disease remain obscure.

        All tissues have an energy requirement that is usually met by metabolizing glucose. The entry of glucose from the blood into the cells, of liver, skeletal muscle, and adipose tissue is promoted by the presence of insulin. In the diabetic, the insulin-dependent tissues cannot assimilate glucose normally, and glucose accumulates within the blood (hyperglycemia). As the blood glucose concentration increases, osmotic forces come into play that tend to increase the blood volume and urine output (polyuria). As the blood glucose level exceeds its renal threshold, glucose appears in the urine (glucouria). The increased loss of water from the body triggers compensatory adjustments that lead to an increase in thirst (polydipsia). The inability of glucose to enter some tissues increases the need for alternate sources of energy, such as ketone bodies, which are synthesized by the liver. Increased concentrations of ketone bodies appear in the blood (ketonemia) and ultimately in the urine (ketouria).

        Diabetes is characterized by a deficiency of effective insulin, a proteinaceous hormone secreted by the b-cells of the islets of Langerhans of the pancreas. The structure of insulin was elucidated by Sanger in 1950s. Insulin molecule is composed of two polypeptide chains : an A chain consisting of 21 amino acid residues and a B chain containing 30 residues. The two chains are connected by two disulfide bonds and there is an additional disulfide linkage within the A chain. (To view a three-dimensional structure of insulin click here.)

        The most familiar action of insulin is its ability to promote glucose uptake by the cells of responsive tissues. Glucose uptake in virtually all cells occurs through the process of facilitated diffusion mediated by proteins known as glucose transporters. The primary goal in the treatment of diabetes is to prevent the development of hypoglycemic conditions in tissues. For type I diabetic this could be achieved by supplemental or replacement insulin therapy. Some type II diabetics who do not respond to oral hypoglycemic agents have to be maintained on insulin. The number and types of insulin preparations currently available are numerous. These preparations differ in the duration and onset of action.

        Oral Antidiabetic Agents

        Insulin therapy suffers from several problems. Insulin alleviates the symptoms associated with the cause and hence the disease persists endlessly. Insulin is a proteinaceous substance capable of inducing an immune response in the patient. Hypersensitivity to insulin is common. Because of its nature it has to be injected causing some discomfort to the patient. Insulin resistance is another problem.

        A great deal of research toward the development of more effective ways of treating the disease has led to the development of orally active agents including the sulfonylureas and the biguanides. These oral agents have been widely received and are primarily used for the treatment of noninsulin-dependent type of diabetes.

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©2003 VCU School of Pharmacy
Revised: October 30, 2003
Questions or Comments : Dr. Umesh R. Desai