Tratamiento De Diabetes

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Insulin Secretagogues: Sulfonylureas, Meglitinides, and Phenylalanine Derivatives
Harold E. Lebovitz
Hyperglycemia in patients with DM is always the result of a mismatch between the quantity of insulin necessary to regulate the person’s metabolic processes and the amount of insulin being secreted by the person’s β-cells. Patients with type 1 DM or insulin-sensitive type 2 DM who have normalinsulin action have an absolute insulin deficiency. Patients with insulin resistance start with a relative insulin deficiency and with passing years frequently progress to an absolute insulin deficiency.
Therapy to correct hyperglycemia in type 2 diabetic patients must therefore be directed at decreasing insulin requirements in those who are insulin resistant, thereby bringing endogenous insulinsecretion more closely in alignment with insulin need, or at increasing the insulin available adequately to meet the insulin requirements, whether normal or increased. Oral antihyperglycemic agents such as thiazolidinediones or metformin decrease insulin resistance; α-glucosidase inhibitors decrease postprandial insulin needs; insulin secretagogues improve and increase endogenous insulinsecretion; and insulin and its analogues replace endogenous insulin secretion by exogenous insulin administration.
Effective glycemic control in diabetic patients requires appropriate regulation of both fasting and postprandial plasma glucose levels. Therapeutic agents may have more specific effects on one or the other. Metformin and the long-acting sulfonylureas such as glyburide primarily improvefasting hyperglycemia. The newer rapid-acting nonsulfonylurea insulin secretagogues markedly reduce postprandial hyperglycemia. The decisions concerning the use of insulin secretagogues requires a through understanding of the differences among them and a proper assessment of how they will influence the pathophysiology of the particular patient for which their use is being considered.
Insulin SecretoryMechanisms in Normal and Type 2 Diabetic Subjects
Insulin secretion from the β-cell is regulated by the extracellular glucose concentration and is modulated by factors such as gastrointestinal hormones, nonglucose nutrients, and neural inputs. The β-cell contains an intricate glucose-sensing mechanism that consists of GLUT-2, glucokinase, and glycolytic and mitochondrial pathways that oxidizeglucose to convert adenosine diphosphate (ADP) to adenosine triphosphate (ATP). The intracellular β-cell message that reflects the extracellular glucose concentration is the ATP:ADP ratio. This message controls an ATP-sensitive potassium ion channel (KATP) located in the β-cell plasma membrane. The KATP channels are open when the extracellular glucose concentration is low (fasting state with a lowATP:ADP ratio) and transport K+ from the intracellular to the extracellular compartment. As extracellular glucose concentration increases, the ATP:ADP ratio increases and an increasing number of KATP channels close. This causes K+ to accumulate at the plasma membrane, which then depolarizes, causing voltage-dependent L-type calcium channels in the plasma membrane to open. Extracellular calcium ionsenter the β-cell and increase the cytosolic calcium ion concentration. Increasing cytosolic Ca2+ stimulates the movement and secretion of insulin granules.
The KATP channel in the β-cell consists of two subunits: one that contains sulfonylurea and ATP binding sites, called the sulfonylurea receptor type 1 (SUR1) subunit, and an inwardly rectifying potassium channel (KIR6.2) that acts as thepore-forming subunit. Both subunits are necessary for a functional KATP channel. Four KIR6.2 subunits form the pore, and they are surrounded by four SUR1 subunits. Both ATP and sulfonylurea binding sites appear to be on the cytoplasmic surface of the KATP channel. Either an increase in ATP:ADP ratio, as occurs with increased nutrient flux through the β-cell, or binding of a ligand to the SUR subunit...