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Insulin first became available for use in 1922 after Banting and Best successfully treated diabetic patients with pancreatic extracts.10 In an attempt to more closely simulate physiologic conditions, additional “designer” insulins with unique kinetic properties have been developed, including a rapid-acting basal insulin that mimics baseline insulin secretion known as lispro.67,140 Several oral delivery systems for insulin have been studied.94 However, the development of an oral delivery system for use in humans has not been successful because of poor intestinal absorption and degradation of the oral form of insulin by digestive enzymes. Using zonula occludens toxin, modulation of intestinal tight junctions in animal models significantly increases enteral absorption of insulin.42 An inhaled form of insulin was withdrawn from the market due to poor sales and inability to demonstrate better glucose control than short-acting insulins.90

The hypoglycemic activity of a sulfonamide derivative used for typhoid fever was noted during World War II.76 This discovery was verified later in animals. The sulfonylureas in use today are chemical modifications of that original sulfonamide compound. In the mid-1960s, the first generation ­sulfonylureas were widely used. Newer second generation drugs differ ­primarily in their potency.

Although insulin is widely used for treating diabetes mellitus, oral hypoglycemic exposures are more commonly reported to poison centers than are insulin exposures, based on 15 years of data from 1996 to 2010 (Chap. 136). In an older review of 1418 medication-related cases of hypoglycemia, sulfonylureas (especially the long-acting chlorpropamide and glyburide) alone or with a second hypoglycemic accounted for the largest percentage of cases (63%).130 Only 18 of the sulfonylurea cases in this series involved intentional overdose. However, hypoglycemia is reported in as many as 20% of patients using sulfonylureas.59 In a study of 99,628 emergency hospitalizations for adverse drug events in adults older than 65 years of age, 14% were due to insulin and 11% were due to oral hypoglycemics. The majority (95%) of the hospitalizations related to these groups of endocrine agents were due to hypoglycemia.19 Other causes of hypoglycemia are listed in Table 53–1.

TABLE 53–1.Causes of Hypoglycemia

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