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Diabetes Treatment: Insulin and Incretins

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Diabetes Treatment: Insulin and Incretins DIABETES FOUNDATION Diabetes Treatment: Insulin and Incretins Michael J. Fowler, MD Editor’s note: This article is the fourth contrast, type 2 diabetes is char- onset of regular insulin, patients in an eight-part series reviewing the acterized by preexisting insulin are typically instructed to inject it fundamentals of diabetes care for resistance followed by a relative ~ 30 minutes before meals. This can physicians in training. This series is an insulin deficiency. As a result of be more cumbersome than the use updated adaptation of a 12-part series insulin resistance and progressive of insulin analogs, which can be published in Clinical Diabetes between insulin deficiency, patients with type injected much closer to mealtimes. 2006 and 2009. The previous series, 2 diabetes typically require higher Another disadvantage of regular and earlier installments of this one, can doses of insulin with gradual upward insulin is that its pharmacokinetic be found online at the journal Web site titration of doses. profile does not overlap with the (http://clinical.diabetesjournals.org). Since the discovery of insulin and rate of carbohydrate absorption as its use to treat diabetes, insulin has well as that of insulin analogs. As a Part 1: Insulin Basics been combined with additives and result, regular insulin can produce nsulin is the original and the most even modified at the molecular level more postprandial hyperglycemia effective treatment to control to change its pharmacokinetic prop- soon after meals and delayed hypo- Iglucose levels in diabetic patients. erties. Some insulin preparations glycemia several hours after meals. It was first used in the treatment accelerate insulin’s effects in the This effect may be more pronounced of diabetes by Frederick Banting bloodstream, whereas others prolong in patients with type 1 diabetes and Charles Best in 1922. Although the pharmacokinetic profile. These because of their relatively high insu- originally thought to be a cure for insulin preparations may be used lin sensitivity. diabetes, it soon became evident alone or in combination with other Regular insulin have some that insulin was a method of con- insulins in formulating an insulin advantages over other insulin for- trolling the disorder. We now know regimen. mulations, however. Because it is that insulin may be used to control bioidentical to endogenous insulin, the hyperglycemia of virtually any Short- and rapid-acting insulins immunogenicity is very low—much form of diabetes. Although it was Regular insulin was the first available lower than with animal insulin initially prepared by isolation from insulin preparation and therefore the preparations. Cost is also a major animal pancreatic tissue, insulin is first short-acting insulin. At the time advantage; regular human insulin now prepared through recombinant of injection, regular insulin self-asso- sells for about one-fourth the price DNA techniques using microorgan- ciates to form hexamers, which are of insulin analogs.1–3 isms. Use of recombinant insulin has poorly absorbed into the circulation. There are currently three rapid- decreased the immunogenicity of Gradually, insulin hexamers dissoci- acting insulin analogs available in commercially available insulin. ate into dimers and monomers, which the United States: lispro, aspart, and Type 1 diabetes is character- enter the bloodstream more rapidly. glulisine. All three feature modifica- ized by a loss of pancreatic β-cells Formation of hexamers therefore tions to the insulin molecule that and therefore an absolute insulin delays absorption and activity of cause rapid dissociation of hexam- deficiency. The mainstay of therapy, regular insulin. ers into dimers and monomers after therefore, is insulin treatment. Regular insulin tends to have an injection. Because the disease does not affect onset of action 30–60 minutes after Rapid dissociation leads to insulin sensitivity, patients typi- injection, a peak effect in 2–3 hours, rapid absorption. As a result, these cally require small doses of insulin and a total duration of action of formulations may be administered to maintain glucose control. By 8–10 hours. Because of the delayed at the beginning of a meal, which CLINICAL DIABETES • Volume 28, Number 4, 2010 177 DIABETES FOUNDATION many patients find more acceptable 2–4 hours, with a peak in activity reservoir of insulin. It is the pre- and easier to remember than hav- within 4–10 hours and an effective cipitation of insulin out of solution ing to inject a full 30 minutes before duration of 10–16 hours. Because of that produces the extended half-life meals.4 its peaking action, NPH is associ- of glargine, which approaches 24 All rapid-acting insulin prepa- ated with a higher incidence of hours.3,4 The prolonged action of the rations are available in both vial hypoglycemia than are the analogs insulin reduces the peaking effect and pen devices. Insulin lispro and detemir and glargine, which tend to and results in a lower risk of hypo- have less peaking action. NPH may insulin aspart each have an onset glycemia than NPH. of action of 5–15 minutes, a peak of be used two or three times daily as a Glargine is administered once activity in 30–90 minutes, and dura- basal insulin or used in the morning daily, which may improve compli- tion of action of 4–6 hours. These to act as a combination of basal and ance. However, it is two to three insulins deliver approximately twice bolus insulin to cover the noon meal. the maximal concentration of insulin Two rapid-acting insulins, lispro times more expensive than NPH and and take approximately half as much and aspart, are also available in has not been shown conclusively time to reach maximal concentra- protamine solutions that prolong to reduce A1C compared to NPH. tions as regular insulin injected their effects. When in such solutions, Injection of glargine, especially in subcutaneously.4,5 Glulisine, the new- their long-acting component is simi- larger doses, may cause a burning est of these agents, has a faster onset lar to NPH.5 sensation, likely as a result of the than lispro.6 As a result, it may be NPH insulin is inexpensive and acidity of the solution. administered after meals rather than available without a prescription. Detemir was introduced more immediately before them. However, it has other potential recently and uses a different Rapid-acting insulins exhibit bet- disadvantages, such as significant approach to extend its half-life. ter control of postprandial glucose intra-patient variation in absorption, The insulin molecule is bound to a levels and have a lower frequency of which may cause variations in peak 14-carbon fatty acid. The addition of and duration from one injection to causing postprandial hypoglycemia the hydrophobic fatty acid leads to another.3,7 than regular insulin. There may albumin affinity, allowing the insulin also be less variability in insulin The action of insulin may also to travel through the bloodstream levels from injection to injection be prolonged by adding zinc. Such a bound to albumin. with rapid-acting insulin analogs.1 A solution yields lente and ultralente Because only the free fraction major disadvantage of rapid-acting insulin, which are no longer avail- analogs, however, is price. The cost able in the United States. of the insulin molecule is active, of these products is approximately Long-acting insulin attempts to the effective half-life of detemir four times that of regular human replicate the body’s basal insulin is prolonged compared to regular insulin. secretion. Currently, glargine and insulin. Its duration is 14–21 hours detemir insulins are available for at commonly prescribed doses, but Intermediate- and long-acting insulins such therapy. Both are available in like other insulin formulations, the The effects of regular insulin may vial and pen forms. duration is longer at higher doses. be delayed and prolonged by several Glargine was originally released Detemir may also have a more pre- modifications to either the solution in 2001. Like short-acting insulin dictable glucose-lowering effect than containing the insulin or to the insu- analogs, glargine is a modified insu- NPH insulin.8,9 It is approved for use lin molecule itself. The result of such lin molecule that contains changes in once or twice daily. changes is a pharmacokinetic profile amino acids to alter the absorption Detemir is associated with a that allows the product to be used of glargine into the bloodstream. lower risk of hypoglycemia than to replace the body’s basal insulin These substitutions in glargine, how- NPH in patients with type 1 or type requirements. ever, affect its solubility such that 9,10 Currently, there are one interme- it is only soluble in an acidic solu- 2 diabetes. Like glargine, it is diate- and two long-acting insulins tion (which is present in the vial of available in pen or vial, but also like available in the United States. The insulin). Once injected beneath the glargine, it has the disadvantage of addition of protamine to regular skin, the buffering action of inter- being much more expensive than insulin yields neutral protamine stitial fluid neutralizes the pH such NPH. Also, it has not been shown Hagedorn (NPH) insulin. The onset that glargine is no longer soluble and definitively to improve A1C com- of action of NPH insulin is typically precipitates under the skin to form a pared to NPH. 178 Volume 28, Number 4, 2010 • CLINICAL DIABETES DIABETES FOUNDATION Insulin regimens analogs (lispro, aspart, or glulisine) European Association for the Study Traditionally, glucose has been to cover mealtime glucose excur- of Diabetes, indications for insulin controlled using an injection of NPH sions. This more intensive approach therapy in type 2 diabetes include and regular insulin in the morning requires at least four injections daily an A1C level > 7% despite lifestyle and in the evening.
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