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Chapter: Modern Pharmacology with Clinical Applications: Insulin and Oral Drugs for Diabetes Mellitus

Clinical Management of Diabetes

Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes.



Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes. Exercise is also an important component in managing diabetes, particularly in obese individuals with NIDDM who may have a component of insulin re-sistance as a consequence of obesity. Treatment regi-mens that have proved effective include a calorie-restricted diet in combination with exogenous insulin or oral hypoglycemic drugs. However, since diet, exercise, and oral hypoglycemic drugs (Table 67.2), often be-cause of noncompliance by the patient, will not always achieve the clinical objectives of controlling the symp-toms of diabetes, insulin remains universally important in therapeutic management. The administration of in-sulin is required for the treatment of type I (IDDM) and in cases of type II (NIDDM) that are refractory to management with oral hypoglycemic drugs.


Because the spectrum of patients with diabetes ex-tends from the totally asymptomatic individual to one with life-threatening ketoacidosis, therapeutic manage-ment must be highly individualized. An important ob-jective is to maintain a glucose level as close to normal as possible without producing frequent hypoglycemia or overly restricting the patient’s lifestyle. Many diabet-ics aim to achieve an average blood glucose below 150 (hemoglobin A1c < 7%). Unstable or ketoacidosis-prone diabetics are difficult to maintain with a single dose of either intermediate- or long-acting insulin; they usually require multiple injections of combinations of short-, intermediate-, and/or long-acting insulin prepa-rations.



Insulin Preparations


Commercially available insulins differ in their onset of action, maximal activity, and duration of action (Table 67.3). They can be classified as rapid acting (0–5 hours), short acting (0–8 hours), intermediate acting (2 to 16 hours), and long acting (4 to 36 hours). Human insulin (e.g. Humulin, Novolin) produced by rDNA technology is now widely available and has largely supplanted insulins derived from beef and pork. 


Some insulins have been modified through genetic engineering to produce insulin analogues, derivatives that possess novel phar-macokinetic properties (lispro, insulin aspart, and in-sulin glargine). The duration of action can vary with fac-tors such as injection volume, injection site, and blood flow at the site of administration.


Rapid-acting insulin analogues (lispro, insulin aspart [Humalog, Novolog]) have been engineered to contain amino acid modifications that promote rapid entry into the circulation from subcutaneous tissue. They begin to exert their effects as early as 5 to 10 minutes after admin-istration. Lispro insulin, the first insulin analogue to be ap-proved in Europe and the United States, is produced by switching the positions of lysine-proline amino acid residues 28 and 29 of the carboxy terminus of the β-chain. Lispro insulin displays very similar actions to insulin and has a similar affinity for the insulin receptor, but it cannot form stable hexamers or dimers in subcutaneous tissue, which promotes its rapid uptake and absorption.


Insulin aspart is absorbed nearly twice as fast as regular insulin. In addition to binding to the insulin re-ceptor, insulin aspart also binds to the insulinlike growth factor (IGF-1) receptor, which shares structural homology with the insulin receptor. However, at physi-ological and pharmacological levels, the metabolic ef-fects of insulin aspart predominate. Both lispro insulin and insulin aspart have relatively fast onsets and short half-lives, making them ideal for controlling the upward glycemic excursions that occur immediately after meals in diabetics.


Short-acting or regular insulins (Humulin R, Novolin R) take 30 minutes to begin to exert their effect but have a longer duration of action than does either lispro insulin or insulin aspart. Typically, regular insulin is ad-ministered several minutes before a meal; it has a more gradual onset of action and is designed to control post-prandial hyperglycemia. Regular insulin is primarily used to supplement intermediate- and long-acting in-sulin preparations; however, it is also the preparation of choice for glucose management during surgery, trauma, shock, or diabetic ketoacidosis. Regular insulin can be given intravenously when emergency diabetes manage-ment is required (e.g., diabetes ketoacidosis). Prompt insulin zinc suspension (Semilente) is also a fast-acting form of insulin, but unlike regular insulin, it should be mixed only with Lente or Ultralente insulin prepara-tions. Rapid-acting and short-acting insulins are often administered two to three times a day or more. These insulins are also employed in sliding scale insulin regi-mens, which supplement a person’s glucose control based on blood glucose monitoring equipment.


Intermediate-acting preparations (e.g., isophane in-sulin suspension [NPH insulin] or insulin zinc suspen-sion [Lente insulin]) have a more delayed onset of ac-tion, but they act longer. Conjugation of the insulin molecule with either zinc or protamine or both will con-vert the normally rapidly absorbed parenterally admin-istered insulin to a preparation with a longer duration of action. Isophane insulin suspension (Neutral protamine Hagedorn, NPH) has a rate of absorption that has been slowed by complexing insulin with protamine, a polyva-lent cation. Both NPH and Lente insulin are used to con-trol diabetes in a variety of situations except during emergencies (e.g., diabetic ketoacidosis). Intermediate-acting insulin preparations are usually given once or twice a day.


Protamine zinc and extended insulin zinc suspension (Ultralente) are often referred to as long-acting insulin preparations. These insulins have more protamine and zinc in the mixture than is found in isophane insulin sus-pension. Insulin zinc suspension, extended (Ultralente Insulin), is quite similar to the protamine zinc insulin suspension except that it does not contain protamine. Both of these long-acting insulins have an approximate duration of action of 36 hours.


Insulin glargine (Lantus) is a long-acting insulin analogue that does not use zinc or protamine to modu-late insulin solubility. The introduction of two positive arginine residues at the carboxy terminus of the β-chain shifts the isoelectric point of the peptide from 5.4 to 6.7, thus creating a molecule that is soluble at pH 4 but less soluble at neutral (physiological) pH (in subcutaneous tissue). A second modification of insulin, glargine, in-volves the substitution of a charge-neutral glycine for a negatively charged asparagine at the amino terminal end of the β-chain; this prevents deamidation and dimerization and enhances stability at physiological pH. Injection of insulin glargine forms microprecipitates in subcutaneous tissue as the pH is raised from 4 to phys-iological. A steady, sustained release of insulin from the site of injection mimics the basal secretion of insulin from the pancreas. Absorption of insulin glargine com-mences within a few hours of injection, and there is usu-ally little or no peak or trough in the levels of insulin glargine as it dissolves from its site of injection. Because it is necessary to maintain its acidic pH prior to injec-tion, insulin glargine must not be mixed with any other form of insulin during injection.



Adverse Reactions to Insulin Therapy


The most common side effect associated with insulin therapy is hypoglycemia, which may result in such CNS symptoms as tremors, lethargy, hunger, confusion, mo-tor and sensory deficits, seizures, and unconsciousness. Adrenergic manifestations include anxiety, palpitations, tachycardia, and diaphoresis. In many cases, diabetics are aware that hypoglycemia is developing, and prompt administration of oral carbohydrates (e.g., fruit juice or glucose tablets) can restore normoglycemia. In more se-vere cases (e.g., unconsciousness, seizures), intravenous glucose or intramuscular glucagon is required to reverse the hypoglycemia.


Another frequent side effect of insulin therapy is weight gain. Some is due to increased caloric storage of glucose by insulin, and some is due to renal sodium re-tention resulting in fluid retention and edema. These ef-fects can synergize with oral agents that are often coad-ministered with insulin, particularly sulfonylureas and thiazolidinediones.


Other complications arising from insulin therapy are uncommon. Sometimes, diabetics treated with exogenous insulin develop insulin-binding immunoglobulins, although the clinical significance of these antibodies remains unclear. Allergic reactions due to the use of animal-derived insulins has subsided since the use of re-combinant DNA-derived human insulin became wide-spread. Over time, repeated subcutaneous injections of insulin can cause local lipodystrophy (lipohypertrophy or lipoatrophy), which may alter the pharmacokinetics of insulin absorption from this site. Also, hypokalemia can follow acute insulin administration, an effect that is due to the stimulation of NA+ –K+ –ATPase (adenosine triphosphatase) with its resultant redistribution of K+ to the intracellular compartment. This property of insulin is sometimes used in the emergency treatment of hy-perkalemia.


Insulin Regimens


The rational design of insulin regimens involves esti-mates and consideration of the patient’s diet, lifestyle, level of physical activity, and type of diabetes. A thin, ac-tive type I diabetic will have very different insulin re-quirements from those of a sedentary, obese type II di-abetic. Hence, it is not possible to provide a cookbook approach for designing all diabetes regimens. There is usually less insulin resistance in type I diabetics, and it is possible to estimate metabolic needs of insulin based on the type I diabetic patient’s weight (typically 0.5 to 1 units/kg/day). Other considerations, such as work schedule and mealtimes, are important in determining the way the insulin is divided proportionally to cover short-range and long-range glycemic control. Although there is quite a bit of variation, most diabetics have about half to two-thirds of their insulin as a long-acting preparation, and the rest is usually delivered as a rapid-or short-acting insulin.


Some insulin preparations are combinations of NPH and regular insulin packaged in premixed ratios of 70:30 or 50:50 of NPH and regular insulin (70/30 Humulin, 70/30 Novolin, 50/50 Humulin). A similar combination product is 75/25 insulin, which contains 75% protamine lispro and 25% lispro insulin. Insulin zinc suspension (Lente insulin) is an intermediate-acting mixture of prompt insulin zinc suspension (30%) and extended in-sulin zinc suspension (70%). While these combination products may be convenient for some patients and can improve compliance, they are not ideal regimens for most diabetics, who may achieve better control by sep-arately mixing their rapid- or short-acting insulin with an intermediate- or long-acting insulin to arrive at a ra-tio that is better suited to manage their diabetes.


Insulin pumps are small, portable devices worn ex-ternally that deliver a continuous supply of insulin sub-cutaneously through a hypodermic needle. The pumps provide a basal rate of insulin between meals and can be manually adjusted to facilitate glycemic control at mealtimes. Rapid and short-acting insulins are typically used in insulin pumps. Pumps are usually worn 2 to 3 days before the tubing and needle are changed.


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