Medication Summary
Insulin
Insulin is always required to treat type 1 diabetes mellitus. Originally, all insulin was derived from the highly purified pancreatic extracts of pigs and cattle, and this form of insulin is still available. Human insulin was later manufactured using recombinant deoxyribonucleic acid (DNA) technology. "Designer" insulins are also now being produced; they are based on the human molecule and are tailored to meet specific pharmacologic targets, particularly duration of action. Insulin must be given parenterally, and this effectively means subcutaneous injection. [74]
Alternatives to injecting insulin have been constantly sought, including an inhaled form of insulin. Several products were in development, and one (Exubera) was licensed for use but failed to generate sufficient market penetration to justify continued production. The search for alternatives continues, including oral sprays, sublingual lozenges, and delayed-absorption capsules.
Insulin has 4 basic formulations: ultra ̶ short-acting (eg, lispro, aspart, glulisine), traditional short-acting (eg, regular, soluble), medium- or intermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, ultralente, glargine).
Regular or soluble insulin is bound to either protamine (eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duration of action. Combinations of isophane and regular, lispro, or aspart insulins are also available in a limited number of concentrations that vary around the world, ranging from 25:75 mixtures (ie, 25% lispro, 90% isophane) to 50:50 mixtures. The following image illustrates the activity profile of various insulins.
The development of insulin analogues has attempted to address some of the shortcomings of traditional insulin. [75] Insulins lispro, glulisine, and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia. (See the graph below.) They are also more suitable for use with insulin pumps. An intermediate-acting insulin (detemir) has a similar profile of action to NPH but is more pharmacologically predictable and is less likely to cause weight gain, whereas glargine has a relatively flat profile of action, lasting some 18-26 hours. Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates. [76]
With so many various insulins and mixtures available, a wide range of possible injection regimens exist. These can be broadly categorized into 4 types, as follows:
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Twice-daily combinations of short- and intermediate-acting insulin.
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Multiple injection regimens using once-daily or twice-daily injections of long-acting or intermediate-acting insulin and short-acting insulins given at each meal
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A combination of the above 2 regimens, with a morning injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection of intermediate- or long-acting insulin
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Continuous subcutaneous insulin infusion (CSII) using an insulin pump
Although controlled clinical trials suggest improved short-term metabolic control in children using multiple injections or CSII, [77] international comparisons do not support any particular insulin regimen, [78, 79] and all have their advantages and disadvantages.
A wide variety of insulin-injection devices are available, including a simple syringe and needle, semiautomatic pen injector devices, and needle-free jet injectors. Increasing numbers of young people use insulin pumps to deliver continuous subcutaneous insulin, with bolus doses at meal times.
When prescribing, tailor the insulin dose to the individual child's needs. For instance, if using a twice-daily regimen, then, as a rule of thumb, prepubertal children require between 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and 30-40% in the evening. Insulin resistance is a feature of puberty, and some adolescents may require as much as 2 U/kg/d. About one third of the administered insulin is a short-acting formulation and the remainder is a medium- to long-acting formulation. Basal bolus regimens have a higher proportion of short-acting insulin. Typically, 50% of the total daily dose is given as long- or intermediate-acting insulin. CSII uses only short-acting insulins, most often the analogues lispro or aspart. Typically, they also have around 50% of the insulin given at a basal rate; the remainder is given as food-related boluses.
Teplizumab
Teplizumab is a humanized monoclonal antibody (mAb) that targets the cluster of differentiation 3 (CD3) antigen, which is coexpressed with the T-cell receptor on the surface of T lymphocytes. It is indicated to delay the onset of stage 3 type 1 diabetes mellitus in adults and in children aged 8 years or older.
Approval from the US Food and Drug Administration (FDA) was based a phase 2, randomized, placebo-controlled trial involving 76 at-risk children and adults. The study demonstrated that a single 14-day regimen of daily intravenous (IV) infusions of teplizumab in 44 patients delayed clinical type 1 diabetes mellitus by a median of 2 years compared with 32 participants who received placebo. [80]
Data from an extended follow-up (median 923 days) showed that 50% of the teplizumab group remained diabetes free, compared with 22% of the placebo group. [81]
Antidiabetics, Insulins
Class Summary
These agents are used for the treatment of type 1 diabetes mellitus, as well as for type 2 diabetes mellitus that is unresponsive to treatment with diet and/or oral hypoglycemics.
Insulin aspart (NovoLog)
Rapid-acting insulin. Insulin aspart is approved by the FDA for use in children aged >2 y with type 1 DM for SC daily injections and for SC continuous infusion by external insulin pump; however, it has not been studied in pediatric patients with type 2 DM. Onset of action is 10-30 minutes, peak activity is 1-2 h, and duration of action is 3-6 h. Insulin aspart is homologous with regular human insulin, with the exception of the single substitution of the amino acid proline with aspartic acid in position B28. The drug is produced by recombinant DNA technology. Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. It inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis. Insulin is the principal hormone required for proper glucose use in normal metabolic processes.
Insulin glulisine (Apidra)
Rapid-acting insulin. The safety and effectiveness of SC injections of insulin glulisine have been established in pediatric patients (aged 4-17 y) with type 1 DM; however, it has not been studied in pediatric patients with type 2 DM. Onset of action is 20-30 minutes, peak activity is 1 h, and duration of action is 5 h. Insulin glulisine is a human insulin analog produced by recombinant DNA technology using a nonpathogenic laboratory strain of Escherichia coli (K12). It differs from human insulin by replacement of asparagine at the B3 position with lysine, and the replacement of lysine at the B29 position with glutamic acid. Insulin regulates glucose metabolism by stimulating peripheral glucose uptake by skeletal muscle and fat, and inhibits hepatic glucose production.
Glucose lowering with insulin glulisine is equipotent to that of regular human insulin when it is administered intravenously. After subcutaneous administration, insulin glulisine has a more rapid onset and a shorter duration of action than does regular human insulin. It is useful for the regulation of mealtime blood glucose elevation.
Insulin lispro (Humalog)
Rapid-acting insulin. Only lispro U-100 is approved by the FDA to improve glycemic control in children aged >3 y with type 1 DM; however, it has not been studied in children with type 2 DM. Onset of action is 10-30 minutes, peak activity is 1-2 h, and duration of action is 2-4 h.
Regular insulin (Humulin R, Novolin R, Myxredlin)
Short-acting insulin. Novolin R has been approved by the FDA to improve glycemic control in pediatric patients aged 2-18 y with type 1 DM; however, it has not been studied in pediatric patients with type 2 DM. Humulin R is indicated to improve glycemic control in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day; however, there are no well-controlled studies of use of concentrated Humulin R U-500 in children. Onset of action is 0.25-1 h, peak activity is 1.5-4 h, and duration of action is 5-9 h.
Insulin NPH (Humulin N, Novolin N)
Intermediate-acting insulin. It is indicated to improve glycemic control in pediatric patients with type 1 diabetes mellitus. Onset of action is 3-4 h, peak effect is in 8-14 h, and usual duration of action is 16-24 h.
Insulin glargine (Lantus)
Long-acting insulin. The safety and effectiveness of glargine U-100 have been established in pediatric patients (6-15 y) with type 1 DM; however, it has not been studied in pediatric patients with type 2 DM. In addition, the safety and effectiveness of glargine U-300 have not been established in pediatric patients. Onset of action is 3-4 h, no pronounced peaks, and duration of action ranges from 10.8 h to more than 24 h.
Insulin detemir (Levemir)
Long-acting insulin. Insulin detemir is indicated for once- or twice-daily SC administration for the treatment of pediatric patients (aged 6-17 years) with type 1 DM; however, detemir has not been studied in pediatric patients with type 2 DM. Onset of action is 3-4 h, peak activity is 6-8 h, and duration of action ranges from 5.7 h (low dose) to 23.2 h (high dose). Prolonged action is a result of the slow systemic absorption of detemir molecules from the injection site. This agent is indicated not only for daily or twice-daily SC administration for adults and pediatric patients with type 1 DM, it is also indicated for adults with type 2 DM who require long-acting basal insulin for hyperglycemic control.
Insulin detemir's primary activity is regulation of glucose metabolism. It binds to insulin receptors and lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat. The drug also inhibits glucose output from the liver. It inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.
Insulin degludec (Tresiba)
Ultra–long-acting insulin. Insulin degludec is approved by the FDA to improve glycemic control in pediatric patients aged >1 y with type 1 or type 2 DM. It usually takes 3-4 days for insulin degludec to reach steady state, peak plasma time is 9 h and the durations of action is at least 42 h. It is highly protein bound, and following SC, the protein-binding provides a depot effect.
Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached.
Glucose-Elevating Agents
Class Summary
Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis.
Glucagon (GlucaGen HypoKit, Gvoke)
Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract. Available as a powder for reconstitution. It is also available as a ready-to-use SC solution in prefilled syringes or an autoinjector.
Glucagon intranasal (Baqsimi)
Activates hepatic glucagon receptors that stimulate cAMP synthesis. This action accelerates hepatic glycogenolysis and gluconeogenesis, causing an increase in blood glucose levels. Preexisting hepatic glycogen stores necessary to be effective in treating hypoglycemia. It is indicated for severe hypoglycemic reactions in adults and children aged 4 y or older with diabetes.
Monoclonal Antibodies
Class Summary
Teplizumab is a humanized monoclonal antibody (mAb) that targets the CD3 antigen, which is coexpressed with the T-cell receptor on the surface of T lymphocytes.
Teplizumab (Tzield)
Indicated to delay onset of stage 3 type 1 diabetes mellitus in adults and in children aged 8 y or older.
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Possible mechanism for development of type 1 diabetes.
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The effects of insulin deficiency.
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Representation of activity profile of some available insulins.
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Some of the available insulin injection devices.
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A selection of available insulin pumps.
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Some of the available blood glucose monitors.
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Diabetes Sick Day Rules.
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Taking Diabetes Back to School.
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Carbs for Kids-Count Them In: The Constant Carbohydrates Diet.
