Pediatric Type 1 Diabetes Mellitus Medication

  • Author: William H Lamb, MBBS, MD, FRCP(Edin), FRCP, FRCPCH; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Oct 4, 2011
 

Medication Summary

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.[48]

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.

Representation of activity profile of some availabRepresentation of activity profile of some available insulins.

The development of insulin analogues has attempted to address some of the shortcomings of traditional insulin.[49] 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 isophane 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.[50]

Representation of activity profile of some availabRepresentation of activity profile of some available insulins.

The FDA issued an early communication to health care practitioners regarding 4 published observational studies that described the possible association of insulin glargine (Lantus) with an increased risk of cancer.[51] Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that which is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raised further questions about the actual risk and, therefore, further evaluation is warranted.

The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

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:

  • Twice-daily combinations of short- and intermediate-acting insulin.
  • 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
  • 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
  • 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,[52] international comparisons do not support any particular insulin regimen,[53, 54] 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.

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Antidiabetic Agents

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.

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Insulin detemir (Levemir)

 

This agent is indicated for daily or twice-daily subcutaneous administration for adults and pediatric patients with type 1 diabetes mellitus; it is also indicated for adults with type 2 diabetes mellitus who require long-acting basal insulin for hyperglycemic control. The duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). Prolonged action is a result of the slow systemic absorption of detemir molecules from the injection site.

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.

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Insulin lispro (Humalog)

 

Onset of action for insulin lispro is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 2-4 hours.

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Regular insulin (Humulin R, Novolin R)

 

Onset of action is 0.25-1 hours, peak activity is 1.5-4 hours, and duration of action is 5-9 hours.

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Insulin NPH (Humulin N, Novolin N)

 

Onset of action is 3-4 hours, peak effect is in 8-14 hours, and usual duration of action is 16-24 hours.

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Insulin aspart (NovoLog)

 

Onset of action is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 3-6 hours. 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.

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Insulin glargine (Lantus)

 

This is a long-acting insulin analogue. Its typical onset of action is 1-2 hours, and its duration is 20-26 hours.

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Insulin glulisine (Apidra)

 

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.

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Contributor Information and Disclosures
Author

William H Lamb, MBBS, MD, FRCP(Edin), FRCP, FRCPCH  Clinical Lecturer, Department of Child Health, The General Hospital, Bishop Auckland, UK

William H Lamb, MBBS, MD, FRCP(Edin), FRCP, FRCPCH is a member of the following medical societies: British Medical Association, British Society of Paediatric Endocrinology and Diabetes, International Society of Pediatric and Adolescent Diabetes, Royal College of Paediatrics and Child Health, and Royal College of Physicians

Disclosure: Roche Diabetes Care Honoraria Speaking and teaching

Specialty Editor Board

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

The author would like to thank Dr. Tim Cheetham and Dr. Debbie Matthews, Colleagues at the Royal Victoria Infirmary, Newcastle upon Tyne, for reading through the manuscript and for years of support.

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Possible mechanism for development of type 1 diabetes.
The effects of insulin deficiency.
Representation of activity profile of some available insulins.
Some of the available insulin injection devices.
A selection of available insulin pumps.
Some of the available blood glucose monitors.
Diabetes Sick Day Rules.
Taking Diabetes Back to School.
Carbs for Kids-Count Them In: The Constant Carbohydrates Diet.
 
 
 
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