Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor
PEDIATRICS – Jane Lee Chiang, MD, and Georgeanna J. Klingensmith, MD
The normal pancreas deftly releases basal insulin, superimposed with bursts of insulin for rising glucose levels associated with food intake, life stressors, and medications. Insulin is secreted into the portal system, which clears half of the insulin. Those afflicted with type 1 diabetes (T1D) have near-absolute deficiency of endogenous insulin secretion due to beta-cell destruction. Therefore, exogenously administered insulin must attempt to mimic the critical role played by the normal pancreas….
Banting and Best’s discovery of insulin in 1921 enabled the use of animal-based soluble (regular) insulin to treat individuals with T1D. Six decades later, human insulin, made by recombinant DNA technology, replaced animal-based insulin. This dramatic technology breakthrough enabled purification of insulin (less than one part per million of impurities), resulting in reduced insulin antibodies, fewer insulin allergies, and near elimination of injection site lipoatrophy.
In characterizing insulin, we need to review its actions. Pharmacokinetics is the profile of insulin measured in blood after subcutaneous injection. Pharmacodynamics is the time required for insulin to move glucose into cells. Pharmacodynamics is a longer time interval than pharmacokinetics and is measured by performing euglycemic insulin clamps. Both terms are measured as time to onset, peak, and duration of action and are influenced by the injected insulin dose.
Below are commonly used terms for insulin management:
- Analog insulins (rapid-acting analog [RAA] and long-acting analog [LAA]) are altered forms of insulin (i.e., not human or animal) made by recombinant DNA techniques. The Food and Drug Administration (FDA) refers to them as insulin receptor ligands, but they are commonly referred to as insulin analogs.
- Non-analog insulins (e.g., regular and NPH). Regular insulin (U-100 standard) is recombinant human insulin, stabilized, and is considered a short-acting insulin. NPH insulin is regular insulin complexed with protamine to form hexamers, which does not bind to insulin receptors, and therefore must slowly dissociate back into its monomeric form to be effective. Thus, its action is prolonged, and it is considered an intermediate-acting insulin. It may be used as a sort of basal insulin.
- Basal insulin provides the maintenance level required to maintain glucose in a target range when food is not consumed and prevents unrestrained hepatic gluconeogenesis, hyperglycemia, and subsequent ketosis.
- Prandial insulin is given at (or preferably before) mealtime to prevent the postmeal rise in blood glucose by allowing peripheral glucose disposal by the muscles.
- Nutritional (vs. prandial) insulin is used when calories are provided continuously via tube feeds, parenterally (TPN).
- Correction (or supplemental) insulin refers to additional insulin needed to correct pre- or postmeal hyperglycemia to target levels. Correction is usually RAA and rarely regular insulin.
- Insulin sensitivity factor (ISF, or correction factor) refers to how much one unit of insulin will lower plasma glucose.
- Insulin-to-carbohydrate (I:C) ratio refers to the carbohydrate grams covered by one unit of prandial insulin to maintain plasma glucose.
- Lag time refers to the time between prandial insulin dose and the meal start.
- Active insulin (insulin on board [IOB]) refers to the remaining insulin activity (see pharmacodynamic) when considering a correction dose.
In healthy individuals with normal insulin sensitivity and oral intake, basal and prandial insulin each account for about 50% of the total daily dose. Basal insulin provides constant background coverage, and the bolus component covers food consumption and corrects high blood glucoses. Previously, insulin was dosed twice daily (usually before breakfast and before dinner), and was known as conventional insulin therapy (CIT). Although this method was simple and required limited injections, nocturnal hypoglycemia (midnight to 4 a.m.) and early morning (4-8 a.m.) and later afternoon (3-6 p.m.) hyperglycemia were not infrequent. In addition, the Diabetes Control and Complications Trial Research Group (DCCT) proved that twice-daily insulin (CIT) targeted to higher glycemic targets was not as effective as multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) therapy (i.e., insulin pumps) targeted to normal blood glucose levels.1 The introductions of both widespread home blood glucose monitoring and MDI with 4-6 daily insulin injections (or with insulin pump therapy) have enabled a more physiologic method of insulin delivery.
This basal-bolus therapy is now considered standard therapy and, when combined with frequent blood glucose monitoring (and with increasing frequency, continuous glucose monitoring [CGM]), is considered intensified diabetes management. Importantly, a target A1C will not be specified with intensified diabetes management, since that needs to be individualized based on age, duration of diabetes, hypoglycemia unawareness history, and other factors.
Regular human insulin and neutral protamine Hagedorn (NPH, combined with protamine to delay absorption and duration) were long the mainstays of T1D management. However, insulin development has evolved to include a vast array of choices, including three LAAs or basal analogs (insulin glargine, detemir, and degludec [under development]) and RAAs (insulin lispro, insulin aspart, and insulin glulisine) (see Figures 12.I.1 and 12.I.2, and Table 12.I.1). We will not address U-500 regular insulin, since it is rarely used in T1D.2
Insulin glargine and detemir are the currently available LAAs. They are engineered to gradually dissociate to delay insulin absorption into the blood stream. Degludec insulin is an ultralong-acting basal insulin analog currently under development.3,4 Detemir and degludec are bound to albumin, prolonging their activity in the circulation. Detemir lasts 14-20 hours. Glargine is effective 20-24 hours. Degludec lasts over 24 hours, with longer durations seen with larger doses. The long effective activity and limited peak in these insulins make them especially effective as basal insulins since the risk of hypoglycemia, especially nocturnal hypoglycemia, is decreased compared to NPH. Basal insulin dosing is titrated to achieve a target fasting blood glucose value while avoiding premeal or nocturnal hypoglycemia.
Glargine is often given once a day (starting dose 0.2-0.4 units/kg of body weight). In older children and adults, it is usually most effective if given 2-4 h after dinner with the dose titrated upwards until a target fasting blood glucose (BG) is obtained. In children (<10 years of age) and some geriatric (≥65 years old) patients, a morning dose of glargine may prevent early morning hypoglycemia since young children are insulin sensitive and may require little exogenous insulin in the early morning hours.
Detemir may be initiated as daily insulin. If there is evidence of waning insulin action (i.e., hyperglycemia hours prior to the scheduled detemir dose), adding a second dose is usually effective in establishing stable basal glycemia. We recommend dividing it into 12 equal hourly doses. This waning insulin effect makes detemir an attractive option for morning administration in children (<8-10 years old).
Degludec has been shown to provide an action of beyond 24h allowing the development of a steady state insulin action when given daily at a consistent time. Of note, as of the time this book went to press, degludec is not available for commercial use.
As a precaution with all LAAs, it is difficult to adjust the insulin dose for occasional and intermittent changes in daily activities. If using LAAs, it is important to develop strategies to adjust carbohydrate intake and alter prandial insulin doses to prevent hypoglycemia during and after additional physical exercise.
A steady state assessment of basal insulin can be helpful. With LAA therapy, the morning fasting glucose should be in range and ideally an individual should be able to skip a meal without significant hypoglycemia. Individuals should perform a basal rate check by missing the breakfast meal on a morning after the bedtime glucose was in range and no bedtime snack was eaten. The basal rate check should include a glucose value at the usual breakfast time and at a later awakening time (if schedules are erratic). This is particularly important in individuals with variable weekly schedules, especially teens and young adults who tend to sleep in on weekends or nonworkdays.
It is important to emphasize that the bedtime blood glucose levels should be within target range. Occasionally, high bedtime blood glucose levels may not come down overnight and may remain elevated in the morning. If the blood glucose remains elevated, a small correction dose needs to be given, even when skipping breakfast. Teenagers often sleep through breakfast, so a blood glucose check followed by a small correction dose is recommended for fasting hyperglycemia. We do not recommend increasing the basal dose, as this will bring the fasting glucose level too low. Often, patients receive too much basal insulin when they do not understand that the primary issue is starting too high at bedtime. Therefore, ensuring that nighttime glucose levels are within target is critical. Patients who consistently miss meals and have erratic glucose levels despite aggressive MDI should consider CSII. Furthermore, due to changes in basal insulin requirements overnight (e.g., midnight to 4 a.m.) compared to early morning (4-8 a.m.), it may not be possible to replace basal insulin well without CSII. This can be easily seen with frequent glucose monitoring overnight and early morning, especially when skipping breakfast. The use of a diagnostic CGM may be helpful to determine if basal insulin changes are needed to better control overnight glycemia or if CSII would be a better option.
For nonanalog insulins (NPH and regular), the injection site is a major contributor to pharmacokinetics and pharmacodynamics. NPH is an intermediate-acting insulin, but may also be used as a basal insulin. Its onset of action, peak time, and duration of action is less predictable than with the LAAs, so the risk for unexpected hypoglycemia is greater with NPH vs. LAA insulin. NPH is often recommended for twice-daily dosing: prebreakfast and predinner or prebedtime. NPH peaks between 4-10 hours, so giving NPH in the evening increases the risk of nocturnal hypoglycemia compared to a LAA. Likewise the variable timing of the peak may cause unexpected hypoglycemia during the day. NPH increases hypoglycemic risk, so a lower percent of the total daily dose (TDD) is given as the basal dose when using NPH.
Since NPH peaks, a steady state assessment (basal check) is more difficult and a meal or snack may be required at the expected peak time of NPH action. Intermittent determination of blood glucose profiles prior to and 2-3 hours after meals throughout the day and night or a diagnostic 3-6 day CGM assessment may help in assessing the appropriate NPH dose.
We strongly discourage the use of NPH for individuals requiring more intensive diabetes management or for those at greater risk of hypoglycemia (e.g., young children and older adults). In general, we do not recommend NPH for T1D. We would reserve it for certain circumstances (i.e., those with or without insurance >18 years of age who cannot afford analog insulin and cannot get it provided by insulin companies).
Short-acting insulin. Zinc atoms added to regular insulin causes insulin dimers to form hexamers and delay absorption until the hexamers disassociate. Regular insulin is less expensive, but the delayed action leads to greater postprandial glucose excursions unless the dose is given 20-40 min prior to the meal. For example, if insulin absorption is unusually rapid, then hypoglycemia may occur prior to food absorption, or if it unusually delayed, then it may occur 3-4 h postmeal. Regular insulin is preferred to RAA in patients with delayed gastric absorption, such as those with gastroparesis or those taking pramlintide. It is also used for IV insulin infusions. Like NPH, regular insulin is not preferable and is recommended for certain circumstances (e.g., those with or without insurance >18 years of age who cannot afford analog insulin and cannot get it provided by insulin companies).
RAAs. Insulin lispro, aspart, and glulisine are RAAs that are structurally engineered to dissociate and be absorbed more rapidly. The advantages of the RAAs (vs. regular insulin) include quicker onset of action and less postprandial glycemic peak. The shorter duration of RAA often results in less postabsorptive hypoglycemia. This is true particularly at night when the risk of hypoglycemia is greatest.
We do not recommend the use of mixed insulins unless the individual or family is unable to mix insulins. In addition, the individual must always eat consistent carbohydrates for each meal. In children, fixed mixed insulins are used only in adolescents who refuse to take more than two daily doses of insulin and will not mix insulins. Another option is to free mix analog RAA and NPH in the morning and RAA and LAA in the evening.
- Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993.
- Hirsch IB, Skyler JS: Management of type 1 diabetes. In Atlas of Diabetes. Skyler JS, Ed. New York, Springer Science + Business Media, LLC, 2012, p. 95–113.
- Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Francisco AM, Hollander P: NN1250-3582 (BEGIN BB T2D) Trial Investigators: Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with meal-time insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 379:1498–1507, 2012.
- Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell- Jones D, Philotheou A, Francisco AM, Pei H, Bode B: BEGIN Basal-Bolus Type 1 Trial Investigators: Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomized, open-label, treat-to-target non-inferiority trial. Lancet 379:1489–1497, 2012
Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.