ABSTRACT

Since the introduction of insulin analogs in 1996, insulin therapy options for patients with type 1 and type 2 diabetes have expanded. Insulin therapies are now able to more closely mimic physiologic insulin secretion and thus achieve better glycemic control in patients with diabetes. This chapter reviews the pharmacology of available insulins, types of insulin regimens, and principles of dosage selection and adjustment, and provides an overview of insulin pump therapy. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

In 1922, Canadian researchers were the first to demonstrate a physiologic response to injected animal insulin in a patient with type 1 diabetes. Insulin was the first protein to be fully sequenced. The insulin molecule consists of 51 amino acids arranged in two chains, an A chain (21 amino acids) and B chain (30 amino acids) that are linked by two disulfide bonds (1) (Figure 1). Proinsulin is the insulin precursor that is transported to the Golgi apparatus of the beta cell where it is processed and packaged into granules. Proinsulin, a single-chain 86 amino acid peptide, is cleaved into insulin and C-peptide (a connecting peptide); both are secreted in equimolar portions from the beta cell upon stimulation from glucose and other insulin secretagogues. While C-peptide has no known physiologic function, it can be measured to provide an estimate of endogenous insulin secretion.

Figure 1.

Insulin Structure.

SOURCES OF INSULIN

With the availability of human insulin by recombinant DNA technology in the 1980s, use of animal insulin declined dramatically. Beef insulin, beef-pork, and pork insulin are no longer commercially available in the United States. The United States FDA may allow for personal importation of beef or pork insulin from a foreign country if a patient cannot be treated with human insulin (2). Beef insulin differs from human insulin by 3 amino acids and pork insulin differs by one amino acid (2).

Currently, in the United States, insulins used are either human insulin and/or analogs of human insulin. The recombinant DNA technique for producing insulin for commercial use involves insertion of the human proinsulin gene into either Saccharomyces cerevisiae (baker’s yeast) or a non-pathogenic laboratory strain of Escherichia coli (E coli) which serve as the production organism. Human insulin is then isolated and purified (3–11) .

INSULIN ANALOGS

Recombinant DNA technology has allowed for the development and production of analogs to human insulin. With analogs, the insulin molecule structure is modified slightly to alter the pharmacokinetic properties of insulin, primarily affecting the absorption of the drug from the subcutaneous tissue. The B26-B30 region of the insulin molecule is not critical for insulin receptor recognition and it is in this region that amino acids are generally substituted (12).

Thus, the insulin analogs are still recognized by and bind to the insulin receptor. The structures of three rapid-acting insulin analogs are shown in Figure 2 (insulin aspart, lispro and glulisine) and the structures of three long-acting insulin analogs are shown in Figure 3 (insulin glargine, detemir, and degludec).

Figure 2.

Insulin Aspart, Glulisine and Lispro Structures.

Figure 3.

Insulin Glargine and Detemir Structures.

In vitro studies have demonstrated the mitogenic effects of insulin at high concentrations, as well as carcinogenic effects of insulin binding to the insulin like growth factor-1 (IGF-1) receptor,

suggesting that hyperinsulinemia may promote tumorigenesis. Subcutaneously administered insulin bypasses the usual 80% hepatic first pass clearance of pancreatic islet cell-secreted insulin, and therefore contributes to systemic hyperinsulinemia in insulin-treated patients with diabetes (13). Because insulin analogs are modified human insulin, the safety and efficacy profiles of these insulins have been compared to human insulin (12) . Insulin and IGF-1 receptor binding affinities, and the metabolic and mitogenic potencies of insulin analogs relative to human insulin have been assessed. Insulin lispro and aspart are similar to human insulin on all of the above parameters, except insulin lispro was found to be 1.5-fold more potent in binding to the IGF-1 receptor compared to human insulin. Insulin glargine was found to have a 6- to 8-fold increase in mitogenic potency and IGF- 1 receptor affinity compared to human insulin. However, glargine is rapidly degraded to metabolites. The predominant metabolite M1 has been shown to have a 0.4-fold binding affinity to the IGF-1 receptor compared with human insulin (14) . In human studies, meta-analyses comparing exogenous insulin to non-insulin antihyperglycemic therapies have shown associations of insulin with several cancers (15,16) . However, there are inherent limitations to such analyses. A review of large epidemiologic studies did not find evidence of an increased risk of malignancy among glargine-treated patients when compared with other insulin therapies (14). Observational studies with up to 7 years of follow up have also not shown an association of cancer with insulin glargine or detemir use (17).

Insulin detemir was found to be more than 5-fold less potent than human insulin in binding to IGF-1 (12). An in vitro study showed that insulin degludec had a low IGF-1 receptor binding affinity compared to human insulin (18) . The long-term clinical significance of differences in IGF- 1 binding among available insulins is not known.

IMMUNOGENICITY

Because pork and beef insulin differ from human insulin by 1 and 3 amino acids respectively, they are more immunogenic than exogenous human insulin. Older formulations of insulin were less pure, containing islet-cell peptides, proinsulin, C-peptide, pancreatic polypeptides, glucagon, and somatostatin, which contributed to the immunogenicity of insulin (19). Components of insulin preparations (e.g., zinc, protamine) and subcutaneous insulin aggregates are also thought to contribute to antibody formation (19). Because of the availability of human insulin and the increased potential for animal source insulin to be immunogenic, animal source insulins are no longer available in the United States.

Rare hypersensitivity responses to insulin can be immediate-type, local or systemic IgE- mediated reactions (19) . Patients who experience a true allergic reaction to insulin have typically received insulin in the past, and experience the reaction after insulin is restarted. Delayed, IgG-mediated allergic reactions also develop with animal insulins (19). Insulin therapy can rarely result in the production of insulin antibodies of the IgG class, which inactivate insulin. Immunological insulin resistance can develop in patients with very high titers of IgG- antibodies.

Lipodystrophy resulting from insulin injections refers to two conditions: lipoatrophy and lipohypertrophy. Lipoatrophy is an immune-mediated condition resulting in loss of fat at insulin injection sites (19) and occurs rarely with purified human insulins. Treatment for patients who developed lipoatrophy due to animal insulin use was injection of human insulin into the atrophied site. Lipohypertrophy is a common, non-immunological side effect of insulin resulting from insulin’s trophic effects following repeated injections of insulin into the same subcutaneous site (20) . Lipohypertrophy can delay the absorption of insulin and therefore it is best if patients do not continue to administer insulin in these locations.

CONCENTRATION

In the United States, all insulins are available in the concentration of 100 units/ml (denoted as U-100). Insulin syringes are designed to accommodate this concentration of insulin. Regular human insulin (Humulin R, Lilly) is available in a more concentrated insulin, U-500 (500 units/ml), and is used primarily in cases of marked insulin resistance, when large doses of insulin (generally > 200 units per day) are required. Extreme caution must be taken as each marked unit on a U-100 syringe will deliver 5 units of insulin. However, syringes specific to U- 500 insulin are available, and U-500 insulin is also available for administration via a pen device. For both the syringe and pen specific to U-500 insulin, the units, not the volume, of insulin are marked. Insulin glargine is also available in a U-300 concentration, delivering 300 units/ml, and insulin degludec and insulin lispro are available in U-200 concentrations that deliver 200 units/mL. Both U-300 and U-200 insulin are only available in pen devices, and for both U-300 and U-200, the dose of insulin a patient dials into the pen device is in units and not in mL.

Outside the United States, a less concentrated insulin preparation, U-40, (40 units/ml) is still available and sometimes used, although this has become uncommon (21). Specific U-40 syringes are used with this insulin. It is important that patients traveling from one country to the next be aware of the concentration of insulin they use and that the appropriate syringe is used.

PHYSICAL AND CHEMICAL PROPERTIES

Regular human insulin is crystalline zinc insulin dissolved in a clear solution. It may be administered by any parenteral route: subcutaneous, intramuscular, or intravenous. Insulin aspart, glulisine and lispro are also soluble crystalline zinc insulin, but are intended for subcutaneous (SQ) injection. When administered intravenously, the action of these rapid-acting insulin analogs is identical to that of regular insulin. NPH, or neutral protamine Hagedorn, is a suspension of regular insulin complexed with protamine that delays its absorption. Insulin suspensions should not be administered intravenously. All insulins, except insulin glargine, are formulated to a neutral pH.

Long-acting insulin glargine is a soluble, clear insulin, with a pH of 4.0 which affects its SQ absorption characteristics, discussed further in the pharmacokinetics section. Insulin glargine should not be mixed with other insulins, and should only be administered subcutaneously (8). Insulin detemir is an insulin analog coupled to an 18-chain fatty acid that binds to albumin in the SQ tissue. This results in delayed absorption and a prolonged duration of action. Insulin degludec is an ultra-long insulin analog that breaks down into monomers by dissociating from zinc molecules after administration (22). Insulins detemir and degludec should also not be mixed with other insulins and are intended only for subcutaneous use (5,7).

PHARMACOKINETICS

PHARMACODYNAMICS

The onset, peak, and duration of effect vary among insulin preparations. Insulin pharmacodynamics refers to the metabolic effect of insulin. Commercially available insulins are categorized as rapid-acting, short-acting, intermediate-acting, and long- acting. Insulins currently available in the United States are listed in Table 2. Insulin pharmacodynamics of the various insulins are shown in Table 3. Ranges are listed for the onset, peak and duration, accounting for intra/inter-patient variability. By having patients self-monitor their blood glucose frequently, the patient-specific time-action profile of the specific insulin can be better appreciated. Figures 4-6 show the time-activity profiles for available injectable and inhaled insulins.

Figure 4.

Pharmacodynamic Profiles of a Rapid Insulin Analog (insulin lispro) and Regular Insulin (33,36).

Figure 5.

Pharmacodynamic Profiles of Faster Aspart and Insulin Aspart (37).

Figure 6.

Pharmacodynamic Profiles of Long-Acting and Intermediate-Acting Basal Insulins (38,39).

INSULIN PREPARATIONS

STORAGE

All insulins have an expiration date on the package labeling that applies to insulins that are unopened and refrigerated. Unopened insulin (i.e., not previously used) should be stored in the refrigerator at 36°F- 46°F (2°C- 8°C). Insulin should never be frozen, kept in direct sunlight, or stored in an ambient temperature greater than 86°F (30°C). Exposure to extremes of temperature can lead to loss of insulin effectiveness and a deterioration in glycemic control. Insulin that has been removal from the original vial (i.e., for pump use) should be used within two weeks or discarded. Insulin vials, cartridges, or pens may be kept at room temperature, between 59 °F-86°F (15 °C-30°C), for 28 days, or about 1 month. Insulin detemir can be stored at room temperature for up to 42 days.

Regular insulin, the basal insulin analogs (glargine, detemir, and degludec) and the rapid-acting insulin analogs (lispro, aspart, and glulisine) are clear and colorless and should not be used if they become cloudy or viscous.

ADVERSE EFFECTS

TYPES OF REGIMENS

GOALS OF THERAPY

Before starting a patient on insulin, or adjusting their current insulin therapy, it is important to establish glycemic goals tailored to the patient. The American Diabetes Association currently recommends individualized glycemic goals (98). Those with a longer duration of diabetes, shorter life expectancy, presence of important comorbidities or established vascular complications, and at higher risk of hypoglycemia should have higher glycemic targets, with an A1C of < 8% reasonable for those with the least to gain from more intensive control and at highest risk for adverse outcomes from hypoglycemia. For the majority of patients who are otherwise healthy, glycemic targets include the following: preprandial plasma glucose 80-130 mg/dl; postprandial plasma glucose <180 mg/dl; and A1C <7% (98).

In the DCCT, retinopathy initially worsened during the first year in patients with type 1 diabetes who received intensive therapy (86). This was associated with rapid lowering of glucose levels. Thus, in patients with proliferative retinopathy or those with underlying non-proliferative diabetic retinopathy and a high A1C (e.g., >10%), slower lowering of glucose is warranted. Another example of individualizing glycemic goals is a patient with hypoglycemic unawareness, in whom glycemic goals should be less aggressive to reduce the frequency of severe hypoglycemia (115).

REPLACEMENT STRATEGIES

EXAMPLES OF REGIMENS

Once Daily Insulin Regimen (for patients with type 2 diabetes on oral agents)

NPH (Figure 7), insulin glargine (Figure 8), or insulin detemir are most often given at bedtime. However, given their longer duration of action, insulin glargine and insulin degludec can be administered anytime of the day (101). For patients who eat large amounts of carbohydrates at dinner, an insulin mixture, regular and NPH or a premixed insulin, can be given prior to dinner (Figure 9).

Figure 7.

PM NPH Administration.

Figure 8.

Glargine Administration.

Figure 9.

NPH and Regular Insulin at Dinner.

Twice-Daily Insulin Regimen (Split-Mixed and Pre-Mixed Regimens)

Two-thirds of the insulin dose is typically given in the morning before breakfast and one-third is given before dinner. Premixed insulins can be used or a mixture of a short-acting insulin (e.g., regular, insulin aspart/glulisine/lispro) and an intermediate-acting insulin (e.g., NPH) (Figure 10) (114) .

Figure 10.

NPH and Twice a Day Regular Insulin.

2/3 total daily dose at breakfast: given as 2/3 NPH and 1/3 Regular (or insulin aspart/glulisine/lispro) 1/3 total daily dose at dinner: divided in equal amounts of NPH and Regular (or insulin aspart/glulisine/lispro)

For patients who experience nocturnal hypoglycemia when NPH is administered at dinner with a short-acting insulin, moving the NPH dose to bedtime helps reduce the risk for nocturnal hypoglycemia (120). Conversely, NPH at dinner can result in fasting hyperglycemia due to dissipation of insulin activity and the early morning rise in counter-regulatory hormones cortisol and growth hormone (the dawn phenomenon). Moving the NPH dose to bedtime can also help resolve this problem (121) (Figure 11). An obvious limitation to using premixed insulin is reduced flexibility in dosing; if the dose is adjusted, both types of insulin in the mixture will be adjusted.

Figure 11.

Twice a Day NPH and Regular.

Multiple Daily Insulin Injection Regimen: Basal plus Prandial Insulin

Many different types of regimens are possible with multiple daily injections. Regular, insulin aspart, glulisine and lispro are used to provide prandial insulin. NPH, insulin glargine, insulin detemir, and insulin degludec are used to provide basal insulin.

Regular, insulin aspart/glulisine/lispro before meals and NPH, insulin glargine, insulin detemir, or insulin degludec at bedtime (hs) (Figure 12, 13).

Insulin aspart/glulisine/lispro before meals and NPH twice daily (breakfast and bedtime) (Figure 14).

Figure 12.

Bedtime NPH and Regular Insulin with Meals.

Figure 13.

Bedtime Glargine Insulin and Lispro/Aspart with Meals.

Figure 14.

NPH Twice a Day and Lispro/Aspart with Meals.

ADJUSTMENTS

Insulin doses should be adjusted to achieve glycemic targets. Typically, a 10-20% increase or decrease in an insulin dose is appropriate, based on the degree of hyper- or hypoglycemia, and the insulin sensitivity of the patient. Hypoglycemia that is frequent or severe should prompt an immediate reduction in the responsible insulin dose. Increases to insulin doses should be based on the occurrence of consistently elevated glucose levels at a particular time of day, rather than periodic glucose elevations that are more likely diet-mediated.

SELF-MONITORING OF BLOOD GLUCOSE

Self-monitoring of blood glucose (SMBG) allows patients and physicians to recognize glucose trends to guide insulin dosage adjustments. In those using short or rapid-acting inulin, SMBG also provides a patient with the information needed to give an accurate supplemental insulin dose to return an elevated glucose level back to the target glucose range. Studies in patients with type 1 diabetes have shown a progressive reduction in hemoglobin A1C levels with more frequent glucose monitoring (139) Currently, the ADA recommends that patients with diabetes on multiple daily injections of insulin or on an insulin pump check blood glucose before eating, exercise, and bedtime, for symptoms of hypoglycemia, and periodically after meals. For patients with type 2 diabetes not on multiple daily injections of insulin, no specific frequency of SMBG is recommended but rather it is recommended that SMBG and its assessment be a part of patients’ treatment and management plan (139).

Most glucose meters are now plasma-referenced, correlating better to the ADA’s glycemic goals. Plasma glucose concentrations are approximately 10-15% higher than whole blood glucose concentrations (140) .

CGM, which measures interstitial glucose, is available in 2 forms: an intermittent or “flash” CGM system and real-time CGM systems (141). To date, the intermittent CGM system and one of the real-time CGM systems do not require calibration with blood glucose. Intermittent CGM has been associated with less time spent in hypoglycemia in patients with type 1 diabetes and in patients with type 2 diabetes (142,143) , and the real-time CGM systems have been associated with improved glycemic control, more so when used consistently, and less time spent in hypoglycemia, and less severe hypoglycemia in patients with type 1 diabetes (144,145).

SICK DAY GUIDELINES

A common misconception among patients is that if they are sick enough that they do not eat or they vomit, they should not take their anti-hyperglycemic medications, insulin included. Patients who are ill should be instructed to continue their basal insulin therapy, maintain fluid intake, eat smaller meals as tolerated, and test their glucose levels every 1-4 hours (ketones as well for people with type 1 diabetes when glucose levels are over 200 mg/dl). Supplemental insulin doses to correct hyperglycemia can be given up to every 4 hours as needed for persistent hyperglycemia, or more often when the insulin on board from an insulin pump or a smart insulin pen is taken into account. For patients using the bolus calculator function of their insulin pump, the recommended bolus dose to correct an elevated glucose level automatically takes into account the insulin on board from prior insulin boluses. If the glucose is >240 mg/dl with large ketonuria, patients should contact their provider immediately, or proceed to an emergency room for treatment of ketoacidosis using intravenous fluids and insulin. Sick day guidelines can be found online (146).

ACKNOWLEDGEMENTS

The prior version of this chapter was extensively modified based on a previous chapter written by Lisa Kroon, PharmD, CDE, Ira D. Goldfine, M.D. and Sinan Tanyolac, M.D.

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