The metabolic actions of insulin are primarily anabolic (i.e., conservative, constructive). Insulin promotes the conservation of energy and the buildup of energy stores, such as glycogen.
The hormone also promotes cell growth and division.
Insulin acts in two ways to promote anabolic effects. First, it stimulates cellular transport (uptake) of glucose, amino acids, nucleotides, and potassium. Second, insulin promotes synthesis of complex organic molecules. Under the influence of insulin and other factors, glucose is converted into glycogen (the liver’s way to store glucose for later use), amino acids are assembled into proteins, and fatty acids are incorporated into triglycerides.
The principal metabolic actions of insulin are shown in Table 57.5.
Substance
Affected Insulin Action Site of Action CARBOHYDRATES ↑ Glucose uptake Muscle, adipose
tissue
↑ Glucose oxidation Muscle
↑ Glucose storage ↑ Glycogen synthesis ↓ Glycogenolysis
Muscle, liver
Gluconeogenesisa Liver AMINO ACIDS AND
PROTEINS
↑ Amino acid uptake Muscle
↓ Amino acid release Muscle
↑ Protein synthesis Muscle LIPIDS ↑ Triglyceride synthesis Adipose tissue
↓ Release of FFA and
glycerol Adipose tissue
↓ Oxidation of FFA to
ketoacidsb Liver
TABLE 57.5 ■ Metabolic Actions of Insulin
aBecause of decreased delivery of substrate (fatty acids and amino acids) to the liver.
bBecause of decreased delivery of FFA to the liver.
FFA, Free fatty acids.
Short Duration: Rapid Acting
Short-duration insulins are administered in association with meals to control the postprandial (or after meal) rise in blood glucose. To provide glycemic control between meals and at night, short-acting insulins must be used in conjunction with an intermediate- or long-acting agent in people with type 1 diabetes. All three of the injectable rapid-acting insulins are formulated as clear solutions, and all three require a prescrip-tion. For routine therapy, all three are given subQ. If needed, all three may also be given IV. These products are rarely used IV, however, because regular insulin is a more cost-effective choice in the inpatient setting.
Insulin Lispro. Insulin lispro [Humalog] is a rapid-acting analog of regular insulin. Effects begin within 15 to 30 minutes When classified according to time course, insulin preparations
fall into three major groups: short duration, intermediate dura-tion, and long duration. As shown in Table 57.7, these three main groupings can further be divided based on the properties of the insulins in each group. The short-duration insulins can be subdivided into two groups: rapid acting (insulin lispro, insulin aspart, insulin glulisine, and inhaled human insulin) and slower acting (regular or “natural” insulin). The long-duration insulins can also be subdivided into two groups: long acting (U-100 insulin glargine and insulin detemir) and longer-acting (U-300 insulin glargine and insulin degludec) products that have a duration in excess of 24 hours. Time courses for different insulin types are shown in Fig. 57.2. Selected properties of insulin types are shown in Table 57.8.
Generic Name Brand Name
Time Course
Onset (min) Peak (hr) Duration (hr)
SHORT DURATION: RAPID ACTING
Insulin lispro Humalog 15–30 0.5–2.5 3–6
Insulin aspart NovoLog 10–20 1–3 3–5
Insulin glulisine Apidra 10–15 1–1.5 3–5
SHORT DURATION: SLOWER ACTING
Regular insulin Humulin R, Novolin R 30–60 1–5 6–10
INTERMEDIATE DURATION
NPH insulin Humulin N, Novolin N 60–120 6–14 16–24
LONG DURATION
Insulin glargine (U-100) Lantus 70 Nonea 18–24
Insulin detemir Levemir 60–120 Nonea 12–24
ULTRA-LONG DURATION
Insulin glargine (U-300) Toujeo 360 Nonea > 24
Insulin degludec Tresiba 30–90 Nonea > 24
TABLE 57.7 ■ Types of Insulin: Time Course of Action After Subcutaneous Injection
aLevels are steady with no discernible peak.
Insulin Type
Amino Acids in A-Chain Position Amino Acids in B-Chain Position
A8 A10 A21 B3 B28 B29 B30 B31 B32
HUMAN INSULIN
Nativeb Thr Ilc Asn Asn Pro Lys Thr — —
HUMAN INSULIN ANALOGS
Glargine Thr Ilc Gly Gly Pro Lys Thr Arg Arg
Aspart Thr Ilc Asn Asn Asp Lys Thr — —
Lispro Thr Ilc Asn Asn Lys Pro Thr — —
Glulisine Thr Ilc Asn Lys Pro Glu Thr — —
Detemir Thr Ilc Asn Asn Pro Lysc d — —
TABLE 57.6 ■ Amino Acids Substitutions in Human Insulin Analogsa
aThe human insulin analogs have the same physiologic effects as native human insulin—they just have different pharmacokinetics, such as onset and duration of action.
bHuman insulin (i.e., the form of insulin made by the human pancreas) is also known as native insulin.
cA fatty-acid chain has been added to the lysine in position B29.
dThe amino acid normally in position B30 has been deleted.
Arg, Arginine; Asn, asparagine; Asp, aspartic acid; Glu, glutamine; Gly, glycine; Ilc, isoleucine; Lys, lysine; Pro, proline; Thr, threonine.
CHAPTER 57 Drugs for Diabetes Mellitus
by two amino acids and is available in 10-mL vials and as 3-mL pre-filled insulin pens.
Inhaled Human Insulin. As mentioned briefly before, when regular human insulin is inhaled, the time action profile is altered such that the regular insulin works more quickly and has a shorter duration when compared to regular insulin when injected subQ. Inhaled human insulin [Afrezza] is a mealtime insulin product that can be used in people with type 1 and type 2 diabetes. The insulin product is available commercially in cartridges that contain 4, 8, or 12 units each. The cartridges are inserted into a dry powder inhalation device to administer the insulin by inhalation. The limitation of this particular insulin product is that patients are limited to doses of insulin in incre-ments of 4, 8, or 12 units. For example, if a patient required 24 units of insulin, he or she would need to take 2 inhalations using the 12-unit cartridges (or 3 inhalations with the 8-unit cartridges, and so on).
Short Duration: Slower Acting
Regular Insulin Injection. Regular insulin [Humulin R, Novolin R] is unmodified human insulin. The product can be administered by subQ injection, subQ infusion (although rapid-acting analogs are generally used for this purpose), IM injection (used rarely), and through IV therapy. For IV therapy, only the U-100 formulation should be used.
For routine treatment of diabetes, regular insulin can be (1) injected before meals to control postprandial hyperglycemia and (2) infused subQ to provide basal glycemic control. Fol-lowing subQ injection, molecules of regular insulin form small aggregates (dimers and hexamers) at the injection site. As a result, absorption is slightly delayed. Effects begin in 30 to 60 minutes, peak in 1 to 5 hours, and last up to 10 hours.
Onset is slower than with the rapid-acting insulins and faster than with the longer-acting insulins. Because of this delay, most people using insulin pumps use a rapid-acting insulin analog instead of regular insulin.
Regular insulin is supplied as a clear solution. Two concentra-tions are available: U-100 (100 units/mL) and U-500 (500 of subQ injection and persist for 3 to 6 hours. Insulin lispro
acts faster than regular insulin but has a shorter duration of action. Because of its rapid onset, insulin lispro can be admin-istered immediately before eating, or even after eating in some patients. In contrast, regular insulin is generally administered 30 to 60 minutes before meals. The usual route for insulin lispro is subQ via injection or use in an insulin pump. Insulin lispro (100 units/mL, or U-100) is commercially available in 10-mL vials and as 3-mL pre-filled pens and cartridges. Of note, insulin lispro is also available in a twice-concentrated solution (200 units/mL, or U-200) that is available in pre-filled pen devices. The potential advantage of the concentrated product is to be able to administer larger doses of insulin in a smaller volume for patients requiring large doses at a time.
The structure of insulin lispro is nearly identical to that of natural insulin. The only difference is that the positions of two amino acids have been switched. Because of this switch, molecules of insulin lispro aggregate less than do molecules of regular insulin, which explains why insulin lispro acts more rapidly.
Insulin Aspart. Insulin aspart [NovoLog] is an analog of human insulin with a rapid onset (10 to 20 minutes) and short duration (3 to 5 hours). The drug is structurally identical to human insulin except that one amino acid—proline in position 28 of the B chain—has been changed to aspartic acid. Insulin aspart is very similar to insulin lispro.
Insulin aspart (100 units/mL) is supplied in 10-mL vials and 3-mL pre-filled pens and cartridges. Dosing is almost always done by subQ injection or subQ infusion with an insulin pump. Because insulin aspart acts rapidly, injections should be made 5 to 15 minutes before meals.
Insulin Glulisine. Like insulin lispro and insulin aspart, insulin glulisine [Apidra] is a synthetic analog of natural human insulin with a rapid onset (10 to 15 minutes) and short duration (3 to 5 hours). Owing to its rapid onset, the drug should be administered close to the time of eating. Administration is almost always by subQ injection or continuous subQ infusion.
Insulin glulisine (100 units/mL) differs from natural insulin
Insulin Blood Level
Hours After Injection
2 4 6 8 10 12 14 16 18 20 22 24
SubQ Injection
(Insulin lispro, insulin aspart, insulin glulisine)
Short duration, fastest acting Short duration, slower acting Intermediate duration, slow acting Long duration, slowest acting
(Regular insulin) (NPH insulin)
(Insulin glargine, insulin detemir)
Fig. 57.2 ■ Time-effect relationship for different types of insulin following subcutaneous injection.
Intermediate Duration
Neutral Protamine Hagedorn (NPH) Insulin Suspen-sion. NPH insulin [Humulin N, Novolin N], also known as isophane insulin, is prepared by conjugating regular insulin with protamine (a large protein). The presence of protamine decreases the solubility of NPH insulin and thus delays absorp-tion. As a result, onset of action is delayed and duration of action is extended. Because onset is delayed, NPH insulin cannot be administered at mealtime to control postprandial hyperglycemia. Rather, the drug is injected two or three times daily to provide glycemic control between meals and during the night. Of the longer-acting insulins in current use, NPH units/mL). Regular insulin [Humulin R] is the only type
available in a U-500 strength. U-100 preparations are used by most patients. The U-500 concentration is reserved for patients with extreme insulin resistance who take more than 200 units of insulin per day. Because it is so concentrated, U-500 insulin should never be given IV. U-500 insulin is available in 20-mL vials and in pre-filled U-500 insulin pens. When patients are using the vial, it is important to ensure that they are using U-500 insulin syringes; otherwise, they are at serious risk for an overdose of insulin. For this reason, extra caution and education are critical when working with patients using U-500 insulin. Except for the U-500 formulation, all formulations of regular insulin are available without prescription.
Drug Class Rx or
OTC Strengtha Appearance Route Administration Options SHORT DURATION: RAPID ACTING
Insulin lispro
[Humalog] HA Rx U-100, U-200 Clear subQ, IV subQ inj: within 15 min before or just after
meals
subQ inf: continuous, with bolus just before meals
IV: approved route, but rarely used Insulin aspart
[NovoLog] HA Rx U-100 Clear subQ, IV subQ inj: 5–10 min before meals
subQ inf: continuous, with bolus 5–10 min before meals
IV: approved route, but rarely used Insulin glulisine
[Apidra] HA Rx U-100 Clear subQ, IV subQ inj: within 15 min before meals or within
20 min after
subQ inf: continuous, with bolus 15–20 min before meals
IV: approved route, but rarely used SHORT DURATION: SLOWER ACTING
Regular insulin [Humulin R, Novolin R]
H OTCb U-100, U-500 Clear subQ, IV,
IM subQ inj: 30 min before meals
subQ inf: continuous, with bolus 20–30 min before meals
IV: for emergencies and glycemic management in the inpatient setting (never use U-500 IV) IM: approved route, but rarely used
INTERMEDIATE DURATION NPH insulin
[Humulin N, Novolin N]
H OTC U-100 Cloudy subQ subQ inj: twice daily at the same times each
day; gently agitate before use LONG DURATION
U-100 Insulin
glargine [Lantus] HA Rx U-100 Clear subQ subQ inj: once or twice daily at the same time
each day Insulin detemir
[Levemir] HA Rx U-100 Clear subQ subQ inj: once or twice daily at the same time
each day ULTRA-LONG DURATION
U-300 Insulin
glargine [Toujeo] HA Rx U-300 Clear subQ subQ inj: once daily
Insulin degludec
[Tresiba] HA Rx U-100, U-200 Clear subQ subQ inj: once daily
TABLE 57.8 ■ Properties of Insulin Types
aU-100, 100 units/mL; U-200, 200 units/mL; U-300, 300 units/mL; U-500, 500 units/mL.
bU-100 formulations are OTC; the U-500 formulation is Rx.
H, Human insulin; HA, human insulin analog; inf, infusion; inj, injection; OTC, over the counter (no prescription needed); Rx, prescription needed.
CHAPTER 57 Drugs for Diabetes Mellitus
individuals who do not realize a full 24 hours of effect with the U-100 product.
U-300 insulin glargine is supplied as a clear solution in pre-filled pens only. The pre-filled pens minimize the risk of insulin overdose. To administer a dose of U-300 insulin, the patient simply dials the desired number of units on the pen, and all volume conversions are made automatically. The pre-filled pens eliminate the risk of overdose with U-100 insulin syringes, for example. The product is dosed once daily.
Insulin Degludec. Insulin degludec [Tresiba] is another longer-acting insulin that can be used in type 1 and type 2 diabetes to provide basal insulin coverage. So how does insulin degludec achieve a longer time action profile? In solution insulin degludec exists as soluble dihexamers. Once injected, however, the degludec dihexamers assemble into multihexamer chains that are quite stable in the subQ tissue. Over time monomers of insulin diffuse from the terminal ends of the long insulin chain, which are then absorbed. The slow dissocia-tion of insulin degludec at the injecdissocia-tion site results in a duradissocia-tion of action in excess of 24 hours.
Insulin degludec is available in both U-100 and U-200 concentrations. The more concentrated U-200 product is useful for patients on large doses of insulin. Both concentrations are available in pre-filled insulin pens only. The product is recommended to be dosed once daily for basal insulin needs.