The rapid acting insulin analogues have an onset of action about 15-30 minutes after injection, with peak action around 30-90 minutes after injection, and have an effective duration of action of 4 to 5 hours when injected subcutaneously because they are rapidly converted from hexameric crystals to insulin monomers after injection resulting in more rapid absorption, something which is not the case with regular insulin. These insulins have been genetically engineered via site-specific mutagenesis of the insulin sequence so that insulin lispro differs from human insulin by inversion of the amino acids lysine and proline at positions 28 and 29 of the insulin B-chain; the substitution of aspartic acid for proline at position 28 of the insulin B-chain for insulin aspart and for insulin glulisine the substitution of lysine for asparagine at position B3 of the insulin B-chain as well as the substitution of glutamic acid for lysine at position 29 of the insulin B-chain. These rapid-acting insulin analogues are most suitable as mealtime prandial insulin injections (figure 8) or in insulin pumps for CSII (figure 9).

Figure 8. Idealized insulin curves for morning regular insulin (magenta) and insulins lispro, aspart/, or glulisine (blue). The rapid-acting analogues only provide prandial insulin while regular insulin contributes to both prandial and basal insulinemia. B=breakfast; L=lunch.

Figure 9. Idealized insulin curves for CSII with either insulin lispro, aspart, or glulisine, with a gray background of physiologic insulin levels seen in healthy individuals. Note the basal insulin component can be altered based on changing basal insulin requirements. Typically, insulin rates need to be lowered between midnight and 0400 h (to prevent the “predawn phenomenon” of “sleep-realted hypoglycemia”) and raised between 0400 h and 0800 h (to prevent the hyperglycemia of the “dawn phenomenon”). The basal rate the rest of the day is usually intermediate to the other two. Modern-day pumps can calculate prandial insulin dose by the patient entering into the pump the blood glucose concentration and the anticipated amount of carbohydrate to be consumed. The pump calculates how much previous prandial insulin is still active, and provides the patient a final suggested dose which the patient may activate or override. B=breakfast; L=lunch; S=supper; HS=bedtime.

Regular insulin has an onset of action 30 to 60 minutes after subcutaneous injection, a peak effect around 2 to 3 hours after injection, and an effective duration of action of 6 to 8 hours. Recommended use is for injection to be at least 20 to 30 minutes prior to meals in an attempt to better match insulin action with carbohydrate absorption. In contract to subcutaneous administration, regular insulin acts almost instantly when injected intravenously, with a half-life of approximately 6 minutes.

There is retarded absorption of NPH ( or isophane) insulin due to the addition of protamine to regular insulin during its manufacture. The onset of action of NPH insulin occurs about 2 to 4 hours from the time of its subcutaneous injection, with a peak effect around 6 to 10 hours after injection, and an effective duration of action of 10 to 16 hours. NPH is commonly used as a twice-daily basal insulin. NPH insulin comes as a suspension rather than a solution, and must be appropriately handled to assure uniformity of the suspension.

The currently available long acting insulin analogues are insulin glargine and insulin detemir, both of which have been re-engineered to create insulins with prolonged biological activity. Insulin glargine differs from human insulin by the substitution of glycine for alanine at position 21 of the insulin A-chain plus the addition of two extra amino acids – both arginines – at the end of the insulin B-chain, extending it from its usual length of 30 amino acids to 32 amino acids. Insulin glargine is soluble at acid pH, and forms a microprecipitate in the subcutaneous tissue which is at neutral pH; this microprecipitate is slowly released with near linear kinetics over a period of 20 to 24 hours in most patients. Insulin detemir differs from human insulin by having the terminal amino acid (threonine) removed from the insulin B-chain (position 30) thus shortening this chain to 29 amino acids; in addition, the epsilon amino group of the now terminal lysine at position 29 is covalently acylated with a 14 carbon fatty acid (myristic acid), which binds to albumin both in subcutaneous tissue and in the circulation and thus prolongs its action.