The most commonly used intermediate-acting insulin is neutral protamine Hagedorn (NPH) insulin (isophane). It was developed in the Novo-Hagedorn laboratories in Denmark in 1946 by Krayenbuhl and Rosenberg (37), based on the original observation of Hagedorn that insulin's effect was prolonged when combined with proteins such as protamine (38), and that of Scott and Fisher showing that small amounts of zinc lengthened the action of protamine insulin (39). NPH contains equal amounts of protamine and insulin with a small amount of zinc at neutral pH. Protamine is a basic, highly negatively charged protein derived from fish sperm. It is essentially nonimmunogenic. The commercial preparations of NPH are a suspension of oblong tetragonal crystals with essentially no unprecipi-tated (Regular) insulin (5). Because of the symmetric, even structure of the insu-lin-protamine crystals, and because protamine and insulin are used in equimolar amounts, the term isophane (Greek iso, "even" and phane, "appearance") is often used for this insulin preparation. For both forms of crystallized insulin (NPH and the Lente), the insulin crystals may sediment soon after agitating the bottle. To ensure accurate dosing, then, care must be taken to gently, but thoroughly, mix the vial prior to drawing it up in the syringe. Sedimentation of insulin crystals may in part explain the described day-to-day variability of insulin action for the longer-acting insulins. Also, commercially available NPH preparations contain very small amounts of nonbound protamine—too little to bind significant amounts of Regular insulin when mixed with the NPH—so NPH-Regular mixtures are much more stable than Lente- or Ultralente-Regular mixtures. This has allowed development of commercial fixed mixtures of NPH and Regular insulin. In the United States, 70/30 and 50/50 (%NPH/%Regular) are available, while in other parts of the world many more proportions are obtainable. The onset of action and duration of the preparation depend on the relative amounts
of NPH and Regular insulin in the mixture, in general, the more NPH, the later the onset and the longer the duration of action. A similar mixture using 75% neutral protamine lispro (NPL) and 25% Lispro has recently been marketed.
The absorption of both NPH and human Lente insulin follows a monoexpo-nential course, as does Regular insulin. For the most part, there seem to be no clinically important differences in absorption between these two insulin preparations, although NPH insulin has been reported to have a somewhat faster onset and shorter duration (40). Both insulins after subcutaneous injection have a slow on-off pattern that is interspersed by a considerable peak, plus there is a large day-to-day variability of up to 50% for both NPH and Lente (9). It therefore seems that neither Lente nor NPH fulfills the criteria for an ideal basal insulin.
In summary, NPH and Lente have been mainstays of insulin regimens for a half-century. They provide basal insulin coverage, but at a price: absorption is variable, they have a distinct peak, and human preparations generally last for considerably less than 24 hours, necessitating multiple injections.
Was this article helpful?
Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...