Insulin was initially available as a soluble, clear solution. The relatively short duration of action meant that individuals had to take multiple daily injections. Combining insulin with protamine or high concentrations of zinc led to the formation of suspensions that are slowly absorbed with a longer and variable duration of action. Insulin analogs were designed with more predictable characteristics of rapid or attenuated absorption and action. The pharmacodynamic profiles of the different types of insulin and insulin analogs are summarized in Table 9.
In solution, and in the b-cell where its concentration is high, insulin tends to self-associate, forming dimers, hexamers, and larger aggregates. In the b-cell, this self-association facilitates the transportation, conversion, and intracellular storage of insulin crystals. However, self-association retards absorption of soluble insulin after subcutaneous administration because hexamers must dissociate to monomers before entering the bloodstream. The rapid-acting analogs differ from regular insulin by virtue of their capacity to dissociate rapidly into monomers in subcutaneous tissue. The rate of absorption from a subcutaneous site also varies day to day and from one injection site to another, and is also influenced by ambient temperature and physical activity.
Subcutaneous administration of insulin does not truly duplicate endogenous insulin physiology. In normal individuals the pancreas secretes insulin with a rapid first-phase secretion followed by a prolonged second-phase release directly into the portal circulation. High insulin concentrations reach the liver, regulate endogenous glucose production, and undergo first-pass hepatic metabolism, resulting in lower circulating insulin concentrations to peripheral tissues. Subcutaneous insulin, on the other hand, is absorbed peripherally, allowing the highest plasma insulin concentrations to reach the peripheral tissues before arriving at the liver.
The liver and kidneys account for the majority of insulin degradation. Normally, the liver degrades 60% of endogenous insulin (delivered via portal vein blood flow) and the kidneys 30-40%.75 When insulin is injected exogenously, the degradation profile is altered, as insulin is not delivered directly to the portal vein. The kidney plays a greater role in insulin degradation with subcutaneous insulin (approximately 60%), with the liver degrading 30-40%.76 Severe renal dysfunction reduces the clearance of insulin and prolongs its effect.77
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