Shortacting Insulins

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Regular human insulin exists mostly as complexes of six insulin molecules (hex-amers) because of spontaneous self-association, and a smaller proportion of singles (monomer) and doubles (dimers). When given intravenously, Regular human insulin rapidly dissociates into monomers. However, after subcutaneous injection, dissociation is much slower. Because insulin needs to be monomelic for absorption from the subcutaneous space into the blood, this slow dissociation delays the appearance of insulin into the blood, and thus its onset of action (16). As shown in Table 2, the onset of action of subcutaneously injected Regular human insulin is approximately 15-30 minutes, its peak action occurs at about 120 minutes, and the duration of action at doses used clinically is generally between 6 and 8 hours. These values relate to abdominal subcutaneous injection, which is the preferred site of injection. Absorption from the abdomen is more rapid than that following subcutaneous injection in the arm, which in turn is more rapid than that following subcutaneous injection in the thigh (10).

As a result of studying the structural basis for the self-association of human insulin, analogs with amino acid substitutions were developed that eliminate self-aggregation. Two of these, lispro and aspart, are commercially available (12,15).

Insulin lispro (Humalog) is the result of altering the 28th and 29th B-chain amino acids from proline, lysine to lysine, proline, which eliminates the ability to self-aggregate so only monomers exist after injection in die subcutaneous space. Absorption is thus much faster than with Regular insulin (17). Lispro binds to the insulin receptor with approximately the same affinity as native human insulin, but has a slightly higher affinity for the IGF-1 receptor. The clinical significance of the latter remains to be determined. Euglycemic clamp studies in normally glucose-tolerant subjects reveal that when given subcutaneously, lispro results in two- to threefold higher peak serum insulin levels sooner (42 versus 101 minutes)

than Regular, and its duration of action is shorter at 3-4 hours (17). Importantly, there is no significant difference in total hypoglycemic potency between these two insulins. Other clinically useful differences from Regular insulin are fewer anatomical effects on absorption (18), and the time to peak activity is not dose-dependent as it is with Regular (2).

Large clinical trials that compared insulin lispro with Regular insulin have shown lower postprandial glucose rises in type I and type 2 patients with lispro, although overall glycemic control as measured by HbA]C is not substantially different. One explanation may be that lispro is less likely to cause mild hypoglycemia than Regular insulin when used in doses that yield comparable postprandial control in type 1 patients (19-22), which results in a reduced need for between-meal snacks. Also, meta-analysis in type 1 patients suggests that lispro reduced severe hypoglycemia (23). No difference in serum lipid concentrations has been demonstrated. In both type 1 and type 2 patients, insulin antibody concentrations with lispro use was no different than with Regular insulin (24). Initial studies in patients treated with CSII suggest a benefit of insulin lispro over Regular insulin in reduction of both HbA,c and postprandial glycemia (25,26). In most patients, doses of lispro and Regular insulin are comparable, although minor adjustments may be required in individual patients. Insulin lispro should be given up to 15 minutes before a meal (27).

In summary, advantages of insulin lispro are its ease of use with no need to wait before eating and better prandial control in type 1 patients with less hypoglycemia than Regular insulin. Disadvantages relate to the rapidity of onset and short duration. Type 1 patients may "run out" of insulin if sufficient basal insulin or mixture with Regular insulin is not used. Finally, its safety in pregnancy has not been established.

Insulin aspart (Novolog) is similar in concept to lispro, and was created by substituting aspartic acid for proline at position 28 on the B chain (15,28). Self-association is decreased similarly to insulin lispro, resulting in a monomeric/ dimeric insulin analog. Because aspartic acid is negatively charged, the lack of association may be charge-mediated rather than steric. Potency of aspart is similar to that of human insulin, with approximately 90% binding affinity to the insulin receptor (29). Also, binding to the IGF-1 receptor is similar to human insulin.

Insulin aspart is absorbed twice as fast as Regular insulin (30). Site effects in terms of absorption and glucose-lowering action are negligible (31). The peak insulin levels attained are approximately twice as high for aspart versus Regular insulin at 52 minutes and 109 minutes, respectively. The duration of action is 3-4 hours. A study comparing aspart and lispro showed no major clinical differences (32).

A brief clinical trial of insulin aspart versus Regular insulin showed the expected reduction in postprandial glycemia (33). However, after 1 month no difference in fructosamine (a measure of overall glycemia like HbA]C, but for

the last 7-10 days) was noted. A longer, 6-month trial showed a small 0.15% reduction in HbA,c with insulin aspart versus Regular, the former being given at mealtime and the latter 30 minutes before meals (34). Also, there were fewer episodes of severe hypoglycemia.

Overall, the pharmacodynamics of lispro and aspart in terms of rapidity of action and short duration are similar, and, not surprisingly, their advantages, disadvantages, and how they are used are comparable. Both appear to reduce postprandial glycemia and lessen the risk for hypoglycemia. Both should be administered 0 to 15 minutes before a meal, and no dosing adjustment is generally made when switching from Regular insulin to aspart or lispro. Studies support the use of either in insulin pumps (25,26,35). In contrast, there is no advantage of the monomeric analogs during intravenous infusion, which should probably be reserved, at present, for Regular insulin.

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Diabetes 2

Diabetes 2

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...

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