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Human Insulin

A Review of its Biological Activity, Pharmacokinetics and Therapeutic Use

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Summary

Synopsis

Human insulin, whether produced by recombinant DNA techniques (biosynthetic, insulin crb)1 or enzymatic modification of porcine insulin (semisynthetic, insulin emp)2 tis equivalent in biological activity to porcine insulin following intravenous administration. Slight differences between human and porcine insulin in hypoglycaemic activity after subcutaneous injection appear to be related to differences in absorption, and are unlikely to be of major clinical importance. Similarly, reported minor differences in counterregulator hormone response to human insulin compared with porcine insulin need further study, but they are unlikely to have important clinical implications. In clinical use the therapeutic efficacy of human insulin is similar to that of porcine insulin. The lower antigenicity with human insulin relative to purified porcine insulin is of potential therapeutic value, and it is logical to use human insulin in newly diagnosed diabetics, in patients treated intermittently with insulin, in cases of immunological insulin resistance, and in patients with allergy and local reaction against animal insulin.

Thus, human insulin seems to have no disadvantages compared with purified porcine insulin and may have some advantages. While there appears to be no compelling reason to change patients whose diabetes is presently well controlled with purified porcine insulin to human insulin, the availability of human insulin at a price equal to or less than that of animal origin makes such a change logical. In the meantime, human insulin should be considered the insulin of ‘first choice’ for newly diagnosed diabetics requiring insulin therapy and in carbohydrate intolerance and diabetes occurring during pregnancy.

Pharmacodynamic Properties

Human insulin, whether of recombinant DNA origin using bacteria (biosynthetic or insulin crb) or produced by enzymatic modification of porcine insulin (semisynthetic or insulin emp) is not significantly different in potency from purified porcine insulin in a variety of in vitro assays. The hypoglycaemic effect of intravenously administered human insulin is likewise indistinguishable from that of equal doses of purified porcine insulin in healthy subjects or diabetic patients studied using ‘glucose clamp’ or glucose-controlled insulin infusion techniques. A tendency for an earlier and larger hypoglycaemic effect with soluble and isophane formulations of biosynthetic human insulin than with equivalent formations of purified porcine insulin, possibly due to differences in absorption, has been noted in several studies, but this is unlikely to be of clinical importance. The hypoglycaemic response to semisynthetic human insulin has usually been very similar to that of purified porcine insulin following subcutaneous administration, although in one study the overall hypoglycaemic effect of isophane semisynthetic human insulin (0.3 U/kg) in non-diabetic volunteers was greater than that of the same dose of biosynthetic human insulin, due to the faster recovery of blood sugar concentrations after the latter.

Small differences in secretion of counterregulatory hormones, which have not always been consistent, have been reported following administration of biosynthetic or semisynthetic human insulin and purified porcine insulin, but their clinical significance, if any, has yet to be evaluated. The same applies to the minor differences in the response of intermediary metabolites to these insulins.

As is the case with porcine or bovine insulins, results of studies in which newly diagnosed diabetic patients were treated for the first time with biosynthetic or semisynthetic human insulins indicate that these insulins are immunogenic in some patients. However, production of IgG antibodies occurs less often with human than with purified or conventional bovine insulin and generally less often than with the equivalent formulation of purified porcine insulin. Such differences were less apparent in patients changed from porcine to human insulin than from bovine to human insulin, except in patients with immunological insulin resistance or an initially high level of anti-insulin antibodies. Potential benefit of human insulin in patients with insulin allergy is evidenced in anecdotal reports of improved tolerance to human insulin in such patients. Since cross-reactivity between human insulin and pancreatic insulin of animal origin has been reported, it is to be expected that some patients with local or systemic allergy to porcine and/or bovine insulins will also exhibit allergy to human insulin.

Pharmacokinetic Properties

A tendency for a more rapid initial absorption of neutral soluble human insulin relative to the same formulation of purified porcine insulin after subcutaneous injection has been noted in most studies, possibly due in part to the more hydrophilic nature of human insulin. As with other insulins, the rate of absorption of human insulin is increased by exercise, is dose dependent and is more rapid from the anterior abdominal wall than from the thigh. Total metabolic clearance of human insulin was within the range usually reported for unlabelled insulin of animal origin and was lower in diabetic patients than in healthy subjects. Distribution volume of human insulin was higher in diabetic patients than in healthy subjects.

Therapeutic Trials

Results of double-blind therapeutic trials indicate that human insulin is similar in efficacy to the same formulation of purified porcine insulin in patients transferred from one to the other. There has been a tendency for a slightly higher early morning blood glucose after transfer from porcine to human insulin, and in a few studies glycosylated haemoglobin has indicated some deterioration of blood glucose control after changing to human insulin. Under the controlled conditions of continuous subcutaneous insulin infusion, human and porcine insulins of the same formulation were very similar in efficacy. The close similarity in efficacy between human and porcine insulin has also been demonstrated in newly diagnosed type I diabetic children, in type II diabetics with secondary failure to oral hypoglycaemic drugs and in the treatment of diabetic ketoacidosis and severe non-ketotic hyperglycaemia.

Dosage and Administration

As with other insulins, the dosage of human insulin must be determined by the physician in accordance with the needs of the patient. When patients controlled on purified porcine insulin are changed to human insulin, little change in dosage is needed. However, a modest reduction in dosage may be necessary especially in patients currently stabilised on high doses of mixed species or bovine insulin, depending on the purity and formulation of the animal insulin preparation(s).

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    Rex N. Brogden & R.C. Heel

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Various sections of the manuscript reviewed by: D.W. Beaven, Department of Medicine, Princess Margaret Hospital, Christchurch, New Zealand; M.A. Charles, Department of Medicine, University of California, Irvine, California, USA; S.E. Christensen, Second University Clinic of Internal Medicine, Kommunehospitalet, Harhus, Denmark; A. Ebihara, Department of Clinical Pharmacology, Oita National Medical School, Idaigaoka, Hazama-cho, Oita-gun, Oita-ken, Japan; P.D. Home, Department of Medicine, The Medical School, Framlington Place, Newcastle upon Tyne, England; J.H. Karam, Metabolic Research Unit, University of California, San Francisco, California, USA; R.G. Larkins, Department of Medicine, Royal Melbourne Hospital, Victoria, Australia; N. Mann, Royal Berkshire Hospital, Reading, Berkshire, England; M. Massi Benedetti, Istituto di Patologia Speciale Medica e Metodologia Clinica, Universita di Perugia, Perugia, Italy

‘Humulin’, ‘Humuline’, ‘Huminsulin’, ‘Umuline’, ‘Humulina’ (Eli Lilly & Co.); ‘Humulin’ (Shionogi), ‘Humulin’ (Star/Kabivitrum) ‘Bio-Insulin’ (Guidotti)

‘Actrapid HM’, ‘Actrapid HM Penfill’, ‘Monotard HM’, ‘Actraphane HM’, ‘Actraphane HM Penfill’, ‘Protaphane HM’, ‘Protaphane HM Penfill’, ‘Ultratard HM’ (Novo); ‘Novolin’ (Connaught Novo and Squibb Novo); ‘Semisyn’, ‘Insulatard’, ‘Mixtard’, ‘Velosulin’, ‘Initard’ (Nordisk; Nordisk/Well-come); ‘Insulin mixtard Human’ (Norsk Gentofte), ‘Depot-H-Insulin’ (Hoechst) ‘Insulin Human HCH’ (Hormon Chemie)

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Brogden, R.N., Heel, R. Human Insulin. Drugs 34, 350–371 (1987). https://doi.org/10.2165/00003495-198734030-00003

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