Patients with Type 1 and Type 2 diabetes who had never been given hsulin were treated either with semisynthetic human insulin (SHI), produced by a modification of pork insulin, or with purified pork insulin (PPI), and their efficacy, safety, and antigenicity were compared. Monotard and Actrapid insulins (Novo) were used. The choice of insulin preparations, number of insulin injections, and doses of insulin were decided by each physician. Blood and urine glucose, glycosylated hemoglobin and insulin antibodies were regularly measured.
The SHI-treated patients (59 cases) and PPI-treated patients (35 cases) did not differ initially in the distribution of age, type of diabetes, fasting blood glucose, HbA₁, obesity and diabetic complications. After 36 weeks of insulin treatment, there were no significant differences between the SHI and PPI groups in the doses of insulin, fasting blood glucose and HbA₁. After 8 weeks of treatment, insulin antibodies began to appear in both groups. The titers of total anti-insulin antibodies increased gradually with time, while IgE antibodies were observed only temporarily in a few cases. There was no difference in antibody production between the SHI and PPI groups. No serious side effects were observed with either insulin. SHI thus appears to be as safe and as effective as PPI. A weak antigenicity was demonstrated by SHI as well as by PPI.

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Human monocomponent insulin, semi-synthetized enzymatically by modification of porcine insulin, was compared with purified porcine insulin with respect to its safety, efficacy and immunological changes. A double-blind method was applied.
The preparations tested were Actrapid and Monotard insulins. The scheduled testing period is 96 weeks and is in progress. The results analyzed at this time are the interim results in patients who have been treated and observed for more than 24 weeks.
A total of 153 patients were collected, all diabetics of either type 1 or type 2 and treated exclusively with purified porcine insulin priror to the present study.
Analysis was carried out on 145 cases, with the remaining 8 cases excuded because they were judged to fall within the exclusion criteria.
No marked differences in the patients' backgroud data, i.e., age, type of diabetes, obesity index, age at onset of diabetes, duration of diabetes and diabetic complications, were observed between the group treated with human monocomponent insulin and the group given purified porcine insulin.
There was a tendency for the purified porcine insulin group to show a higher incidence of “improved” cases in the global improvement rating and “useful” cases in the global utility rating compared with the human monocomponent insulin group.
No statistical differences in body weight, anti-insulin IgG antibodies or insulin-specific IgE antibodies were observed between the two groups.
There were no adverse effects, although one case did develop an insulin allergy at about one month, and another case showed lipoatrophy in the 12th week of the study. These two cases were, however, able to continue the treatment.
There were no abnormal laboratory findings judged to be directly due to either of the test drugs.
These results suggest that human monocomponent insulin is as safe and effective as purified porcine insulin. In conclusion, the human monocomponent insulin can be considered to have a similar clinical usefulness to the purified porcine insulin.

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Diurnal changes in blood glucose were compared in diabetic patients during treatment with porcine monocomponent insulin and semisynthetic human insulin. Monotard and Actrapid preparations (Novo) were employed in these experiments. In patients whose diabetic control was stabilized with porcine insulin treatment, the diurnal blood glucose levels were examined. They were then transferred to human insulin treatment with the same doses and same preparations. After 7 days treatment, the diurnal blood glucose was again examined. In 5 patients who had one morning injection of Monotard preparation, no significant difference was detected in the diurnal blood glucose values between the periods of pork and human insulin treatment, although there was some tendency for higher blood glucose in the daytime with porcine insulin treatment and in the evening during treatment with human insulin. In patients who received two injections of Monotard plus Actrapid, there was no difference in diurnal blood glucose profiles between the two treatment periods. None of the patients had ketonuria during the study periods with both insulin. A few patients exhibited hypoglycemic reactions during human insulin treatment. Although Actrapid insulin of human origin is known to be absorbed somewhat faster than porcine Actrapid insulin, when administerd subcutaneously to healthy subjects, no evidence of any differences in time of action between Monotard of porcine and human insulin was obtained in this study.

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Semisynthetic human insulin was administered in order to evaluate its safety in diabetic patients who had been treated with porcine monocomponent insulin, as a preliminary trial for a multiinstitutional double-blind study of human insulin (HMI) and porcine insulin (PMI). Two type-1 and 5 type-2 diabetic patients were transferred from PMI to HMI treatment and closely observed for 6-8 weeks. There were no significant differences in insulin doses (17.7±2.1 units/day (PMI) vs. 20.0±9.5 (HMI)), fasting plasma glucose (107.4±83.7 (PMI) vs. 121.2±72.8 (HMI)) and glycohemoglobin (9.9±1.0 (PMI) vs. 8.0±1.2 (HMI)) between the periods of pork and human insulin treatment. It would appear therefore that HMI preparations are approximately as potent as PMI. The data warrent the commencement of a double-blind study on a larger number of patients

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The aim of the present study was to compare the effect and control among treatments using various continuous insulin infusion systems with SHI in 8 newly insulin-treated diabetics. Three type II diabetics and one unclassified case were treated by Biostator; one case of type II was treated by continuous subcutaneous insulin infusion; 2 cases (type I and type II) were treated by low-dose continuous intravenous infusion; and the other case (type I) was treated using an artificial endocrine pancreas. Seven cases were in ketosis or ketoacidosis at the beginning of the treatment with SHI, while only one case (treated by Biostator) had just been found diabetic and was not in ketosis.
The results obtained were as follows:
1) The 4 cases treated by Biostator followed by twice daily injection of a mixture of shortacting and intermediate-acting insulin (split and mix), were maintained in good glycemic control.
2) Treatment of ketosis or ketoacidosis with sufficient insulin was effective for recovering and maintaining the residual B-cell function.
3) In 6 cases, insulin antibodies were not increased but both IgG and IgE showed high values in 2 cases after 12 months of SHI treatment.

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Six diabetic patients established on treatment with s.c. (n=3) or a continuous subcutaneous infusion (n=3) of porcine insulin took part in a trial of the continuous subcutaneous infusion of semisynthetic human insulin. The total daily insulin requirement was the same on porcine insulin (31.8±10.2) and human insulin treatment (30.6±12.8 U/day). One of the 3 patients who had been treated with CSII (porcine) showed a significant decrease in mean fasting plasma glucose level after commencement of CSII (human). The same was true regarding the change in HbA₁. The mean fasting plasma glucose was significantly decreased in 2 out of the 3 diabetics pretreated with s.c. porcine insulin after transfer to CSII (human). It seems likely, however, that the change in manner of insulin injection rather than the human insulin per se accounts for the observed effect. No significant change in insulin antibody titer was observed between before and after the CSII (human) treatment.

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The usefulness of Semi-synthetic Human Actrapid Insulin (SHAI, Novo) in the treatment of CSII was investigated in an insulin-dependent diabetic patient. There was no significant difference in the daily profiles of plasma glucose, serum free insulin and plasma glucagon levels with SHAI and purified Porcine Actrapid Insulin (PAI).
The mean value of HbAI during one year decreased from 8.7±0.7 to 8.2±0.7%(p<0.05) after switching to SHAI. The daily insulin doses and amounts of symptomatic hypoglycemia were almost the same in the studies with SHAI and PAI. No complications such as local skin reactions or lipodystrophy were observed. Patients treated with CSII can thus be transferred from PAI to SHAI without any special precautions.

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To investigate the effects of semisynthetic human insulin in diabetic hyperglycemia, 11 diabetic patients with severe hyperglycemia were treated by the continuous intravenous infusion method using low-dose insulin, and the results were compared with those treated with porcine insulin. The plasma glucose HbA₁, plasma inorganic phosphate (Pi), potassium (K), venous bicarbonate (HCO₃^-) and 2, 3-diphosphoglycerate (2, 3-DPG) were determined in the initial and subsequent course of the treatment.
The 11 patients included 7 with diabetic keto-acidosis (DKA), one with hyperglycemic hyperosmolar nonketotic coma and 3 with nonketotic hyperglycemia without consciousness disturbance. 5 patients administered semisynthetic human actrapid insulin (Novo) were defined as the A-HM group, and the remaining 6 patients administered actrapid or MC actrapid insulin (Novo) as the Porcine group. The results obtained were as follows.
1) Before the treatment, the plasma glucose levels were 566±36 mg/dl (M±SE) in the A-HM group and 563±88 mg/dl in the Porcine group, and decreased rapidly until 3 hours after the onset of treatment.
2) The insulin doses for the first 3 hours were 21±4 u in the A-HM group and 16±4 u inthe Porcine group, and they did not differ significantly.
3) Although the rates of decrease of the plasma glucose level in the initial 3 hours were 86 ±18 mg/dl · hr in the A-HM group and 63±14 mg/dl· hr in the Porcine group, no significant difference was seen in both groups.
4) Pi, K and HbA₁ decreased significantly after the onset of insulin treatment, and the responses of each of the parameters were identical in both insulin groups.
5) In the 7 patients with DKA, the concentrations of HCO₃^- and 2, 3-DPG were low before the treatment, and gradually increased after the treatment in both groups.
Thus, in the treatment of severe hyperglycemic diabetics by the continuous intravenous insulin infusion method using a low dose, the potency of semisynthetic human insulin was indistinguishable form that of porcine insulin in the present clinical study.

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Semisynthetic human insulin (SHI), a human insulin preparation, was given to 7 new diabetic patients for one year, and the changes in insulin antibody were investigated. Two kinds of SHI were used: Actrapid-Human Monocomponent Insulin (A-HM) and Monotard-Human Monocomponent Insulin (M-HM), supplied by Novo Inc. A mixture of A-HM and M-HM or single M-HM was given. Blood insulin antibody as the insulin binding capacity (%) was measured by the polyethleneglycol method. In 3 of the 7 SHI-treated patients, a significant increase in insulin antibody level was observed, indicating the existence of insulin antigenicity even if the insulin amino-acid sequence was identical with that of human insulin.

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Two patients with type II diabetes were newly treated with human insulin (Monotard). Significant amounts of anti-insulin antibodies were produced in these patients at 3 months after starting the therapy. The binding affinities of these antibodies towards human insulin and pork insulin were comparable.
Thus, the anti-insulin antibodies produced by the human insulin did not recognize B-30 at least in these 2 cases.

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We investigated whether or not human insulin behaved differently in receptor binding and anti-insulin antibody binding compared with pork insulin. Human insulin, semisynthetized from pork insulin by an enzymatic method, was used for the study. In the receptor binding, no dfference was demonstrated between human and pork insulin both in rat adipocytes and human erythrocyte receptor assay. In contrast, the affinity of pork insulin for antibody binding was increased in the plasma of 2 out of 5 patients treated with Lente insulin (mixture of beef and pork insulin). Thus, the B-30 amino acid residue may play some role in the antibody binding but not in the receptor binding.

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In order to investigate the effects of semisynthe tized human insulin (HM insulin) on insulin allergy, lipoatrophy and insulin resistance, 29 cases of insulin allergy, lipoatrophy and insulin resistance were collected from 19 medical colleges and hospitals, and the results were analyzed. Insulinspecific IgE and IgG antibodies in the serum were determined at intervals. The results obtained may be summarized as follows.
1) The numbers of cases of insulin allergy, lipoatrophy and insulin resistance were 25, 3 and 1 respectively. Among those with insulin allergy, 17 cases had been treated with porcine MC insulin, 7 with Lente (MC) insulin, and 1 previously with porcine MC insulin.
2) The most frequent symptoms and signs of insulin allergy were pruritus and redness or erythema of the skin (each 58%), followed by local swelling and induration. The skin reaction appeared to be prominent in the bovine insulin-treated group compared to the porcine one. Intradermal injection of bovine insulin caused a somewhat stronger reaction than HM or porcine Actrapid insulin injection.
3) A change to HM insulin in the conventional insulin allergy dissipated or ameliorated the allergic reactions in most of the cases (about 90%), and it was effective in some of the insulin lipoatrophy or the insulin resistance.
4) The level of insulin-specific IgE antibody in the serum of insulin allergy cases decreased over a period of 40 weeks after the use of HM insulin, in spite of no remarkable change in IgG antibody.
5) No particular change of HbAi was found by using HM insulin. The use of HM insulin was thus very effective in most of the insulin allergy caused by conventional insulin treatment. It is also worthy of being tried in cases of insulin lipoatrophy or resistance.

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Intradermal tests of human inslun were under taken in 5 diabetics with skin allergy to animal insulin. The tested human insulin preparations were Actrapid-Human Monocomponent Insulin, Monotard-Human Monocomponent Insulin (Semisynthetic human insulin, Novo) and S 3300 Regular, S 3300 NPH (Biosynthetic human insulin, Lilly).
The skin test results showed a strong and immediate allergic reaction to each human insulin after 30 min, although it did disapper in the following 24 hours. On the other hand, skin tests with physiological saline and M-HM diluting medium showed no allergic reaction in the 5 cases.
The study thus demonstrated the cross-reaction of skin allergy between animal and human insulins.

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We recently encountered 3 allergy cases for monocomponent insulin and investigated the effect of M-HM in them.
Case 1, a 77-year-old woman, was diagnosed as diabetes mellitus in 1977. She was admitted to our hospital because of acute heart failure in September, 1982, and Insulin Novo Lente MC, 16 u (0.4ml), was injected subcutaneously every day. In December, she developed whole skin type and local skin type insulin allergy and so her insulin injections were ceased. On insulin skin tests, Actrapid Bovine and Actrapid Porcine were positive and Actrapid Human was probably positive. As a result, a desensitization program of M-HM was planned and put into practice. No allergy phenomena were observed subsequently, and the patient now has good control of blood glucose by subcutaneous insulin injection of M-HM 32 u (0.8 ml).
Case 2, a 49-year-old woman, whose son had bronchial asthma, was diagnosed as diabetes mellitus in 1967, and subcutaneous insulin injection was practiced then every day for a month. She was admitted to our hospital because of acute urinary tract infection in August, 1982, and Insulin Novo Lente MC, 20u (0.5ml), was injected subcutaneously every day. 3 weeks later, she developed whole skin type and local skin type insulin allergy and so her insulin injections were ceased. On insulin skin tests, Lente MC, Ultralente MC, Actrapid MC, Insulatard, M-HM and Regular Human were strongly positive. As a result, subcutaneous insulin injection of M-HM was abandoned.
Case 3, a 38-year-old woman, who had anamnesis of drug allergy phenomena, was diagnosed as diabetes mellitus in 1976. She was admitted to our hospital because of acute urinary cystic infection in June, 1979, and Insulin Retard Reo, 10 u (0.25 ml), was injected subcutaneously every day. 8 months later, she developed whole skin type and local skin type insulin allergy and so her insulin injections were changed. However, Insulin Novo Semilente MC showed similar allergy phenomena. On insulin skin tests, Lente MC, Ultralente MC, Actrapid MC, Insulatard, M-HM and Regular Human were negative and now, as a result, subcutaneous insulin injection of M-HM is being prepared.

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Local cutaneous hypersensitivity reactions (erythema, induration and pruritis) after injection of Lente insulin in a 43-year-old female were investigated using semisynthetic human insulin (Novo) and its vehicle. Intradermal skin tests for any of the commercially available insulin preparations including human Monotard insulin and its vehicle were positive. The degree of erythema and induration parallelled the zinc contenet of the insulin preparations. The patient's insulin allergy was thus indicated to be caused by the zinc in the insulin preparations. Intradermal skin tests also suggested that her local pruritis was ascribable to phenol and glycerol in the insulin preparations.The erythema and pruritis disappeared following application of ointment containing diphenhydramine and hydrocortisone, and using N.P.H.-insulin whose zinc content is the lowest among intermediate insulin preparations. However, the induration was not ameliorated by these treatments.
The dose of intermediate insulin to normalize the patient's blood glucose (30 units/day) was relatively high compared to usual Japanese noninsulin dependent diabetics, and 16 units day of Lente insulin was sufficient to normalize her blood glucose before a local cutaneous reaction appeared. These findings suggested insulin malabsorption and/or degradation at the injection site. However, measurements of the plasma IRI and glucose after subcutaneous insulin injection with or without aprotinin and intramuscular insulin injection (N.P.H.-insulin, 20 u) did not explain this possibility.

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The patient, a 24-year-old woman, was begun on Actrapid MC insulin and Novo Lente MC insulin therapy 6 months before admission. Four months later, her fasting blood glucose levels were around 300 mg/dl. The dose of insulin was gradually increased had Monotard insulin was substituted for the Novo Lente MC. The patient's diabetes was uncontrolled. One month before admission when Insulatard insulin was substituted for Novo Lente MC, she noticed generalized urticaria. She was admitted to our hospital because of the symptoms and uncontrolled diabetes, even on taking 160 units of Monocomponent insulin daily.
On admission, her height was 159 cm and her weight was 40 kg. She did not show any diabetic complications. Immunoglobulin analysis revealed IgE 2510 IU/ml and IgG 1280 mg/dl. The ¹²⁵I-insulin binding rate, total and free IRI levels were 85%, 43151 μU/ml, and 57.3 μU/ml, respectively. The serum and urinary CPR levels were almost zero. Anti-insulin receptor antibody was negative and other hyperglycemic causes were discounted endocrinologically. Direct intradermal skin tests for insulin, i. e. Novo Lente MC, Actrapid MC, Biosynthetic and Semi-synthetic Human insulin, were positive.
She was treated cautiously with continuous. Semi-synthetic Human insulin infusion, with desensitization of insulin by continuous subcutaneous infusion. Although her insulin allergy could not be eliminated completely, addition of hydrocortisone (5 mg) satisfactorily suppressed the reactions. Her diabetes mellitus was controlled well by the intramuscular injection of both 160 units of Semisynthetic Human insulin and 15 mg hydrocortisone daily. Her serum IgE, total and free IRI levels were 1908 μU/ml, 7535 μU/ml and 23.2 μU/ml, respectively, just before discharge.

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A 21-year-old patient with diabetes mellitus was given bovine NPH insulin or Lente insulin, from the time he suffered diabetic coma in his 12th year. Since hyperglycemia could not be preveted by a large dosage (150 U/day) of Lente insulin, he was given human monotard insulin. A reduction in insulin requirement to 57.3% was found, after the change from Lente insulin to human monotard insulin. Although the binding capacity was low (29.1%), the serum total insulin level was higher than the upper assay limit (320 μU/ml) and its level was reduced to 170 μU/ml. at 2 weeks after changing the insulin preparation. From these results, the insulin resistance in this case is thought to have been due to antibodies against bovine or porcine insulin. The usefulness of human insulin in such cases is suggested.

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One of the side effects encountered in insulin therapy using commercially available preparations other than human insulin, is insulin-resistant diabetes mellitus due to insulin antibody.
We followed the effects of human insulin in the treatment of an insulin-resistant diabetic, and examined the possible changes in binding kinetics of the insulin antibody. The case was a poorly controlled 52-year-old diabetic male of 12 years' duration with diabetic triopathy. His laboratory data on admission showed hyperglycemia, no ketosis, hypoalbuminemia, hyperlipidemia, and renal insufficiency. The patient was treated with multiple injections of regular insulin, and 160 U/day of insulin was required to control the DM. ¹²⁵I-insulin binding to the patient's serum yielded a ratio of as high as 75.9%, The presence of insulin antibody prompted us to switch the insulin from regular type of semisynthetic human insulin (A-HM, Novo). The maximum insulin r.were 120 U/day of A-HM, which was followed by a rapid decrease of insulin to 32 U/day with concomitant deterioration of renal function: the serum creatinine was 2.0 on admission, 4.4 at the start of A-HM, and 5.5 mg/dl at the dose of 32 U/day of human insulin.
Analysis of the binding kinetics of insulin antibody revealed the following:
1) a relative binding affinity of 2: 1: 1: 0.13 to beef, pork, human, and desoctapeptide insulin, respectively, and
2) no decrease in inding capacity and affinity on the basis of the insulin concentration for half-maximum binding, and Scatchard analysis after the treatment with A-HM.
The kidney plays an important role in the regulation of circulating insulin in vivo. The remarkable decrease of insulin requirement in our case was accounted for by both the deterioration of renal function and decreased food intake in a poor general condition, rather than the beneficial effects of human insulin.

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Marked lipoa trophy (LA) occurred in the low abdominal quadrant and thigh bilaterally in a57-year-old woman after subcutaneous injection of Lente insulin (beef and pork, Novo Lente Insulin®) for 4 months. Subsequent injection of Monotard monocomponent (MC) insulin (pork) into thedpressed areas resulted in an impressive, but not complete, return of the subcutaneous tissue in thehypogastric region and in a very slight improvement of LA in the thigh after3to4months ofthe pork insulin therapy. This partially improved LA remained at the same degree even after 17months of pork insulin treatment. Thereafter, injection of semi-synthetized human MC insulin (Monotari) into the LA lesions was initiated. All the LA areas disappeared after 5 months of thehuman insulin therapy. The titer of insulin-binding antibody (polyethylene glycol method) didnot change before and during the human MC insulin treatment.
It is suggested that semi-synthetized human MC insulin can exert a beneficial effect on insulin LA.

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A 55-year-old female developed diabetes mellitus with ketosis and was stabilized on a CSIIregimen, using Actrapid MC insulin. This was the first time that the patient had received insulin.Her diabetic control was satisfactory and one month later she was changed to Lente MC insulinat 20 units once daily. Two months later, she experienced pruritic red spots and hives at injectionsites on the arm and thigh, which disappeared spontaneously within a further 3 months. After 5 monthsof insulin treatment, she was found to have moderately severe lipoatrophy over the bilateralabdominal wall in the areas where the CSII had been placed. At that time, the patient's serumshowed a specific binding of ¹²⁵I-porcine insulin (B/T) of 85%, Ig E was slightly increased, whilecomplements and immune complex were within the normal ranges. About 10 months later, semisynthetichuman insulin (Monotard, Novo) was initiated for the lipoatrophy, with application only onthe right side. The lipoatrophy on the treated side became apparently filled after one month andhad almost completely recovered within 4 months. However, the lesions on the opposite side remainedunchanged. The skin allergy and high titer of serum insulin antibody in association with lipoatrophyobserved in this patient suggest that an immune process is implicated in the pathogenesis of lipoatrophy.

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The patient was a 16-year-old high school girl. In October 1981, she noticed thirst, polydipsia, polyuria and easy fatigability, and had lost 8 kg body weight within one month. She was diagnosedassuffering from diabetic ketoacidosis, and regular insulin therapy was commenced immediately. Onemonth later, she discharged from hospital on a 15 U daily injection of Lente insulin U-40. However, her blood glucose was poorly controlled thereafter and the dose of insulin was rapidly increased.Since March, 1982. Lente insulin U-100 was employed because of her increasing requirementof insulin and was injected at more or less 100 U daily with a maximum of 130 U for about ayear. In March, 1983. when she was admitted to our hospital, the patient had a high titer ofanti-insulin antibody, and had developed lipoatrophy in her upper and lower extremities, andabdomen at the site of injection. Semisynthetic human insulin (M-HM U-100) was administered at70 U daily in place of Lente insulin (95 U) under the same dietary conditions. After about onemonth's admission, she was followed up every 2 weeks as an outpatient. The daily profile of bloodsugar examined in August was markedly improved. The titer of insulin binding capacity was alsodecreased from 61.0% in March to 42.2%. with a marked decreased in the total amount of insulinin the serum from 9, 600 to 979 μU/ml. The anti-insulin antibody ih the serum revealed nospecies specificity and bound equally to human, porcine and beef insulin.
The lipoatrophy is gradually improving, and observations are in progress as to whether the doseof SHI should be reduced further. Complete recovery from the lipoatrophy is expected.

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