A new preparation of lente insulin (Lilly Co.) containing less zinc than the 0.2-0.3 mg zinc per 100 units of insulin present in conventional lente, has recently become available for clinical use.
It has been considered that the amount of zinc in conventional preparations of lente is one of the important factors for the maintenance of insulin action over an expected period.
The new lente preparation (B) from Lilly Co. containing 0.14 mg of zinc per 100 units of insulin was compared with a conventional preparation (A) of lente purchased from the same Company which contained a normal amount of zinc, 0.21 mg per 100 units of insulin. In the procedure for comparison, a cross-over method was used on 6 patients with diabetes admitted to our hospital.
The results obtained were as follows:
1) No significant diurnal differences in blood glucose level were observed between preparation A and preparation B in the 6 diabetics. However, blood glucose levels in the case of preparation B were generally at lower levels in the afternoon compared to those with preparation A.
2) The diurnal fluctuation of serum IRI in the case of preparation B was almost the same as that with preparation A.

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Intravenous insulin tolerance tests (ITT) were performed on 16 normal and 35 diabetic subjects. The purpose of the study was to test the plasma IRG response to insulin-induced hypoglycemia in diabetics, and to determine whether any relationship exists between the IRG responses on ITT and IRI responses on O-GTT in diabetics. In normal subjects, the blood sugar level declined from a basal level of 86±3 (mean±SEM) mg/dl to a minimum of 33±2 mg/dl at 20 min after the injection of MC-Actrapid insulin (0.1 unit/kg body weight). In diabetics, it declined from a basal level of 142±10 mg/dl to a minimum of 42±5 mg/dl at 45 min. after the insulin injection (0.2-0.3 unit/kg body weight). Hypoglycemic symptoms were recognized in all subjects, including normals and diabetics. The plasma IRG level of normals rose from a base-line value of 64±11pg/ml to a peak of 262±45 pg/ml at 30 min. after stimulation, whereas that in diabetics rose from 43±4 pg/ml to 137±21 pg/ml. The IRG responses in diabetics were thus significantly reduced (p<0.01) compared to those in normals. There was a significant negative correlation between fasting blood sugar level and IRG response to ITT in diabetic subjects (p<0.025). In 24 diabetics, a significant positive correlation was found between the IRI response in O-GTT and the IRG response in ITT (p<0.05). This suggests a parallelism in the degree of impairment of both pancreatic A and B cells in diabetics. In arginine tolerance tests (ATT), the plasma IRG response in diabetics was more marked than that in normals. Thus, in diabetics, both an IRG hyporesponse to ITT and a hyperresponse to ATT coexist. This discrepancy may be best explained by assuming some involvement of extrapancreatic IRG in ATT. On the other hand, only pancreatic glucagon responds to ITT. The IRG response to ITT may thus be considered as more specific for pancreatic A cell function than the IRG response to ATT.

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Recent studies have demonstrated that diabetes mellitus is a bihormonal disorder characterized by excessive glucagon and diminished insulin secretion. In a previous study, we reported that excessive glucagon response to arginine in diabetic patients was normalized in those successfully treated with sulfonylurea or insulin. However, the plasma glucagon response to oral glucose loading in diabetic patients who undergo successful treatment remains to be studied, although abnormal glucagon responses to oral glucose loading have been extensively reported. Since it is important to elucidate the precise significance of alpha cell hyperfunction in the pathogenesis of diabetes mellitus, we studied the changes in plasma glucagon response to glucose in diabetic patients before and after treatment.
In normal subjects, the plasma glucagon levels decreased substantially following oral glucose loading, reaching a minimum of 60-6pg/ml at 120 min, which was significantly lower than the basal level. In all diabetic patients before treatment with either insulin or sulfonylurea, the plasma glucagon level was not suppressed but tended rather to rise in spite of pronounced hyperglycemia. In diabetic patients treated with insulin and sulfonylurea, the basalplaswa glucagon levels were significantly lower than those in the patients without treatment. However, the plasma glucagon levels in both cases did not decrease following oral glucose loading.
Abnormal glucagon response to oral glucose loading was thus not improved by successful treatment with either sulfonylurea or insulin. The results suggest the existence of alpha cell insensitivity to hyperglycemia after treatment, although the reason for such a phenomenon remains unclear at present. Impaired plasma glucagon response to glucose in diabetics may be caused either by insulin deficiency, which is not necessarily improved on treatment, or by an intrinsic defect of the pancreatic alpha cells. Careful studies on the relationships between insulin and glucagon releas in diabetic conditions should contribute to a solution of this problem.

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The present study was designed to provide a means of diagnosis of insulin allergy by the radioallergosorbent test (RAST), an in vitro method for the detection in serum of reaginic (IgE) antibodies against specific antigens. A positive RAST reaction was defined in the study as being more than twice the mean percent bound radioactivity obtained with 10 control sera. (% bound radioactivity: 4.5±0.3%).
With sera from 18 non-allergic diabetics treated with insulin, negative results were obtained (% bound radioactivity: 5.4±0.3%). With sera from 2 diabetics with insulin allergy, positive results were obtained (% bound radioactivity: 16.6%, 13.0%). Plots of the percent bound radioactivity against the logarithm of allergen concentration indicated that the response to increasing allergen concentration was almost linear.
In the 50% RAST inhibition measures, the percentage of bound radioactivity decreased, after preincubation of the sera with cold allergens. These results suggest that the RAST reaction may be almost allergen specific.
We attempted to eliminate the allergenic potency of insulin components by 50% RAST inhibition measures.
The following results were obtained.
1) Using paper discs coupling crude insulin, the amounts of a- and b-components (inhibitors) required to give 50% inhibition in the RAST were about 2 mg.
2) Using paper discs coupling crude insulin, the amount of purified insulin (inhibitor) required to give 50% inhibition in the RAST was more than 50 mg.
These results support the possibility that purified insulin is less allergenic than the a- and b-components.

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It has been suggested that insulin may play an important role in the pathogenesis of atherosclerosis. Since the discovery of insulin in 1921, cardiovascular death in diabetic patients has increased and it is important to investigate the effect of insulin on the arterial wall. Eighty male Wistar rats, weighing 200 g, were divided into four groups-N group: control, A group: alloxanized-diabetic, Al group: alloxanized-diabetic treated with insulin, and I group: insulin treated. After 3 months, the rat aortae were removed and subjected to analysis for procoagulant activity, histological changes and lipid content. Procoagulant activities were determined by the method of recalcification time and the prothrombin two stage method. Total lipids were isolated and purified by a modification of the method of Folch and separated into esterified cholesterol (CE), free fatty acid (FFA), triglyceride (TG), free cholesterol (CH) and phospholipid (PL) fractions by thin layer chromatography.
The procoagulant activity of aortic extracts from the I group was markedly increased when compared to that in the other groups.
Lipid analysis of the aortic extracts revealed an increase in CE and decrease in FFA and PL in the I and Al groups.
Histological examinations revealed intimal and medial proliferation and most striking lipid droplets in the intimal and medial regions in the I group. The AI and A groups showed medial degeneration and slight lipid deposition in the same region as the I group.
These facts appear to suggest a role for excessive insulin in atherogenesis.

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A 34-year-old male was admitted to the emergency room due to hematemesis and anuria. No history of diabetes mellitus was indicated. Two days prior to admission he had complained of thirst and polyuria after playing golf, followed by oliguria and vomiting of a coffee-like fluid. Suspecting the presence of a peptic ulcer, immediate parenteral fluid therapy was begun, but drowsiness ensued. Twenty-four hours after admission, the patient was transferred to our Diabetes Center due to ketonuria and glucosuria. Intravenous and subcutaneous insulin therapy was initiated. About 13 hr later, despite an improvement of ketoacidosis, the patient remained drowsy. He then suddenly complained of severe abdominal and back pain, associated with hematemesis and melena; the abdominal wall was spastic, suggesting perforation of a peptic ulcer. However, following subcutaneous injection of an analgesic (scopolamine butylbromide, 20 mg), the acute abdominal symptoms disappeared and the patient's consciousness gradually became clear. Gastroscopic examination revealed multiple erosion and reddening of the antral mucosa. The mechanism of gastrointestinal hemorrhage accompanying diabetic ketoacidosis is discussed.

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In a 49-year-old diabetic man who developed right parasagittal meningioma during chlorpropamide plus buformin therapy, transient mild hyponatremia was found in the pre-operationperiod. Persistent profound hyponatremia, which was corrected by replacing the chlorpropamide with acetohexamide, was found one year after subtotal removal of the tumor.
A clinical study was undertaken to determine the patient's response to chlorpropamide. Acetohexamide was replaced by chlorpropamide for a week and all other medications apart from diphenylhydantoin, a prophylactic measure against convulsions, were withdrawn.
A definite fall in serum sodium was detected 3 days after initiating chlorpropamide therapy, followed by a further decrease to 114 mEq/L on the 7th day. Serum chloride also fell together with the sodium, but the level of potassium remained virtually unchanged. The patient was asymptomatic. Compared with the control period, there was an immediate increase in urinary sodium excretion lasting 5 days, which resulted in a negative sodium balance of 203 mEq. Serum osmolality had decreased from 292 to 246 mOsm/L in a similar fashion to the change in serum sodium, while the osmolality of the urine had rapidly increased to 512 mOsm/L on the first day, followed by a gradual return to control levels within the next 5 days. A water balance study revealed the development of a positive water balance which was slightly greater than the control values in only first 2 days, and neither increase in body weight nor decrease in hematocrit was observed. The antidiuretic hormone level in the blood measured by radioimmunoassay was 4.3 μU/ml before commencing chlorpropamide administration and 3.6μU/ml after 6 days of drug administration. When acetohexamide therapy was resumed, metabolic abnomalities such as hyponatremia and serum hypo-osmolality were normalized within 10 days. Fasting blood sugar ranged from 88 to 122 mg/dl and the amount of daily urine sugar excretion was less than 4.0g during the observation period. The results of the present study suggest the occurence of a chlorpropamide-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in the present patient.

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It is well known that diabetes mellitus affects the sexual cycle and pregnancy, although the underlying mechanisms are not clearly understood. We examined two cases with diabetic ketoacidosis who experienced spontaneous abortion.
Case 1 was a 23-yr-old woman with no previous history of diabetes. However, in the 25th week of pregnancy, she fell into a diabetic coma and spontaneous abortion ensued. Her anovulatory cycle extended until 305 days after the abortion, when her diabetes had been successfully controlled. She became pregnant 4 months thereafter.
Case 2 was a 29-yr-old housewife, who had experienced two episodes of spontaneous abortion in the past, but had never been noticed to suffer from diabetes. In the 33rd week of her third pregnancy, she fell into a diabetic coma and had a stillbirth. About one year after the episode, when her ovulation function was studied, she still had second degree amenorrhes, despite the fact that her blood sugar was well-controlled.
In both patients, it was thought that the onset of diabetes or stress induced by diabetic coma acted as a trigger for ovulative failure. The luteinizing hormone-releasing hormone (LH-RH) test revealed an intermediary (low-good) type in both cases, suggesting that the site of ovulation disturbance was located at the level of the hypothalamus and cranial center. In case 2, the premarin test, the serum LH response to premarin injection (20 mg iv), was normal and suggested the maintenance of a positive feedback mechanism for estrogen against the release of LH.

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There is increasing evidence to suggest that insulin-dependent diabetes mellitus is connected with autoimmunity. Antibodies to pancreatic islet cells were detected by indirect immunofluorescence in highest prevalence in insulin-dependent diabetics. That this antibody was complement fixing and of the IgG class has been reported by Bottazzo and Lendrum. The ¹²⁵I-C_1q binding test for detecting soluble immune complexes in native unheated human serum has been modified by Zubler. This radiolabeled C_1q binding test has high sensitivity and reproducibility among the various methods proposed for detecting immune complexes.
The method was applied to the study of sera from 52 child patients (3-15 yr old) with insulin-dependent diabetes mellitus.
The ¹²⁵I-C_1q binding activity (C_1q BA) for the 52 sera, 9.47±2.58%, was significantly higher than the value of 6.94±2.57% for normal controls (p<0.005). Slightly higher values were seen in 3 patients with positive anti-DNA-antibodies.
¹²⁵I-C_1q binding was not significantly increased in patients with positive antithyroid antibodies and insulin antibodies.

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For the purpose of administrating insulin rectally, an insulin suppository was prepared by pestling porcine crystalline insulin with corn oil and surfactant (polyoxyethylene-9-laurylether). The final concentrations of insulin and surfactant were set at 10-50 U/kg and 2-4 w/w%, respectively.
In normal dogs, a significant increase in mean plasma immunoreactive insulin concentration (IRI) (64, 88, 115μU/ml) was observed at 15 min after administration of the insulin suppository (2, 3 and 5 U/kg body weight, respectively), followed by a significant decrease in plasma glucose level (36, 38, 56%, respectively).
Following suppository administration to depancreatized dogs at a dose of 5 U/kg, the mean peak IRI was 167μU/ml at 30 min, which was significantly higher than that in normal dogs (p<0.05, n=5).
The main features of the insulin suppository so prepared were: 1) even at a dose of 2 U/kg by rectal administration, a marked increase in IRI was observed, and 2) insulin was absorbed more rapidly from the rectum than when injected intramuscularly.
It was also shown that insulin is absorbed from the rectum to a greater extent in severe diabetic dogs than in normal dogs.

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