The effects of IV-1-arginine infusion on plasma levels of glucose, CPR, IRG, HGH and IRI were studied in 11 insulin-dependent stable and 11 unstable diabetics, 10 untreated diabetics and 10 normal subjects. The highest IRG response was observed in the untreated diabetic group, followed by the unstable diabetics. On the other hand, the HGH response was highest in the normal subjects, followed by the stable diabetics, unstable diabetics, and untreated diabetics in that order. The plasma CPR was very low in the unstable diabetics throughout the examination, but a slightly higher level was observed in the stable diabetics. The highest CPR value together with that of IRI was found in normal subjects.
These findings suggest that the abnormal responses of IRG and HGH in diabetics may be caused by deranged metabolism due to absolute or relative insulin deficiency, and one of the characteristic findings of unstable diabetes would be a decreased capacity for insulin secretion.

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Large numbers of deliveries to diabetic pregnants have not so far been described in Japan. During a 13 yr period from Feb. 1964 to Feb. 1977, 42 diabetics other than chemical diabetics had 50 deliveries, and 51 newborns were kept in our care at the Tokyo Women's Medical College Hospital. Their clinical features are analyzed here.
The non-diabetic pregnant deliveries during the same 13 yr period numbered 6, 506 cases. The incidence of diabetic delivery was thus 0.76%. The age of onset of diabetes in the pregnant women ranged from 12 to 38 yr (average, 24.4 yr). The average duration of diabetes was 5.1 yr.
Five pregnants (10%) had or had been found to have diabetes during pregnancy, with the duration of diabetes in four being over 10 yr, among the 50 cases of delivery.
At this time, there is no obvious tendency towards increasing diabetic pregnants who have long-term diabetes.
Treatment of diabetes during pregnancy in 34 cases (68%) was performed with insulin, and in four cases (8%) with diet. Ten cases changed to diet or insulin from treatment with an oral hypoglycemic agent.
Eighteen cases (52.9%) showed an increased insulin requirement during pregnancy, 11 (32.3 %) had a decreased insulin requirement, and 2 (5.8%) were unchanged or “others”.
Among the diabetic complications encountered during pregnancy, aggravation of retinopathy from Scott 11 to Scott II was observed in four cases (8 %), while 45 cases (90%) showed no or unchanged Scott I a retinopathy. Only one case, which had Scott I b retinopathy, received photocoagulation and did not worsen further.
Three cases showed deterioration of renal function after delivery.
Concerning complications of pregnancy, the commonest (five cases, 10%), was asymptomatic bacteriuria.
Toxicosis was observed in 3 cases (6%).
Perinatal mortality was 8.2%, or four cases out of 49 cases of delivery, excluding one case of early delivery at 25 weeks. The average term at delivery was 38.2 weeks. Caesarean sections were performed in 27 cases (54%). Births were conducted as vaginal deliveries in 15 cases (30 %), and as spontaneous deliveries in 8 cases (16%).
The mean weight at birth of neonates born after 37 weeks of gestation was 3, 549g. The ccmmonest complication among the newborns was hypoglycemia, followed by respiratory distress syndrome.

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The effects of a high carbohydrate low fat diet (HCHO) and low carbohydrate high fat diet (HF) on serum lipids, insulin and glucagon levels were examined in 5 non-obese controls and 8 obese subjects. After a 2400 Cal isocaloric HCHO diet (carbohydrate 85%, fat 2%, protein 13%) and HF diet (carbohydrate 27%, fat 60%, protein 13%) lasting two successive 4-day periods, the serum triglyceride, immunoreactive insulin (IRI) and pancreatic immunoreactive glucagon (IRG) levels were measured. In the 4 controls and 5 obese subjects, the IRI and IRG responses to intravenous infusion of 30g L-arginine for 30 min were also studies.
The serum triglyceride, basal IRI, basal IRG and basal insulin: glucagon molar ratio were significantly higher in the obese subjects than in the controls (triglyceride, p<0.001; IRI, p<0.05; IRG, n. s.; IRI/IRG, p<0.05). When the HCHO diet was replaced by the HF diet, the serum triglyceride decreased from 77±10 (mean±SEM) to 40±2 mg/dl in the controls (p<0.01), and from 198±17 to 100±10 mg/dl in the obese subjects (p<0.001). The basal IRI changed from 2.4±0.6 to 2.8±0.8μU/ml in the controls (n. s.), and from 11.9±2.8 to 9.3±2.1μU/ml in the obese subjects (n. s.). The basal IRG increased (n.s.) and the basal insulin: glucagon molar ratio decreased (n. s.).
The insulin response to intravenous arginine infusion was significantly higher in the obese subjects than in the controls (p<0.05). The glucagon response was also higher in the obese subjects (n. s.).
Significant correlations existed between serum triglyceride and relative body weight (HCHO diet, r=0.795 p<0.01; HF diet, r=0.812 p<0.01), between basal IRI and relative body weight, (HCHO diet, r=0.683 p<0.05; HF diet, r=0.588 p<0.05) and between basal IRI and serum triglyceride (HCHO diet, r=0.798 p<0.01; HF diet, r=0.887 p<0.01). Serum triglyceride was significantly correlated with the basal insulin: glucagon molar ratio (HCHO diet, r=0.640 p<0.05; HF diet, r=0.674 p<0.05). The above results indicate that triglyceride metabolism is highly dependent on plasma insulin rather than on plasma glucagon.
The decrement in serum triglyceride when the HCHO diet was replaced by the HF diet, was significantly correlated with the basal IRI decrement (r=0.654 p<0.05). When the carbohydrate intake was reduced, the basal IRI and triglyceride levels fell. These observations indicate the importance of carbohydrate intake in determining triglyceride levels.

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Quantitative methods based on mass fragmentography are described for the simultaneous measurement of tolbutamide and its metabolites, 1-p-hydroxymethylbenzensulfonyl-3-butylurea (OHT) and 1-p-carboxyphenylsulfonyl-3-butylurea (COOHT), from human plasma. All three compounds are extracted from acidified plasma into ether and are converted to the corresponding N-1 methyl derivatives by reaction with diazomethane. From the mass spectra it is deduced that methylation of the sulfonamide nitrogen atom has occurred. During the loss of the SO₂ from the molecular ion, aryl rearrangement to both oxygen and nitrogen occurs in the ratio of 1: 2. The peaks at m/e 185 (T), 172 (OHT) and 200 (COOHT) were applied to simultaneous multiple-ion analyses by mass fragmentography. As little as 50 pg of the compounds injected into the column could be measured with good resproducibility, and linearity of response was maintained up to 500 ng. The procedures were simpler and less time-consuming than previously reported methods. The recovery rates of T, OHT and COOHT from plasma were 57.1%, 83.0% and 79.3%, respectively. The specificity of this method surpasses and cannot be compared to any other existing quantitative methods. The plasma level profile of tolbutamide and its metabolites in a diabetic patient following intravenous administration of 1.0 g tolbutamide is presented. Further studies of the mode of action of the sulfonylureas in groups of stable and unstable diabetics are currently in progress in our laboratory.

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The possible role of abnormal platelet function in influencing the appearance and development of microangiopathy in patients with diabetes mellitus has been noted recently. In relation to this phenomenon, we have developed a new method for measuring platelet function and have tried to evaluate the platelet function of patients with diabetes mellitus.
This method is called “Platelet Aldolase Release Rate” and is a method for measuring the rate of release of aldolase from platelets into a low osmotic pressure, artificial medium, as well as into platelet-rich plasma (PRP). It consists of preparing PRP from collected blood and dividing it into three aliquots.
Sample 1 was centrifuged at 600 x G, and the supernatant was incubated at 37°C for2 hours. The aldolase activity of this specimen was called “aldolase activity A”. Next, 1/15 M of phosphate buffer (150 mOsm/kg), the same amount as the removed supernatant, was added to the precipitation to make platelets in an artificial floating medium. This artificial medium was incubated at 37°C for 2 hours and then centrifuged at 600×G. The aldolase activity of this supernatant was called “aldolase activity C'”. Sample 2 was first incubated at 37°C for 2 hours and then centrifuged at 600×G. The aldolase activity of this supernatant was called “aldolase activity C”.
The platelets of Sample 3 were destroyed by freezing at -20°C for 2 hours and then thawing. The aldolase activity of this supernatant was called “aldolase activity B”. By this method, the aldolase release rate was C-A/B-A×100in PRP and C'/B-A ×100 (%) in a low osmotic pressuremedium.
The aldolase release rate in patients with diabetes mellitus was 26.19±12.75%(M±SD) in PRP and 55.94±20.04% in the artificial medium. These values were significantly higher than normal values (9.27±5.93% in PRP and 31.98±7.96% in the artificial medium).
In normal subjects, positive correlation was found between the aldolase release rate and platelet aggregation and between the aldolase release rate and platelet adhesiveness.As these correlations were also found in patients with diabetes mellitus, the aldolase release rate seems to be closely connected with platelet function tests. The relationship between platelet function, including the aldolase release rate, and diabetic complication and control was examined.
In patients with diabetes mellitus, platelet aggregation and platelet adhesiveness were higher than normal values, as seen in the aldolase release rate. But, even in patients without chronic diabetic complications whose degree of control was good or fair, some patients showed higher levels of platelet aggregation, platelet adhesiveness, and aldolase release rate.
From this data, it was concluded that the aldolase release rate expresses a certain side of platelet function in patients with diabetes mellitus. However, in relation to the degree of diabetic control and the presence or severity of complications, further investigation seems to be necessary.

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A case of hyperosmolar, non-ketotic, diabetic coma, complicated by metabolic acidosis, is reported.
The patient was a 62-year-old man, who had been diabetic for 28 years and recently had been treated with 20 units of insulin per day. Last year he was diagnosed as having dementia presenilis in addition to diabetic triopathy. Urinary tract infection and withdrawal of insulin, during hospitalization for psychiatric treatment were considered to be the factors causing the hyperosmolar, non-ketotic, diabetic coma. Physical examination on admission revealed a semicoma. Blood pressure was 68/40 mmHg, and respirations were 32 per minute. Kussmaul's respiration and acetone odor were absent. There was generalized areflexia. No pathological reflexes could be elicited. Laboratory studies revealed the following values; blood glucose, 3, 685 mg/dl; plasma osmolality, 466 mOsm/L; serum sodium, 131 mEq/L; serum potassium, 4.7 mEq/L; serum chloride, 92mEq/L; blood urea nitrogen, 130mg/dl; serum creatinine, 8.2 mg/dl; arterial blood, pH 7.12; bicarbonate, 9.6 mEq/L; blood lactate, 4.9 mEq/L; anion gap, 34.1 mEq/L. Results of urinalysis showed 1+proteinuria and 3+glycosuria, without acetonuria. In spite of treatment with 1, 124 units of insulin and 14, 500 ml of intravenous fluids, shock and anuria persisted, and generalized edema appeared on the second day of hospitalization. Hemodialysis for renal failure was performed in vain, and the patient's general physical state showed no changes. On the morning of the third day of hospitalization, he died of circulatory failure. Autopsy revealed diabetic glomerulosclerosis, mild fibrosis of pancreatic islets, and generalized arteriosclerosis.
In reviewing 204 cases of hyperosmolar, non-ketotic, diabetic coma reported in Japan, there were 29 cases complicated by metabolic acidosis (pH below 7.35). Mortality in the complicated cases was 46.6% in contrast to 40.6% in the other cases (P<0.05). Many cases were accompanied by various renal complications, and a few cases were considered to be of a type between diabetic ketoacidosis and hyperosmolar, non-ketotic, diabetic coma. However, no apparent cause of metabolic acidosis was revealed in the majority of the cases. In the present case, metabolic acidosis was suspected to be caused by uremia and lactic acidosis.

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A 49-yr-old housewife was admitted to hospital due to loss of consciousness. Since 1962 (50 yr of age) she had complained of increased appetite, thirst and loss of body weight. In 1963 she was diagnosed as a diabetic. At first, diet therapy was initiated but later glibenclamide (5-10 mg, daily) and phenformin (100 mg, daily) were administered. No liver damage orrenal damage was observed. The degree of diabetic retinopathy was Scott I. At the end of July 1976, diarrhea appeared. The patient complained of miction pain on August 7 and was administered antibiotics due to urocystitis. Next afternoon, abdominal pain and nausea appeared. She stopped taking the antibiotics, but still continued to have hypoglycemic agents of the same dose irrespective of any nausea and vomitting. On August 10 she was unable to have meal. In the afternoon, impairment of consciousness appeared and she fell into a coma. On admission, the patient was in a state of shock. Her body temperature was 35.7°C and her pulse weak. Her systolic blood pressure was 56 mmHg. Respiration rate was 30/min. All the deep tendon reflexes were absent. The chief laboratory findings were as follows. Blood sugar was 200μg/dl without ketonuria, the arterial pH was 6. 95, and the base excess was-31 mEq/L. The blood level of lactic acid was 27.8 mM and the anion gap was 41 mEq/L. Plasma amino acid analysis revealed hyperalaninemia and the plasma glucagon immunoreactivity was 1, 021 pg/ml. Infusion of sodium bicarbonate, glucose and a small dose insulin was begun and 4 mg prednisolone was injected intravenoushy. Next morning the blood pressure had returned to a normal level. After if: months, the patient left the hospital with impaired intelligence.

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