It is of high interest to know whether the biological activity of purified porcine proinsulin (Eli Lilly Co.) is due to the effect of proinsulin itself or to the effect of insulin produced from proinsulin, both in vitro and in vivo. From this point of view, the influence of a broad spectrum proteolytic trypsin inhibitor, Kunitz pancreatic trypsin inhibitor (KPTI), on the biological activity of proinsulin was investigated in the normal rat. The results obtained were as follows.
1. The degree of hypoglycemia induced by the combined administration of proinsulin and KPTI was significantly lower than that of proinsulin in single intraperitoneal injection. These results suggest indirectly that it is possible that proinsulin is converted to insulin in vivo.
2. KPTI added in the incubation medium with proinsulin did not show any influence on the glucose uptake by proinsulin itself in the hemidiaphragm and epididymal adipose tissues excised from rats. These results indicate that there is extremely little possibility of conversion from proinsulin to insulin in the in vitro system.

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For the purpose of investigating the relationship between oxyhyperglycemia and diabetes mellitus. 95 cases were studied. Of these cases, 70 cases had undergone no gastrectomy in the past, while 25 cases had had a previous history of gastrectomy. The follow-up study was carried out for 3 to 9 years, observing blood glucose, serum IRI and serum NEFA during a 50g glucose tolerance test.
1) Obsrvations in cases without gastrectomy
During the observation period, the number of cases without gastrectomy which developed into diabetic type cases from oxyhyperglycemia had increased. Especially in obese subjects, 10 out of 22 cases (45.5%) of oxyhyperglycemia developed into diabetic type cases. In these cases serum NEFA levels were lowest after 2 or 3 hours during the 50g glucose tolerance test, and the mean value of serum IRI at 30 minutes was 22.6±4.7μ/ml, which was lower than the normal value. In cases which showed oxyhyperglycemia, the mean value of serum IRI was 41.5±3.9μU/m/and ΔIRI/ΔBS was 0.28±0.03 at 30 minutes, which were lower than the normal value.
2) Observations in cases with gastrectomy
None of the cases with a past history of gastrectomy developed into diabetic type cases during 1 to 8 years of observation. The mean value of serum IRI at 30 minutes was 86.8±15.4μU/ml, which was greater than the normal, and ΔIRI/ΔBS at 30 minutes was 0.62±0.11, which remained within the normal range.
3) Conclusion
The above observation indicates that oxyhyperglycemia in cases with gastrectomy is clearly different from oxyhyperglycemia in cases without gastrectomy. The former group has no relation to early diabetes mellitus while in the latter group there appears to be a high number of cases with early diabetes mellitus.

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The globulin fraction was extracted from anti-glucagon serum developed in a rabbit against bovineporcine pancreatic glucagon. The globulin fraction obtained was coupled to Sepharose 4B. The resultant complex (AGS-Sepharose) bound pancreatic glucagon to gut glucagon at pH 8.6 by a specific antigen-antibody reaction.
Affinity chromatography has been applied to isolation of gut glucagon from a crude extract of porcine intestine. Gut glucagon bound specifically to a column of AGS-Sepharose was dissociated by 0.01 M HC1. After washing the column with Tris-HCl buffer, it could be used repeatedly for affinity chromatography.
Affinity chromatography on AGS-Sepharose appears to be an efficient method for the purification of gut glucagon.

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The average daily amount of food and alcoholic beverage consumed prior to admission was estimated by a dietician for 93 subjects with mild diabetes. Calories and grams of protein, fat, carbohydrate and alcohol consumption for each person were calculated and the relationship between calories and body weight was investigated.
The following results were obtained;
1) Average daily alcohol calories consumed were as follows:
Twenty nine of 93 subjects drank beverages with less than 199 Calories (average 89Cal.); 28 subjects, 200-399 Calories (average 279 Cal.); 21 subjects, 400-599 Calories (average 475 Cal.); and 4 subjects, 600-799 Calories (average 686 Cal.). Eleven subjects drank beverages containing 800 or more calories (average 1141 Cal.).
2) Based on the number of calories in the alcoholic beverages consumed, the cases were divided into three groups. Calories from alcohol, food and percent of the standard body weight for these groups are shown in the following table (1). The results show that alcohol calories do not result in any change in body weight.

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Plasma immunoreactive insulin levels following the intravenous injection of glucose (IVGTT) were determined in 38 individuals classified as 10 normal subjects, 19 patients with mild glucose intolerance, 12 moderate diabetics, and 4 severe diabetics.
All the subjects were previously divided into one of the four groups by a 50g oral glucose tolerance test.
The plasma insulin response to IVGTT was lowered in all diabetic groups. In patients with glucose intolerance, plasma insulin levels in the early phase of IVGTT were significantly lowered in comparison with normal subjects (p<0.01).
In order to investigate the effects of drugs on the low plasma insulin response to IVGTT in patients with mild glucose intolerance, or moderate diabetes plasma insulin levels following IVGTT were determined during the intravenous infusion of such as aminophylline, tolbutamide, isoproterenol, phentolamine, glucagon and arginine.
In these experiments, the test substances were infused for 60 minutes, and 25g of glucose was injected 50 minutes after the start of the infusion of drugs.
Results are summarized as follows.
1. The plasma insulin concentration did not increase during the intravenous infusion of aminophylline (500mg), but plasma insulin response to IVGTT was slightly improved by aminophylline (p<0.05).
2. During the intravenous infusion of tolbutamide (0.1g), isoproterenol (0.2mg), and phentolamine (30mg), plasma insulin concentration was found to be increased, and, furthermore, the plasma insulin response to IVGTT was significantly improved (p<0.05).
3. Following the intravenous infusion of glucagon (0.5 mg), significantly increased plasma insulin levels and improved plasma insulin response to IVGTT were observed (p<0.05). However, blood glucose levels markedly increased in this experiment.
4. The intravenous infusion of arginine (30g) not only markedly increased the plasma insulin concentration, but it also improved the plasma insulin response to glucose significantly (p<0.01).
These results suggest that such drugs as tolbutamide, aminophylline, isoproterenol, phentolamine, and glucagon, which increase intracellular cyclic AMP levels, and amino acids, improved early insulin response to intravenous glucose load in low insulin responders.

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In 1, 843 diabetic patients who died between 1968 and 1970 in Japan, the causes of death were studied regarding their relationship to certain conditions of the diabetic patients, severity of the diabetes, its duration and methods of treatment. In the mild diabetes group, the main causes of death were cerebrovascular disease (CD), malignant neoplasms (MN), diabetic nephropathy (DN) and ischemic heart disease (IHD), in decreasing frequency. On the other hand, in the severe diabetes group DN, CD, MN and diabetic coma (DC) were the first to fourth most frequent causes of death, respectively. In each group, frequency rates of DN and IHD as death causes showed a tendency to increase with the duration of the diabetes.
Particularly in the severe diabetes group, DC, DN, IHD and liver cirrhosis caused more mortalities than among the general population of Japan. The incidence of IHD causing death was higher in the tablet-treated group than in the insulin-treated group. However, the incidence of DN causing death was much higher in the latter than in the former group.

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A clinical study was done in a patient with malignant islet cell tumor treated by streptozotoci
A 54-year-old man was transferred to the Hospital of Tohoku University, April 1, 1970, because of severe hypoglycemic attacks. He was well until December, 1934, when he had hypoglycemic attacks characterized by a loss of consciousness. He was admitted to a hospital and treated for seventy dayt. After the discharge, he had remained well until December, 1969, when hypoglycemic attacks appeared frequently and he was admitted to the hospital again. Hypoglycemic symptoms were too severe to control and signs for congestive heart failrue developed.
On physical examination there were rales on the back and systolic murmurs at the apex. The liver was palpable 5cm below the right costal margin and an abdominal mass was observed in the left upper quadrant. The laboratory findings including hemogram, urinalysis, liver function tests, urea N and serum electrolytes were almost normal. The fasting blood glucose levels fluctuated below 40mg/dl and plasma immunoreactive insulin (IRI) exceeded 150μU/ml. Laparoscopy and coeliac arteriograpy revealed an islet cell tumor at the tail of the pancreas with metastases to the liver.
Streptozotocin was administered in a dose of 1.5g initially and 2.0g later every week since June 18, 1970. He had received a total of 79.5g of the drug until July 12, 1971. Following the treatment, fasting plasma IRI decreased and the blood glucose levels rose. The frequency of hypoglycemic attacks and the amount of glucose injected decreased. The enlarged liver and the tumor at the left upper abdomen were reduced in size. Although the levels of plasma IRI remained still high (approximately 60μU/ml), no hypoglycemic attacks appeared again.
Nausea and vomiting developed after each injection of the drug. Although tiny clots of blood were noticed in the urine several times immediately after the injection, they were usually transient and were not detectable in the urine 48 hours after the administration. No changes in the tests for liver function, serum protein, serum electrolytes and hemogram were observed during and after the treatment with streptozotocin. A decrease in the “big” insulin rate of plasma IRI was observed following streptozotocin administration.
The patient was monitored for two years after the discharge from the hospital. He felt well and has been free from hypoglycemic symtoms.

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Two pateients with juvenile diabetes who had been obese before the onset of the disease and in whom the disease was manifested by the sudden onset of diabetic coma completely remitted along with loss in body weight. Examinations included OGTT, IRI, HGH and the following conclusion was arrived at:
The patients showed resistance to insulin at the onset of the disese. The initial excess in food intake and body weight and the later correction could have been responsible for the onset and remission of the disease.
In these cases, the nature of insulin secretion at complete remission of the disease was investigated, and it was found that normalization of glucose tolerance was not always accompanied by improvements in insulin secretion. That is, no close relation was found between glucose tolerance and insulin secretion, but the duration of remission in the patient with normal insulin secretion at the remission stage (9 years, ) was longer than that in the patient with abnormal insulin secretion.
The two patients showed normal HGH levels in a fasted condition, whereas they showed no uniform tendency in secretory response to various loading tests. No conclusion could, therefore, be drawn on the role of HGH in remission or aggravation of diabetes.

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