The biological activity of NSILA-S (Non-suppressible insulin like activity, soluble in acid ethanol) prepared by Froesch, E. R. et al. was examined against that of standard crystalline insulin in the isolated rat hemidiaphragm method and the rat epididymal adipose method. The results obtained were as follows:
1. The basal glucose uptake of the hemidiaphragms was suppressed by NSILA-S of 1.66mg/ml (estimated insulin activity: 1, 000μ/ml), and the glucose uptake promoted by the standard insulin of 1, 000μU/ml was also inhibited by same doses of NSILA-S added simultaneously into the incubation medium.
2. On the other hand, NSILA-S of 0.16mg/ml accelerated independently the glucose uptake of adipose tissues in the same manner as standard insulin of 100μU/ml, and any competitive inhibition could not be seen between NSILA-S and insulin.
3. The antilipolytic effect of NSILA-S was found to be the same as standard insulin in the adipose tissue method when glycerol release was used as an indicator.

View full abstract

A statistical study of 54 cases of hyperosmolar nonketotic diabetic coma reported in Japan was performed. The age of the cases was distributed from 4 to 85 years old, and 70.4% were patients over 50 years old. Forty-one per cent of patients had no diabetic past history, 24% of the patients had suffered from diabetes over 3 years and some had a long term history of insulin treatment.
Main chief complaints or symptoms of the patients on admission were these associated with marked dehydration and loss of consciousness, gastrointestinal symptoms, circulatory failure and hyperpyrexia. The clinical symptoms appeared more severe in this disease than in diabetic coma with ketoacidosis.
Various stresses including infections, surgical involvement, steroid administration, and other conditions which lead patients to dehydration, were the main contributing factors to the coma. Urinary acetone body tests were weakly positive or “trace” in 8 cases. Proteinuria was observed in most of cases. Hemoconcentration and leucocytosis were also prominent.
The mean value of blood sugar in 54 cases was 1, 019mg/100ml, ranging from 285 to3, 300mg /100ml. The mean value of serum sodium in 47 cases was 152.9mEq/l and about 60 % of the cases showed hypernatremia of more than 153mEq/l. Hyponatremia was seen in 6 cases, 4 of which were associated with acute severe renal distresses and showed decreased levels of plasma bicarbonate and blood pH. Elevated blood urea nitrogen and plasma osmotic pressure were observed in almost all cases.
Most cases were treated with 100 to 400 units of insulin and 3 to 6 liters of fluids during the coma. About 70 % of the recovered cases recovered from mental confusion within 3 days and the duration of the coma in lethal cases was 2.9 days on the average. Mortality in 54 cases in this series was 25.9% and the mortality rates of younger patients was higher than that of older patients. Five of 54 patients died from other diseases shortly after recovery from the coma. After recovery from the hyperosmoral state most patients later were controlled satisfactorily with diet alone, small doses of oral drugs, or insulin preparations.
An autopsy was performed in 13 cases. Two cases showed no diabetic changes in any organs. All of the other 11 cases exhibited diabetic changes in the pancreas, which induced atrophy of the organ, decrease of beta-cells, hyaline changes of the islet cells, pancreatic fibrosis and fatty changes. Diabetic glomerulosclerosis was observed in 4 cases and fatty degeneration of the liver in 5 cases.

View full abstract

Investigation of the galactose tolerance test was made using of recently developed enzyme assay techniques in a series of 120 normal, diabetic, hepatopathic subjects receiving 40g of galactose orally, and in 10 normal and hepatopathic cases undergoing Tengström's intravenous test.
The oral administration of 40g of galactose led to a slight elevation in blood glucose followed by a return to the initial level in 2 hours in normal subjects, whereas in subjects with diabetes or liver impairment, it produced a persistent elevation in blood glucose. NEFA, on the other hand, invariably diminished markedly after an oral dose of galactose irrespective of the level of blood galactose retention.
No significant alterations in blood IRI levels were observed to take place in either the oral or the intravenous galactose tolerance tests, in contrast to the usually noted marked changes occurring in glucose tolerance tests. It was not clear, however, as to whether the administration of galactose gave rise to a release of insulin from pancreas. Therefore, the decrease in plasma NEFA levels will have to be considered from a different viewpoint from that of the glucose tolerance test, since no appreciable differences in response could be observed between normal and diabetic subjects.
Also studied were changes in blood lactate and pyruvate concentrations, and in blood L/P ratios in subjects undergoing galactose tolerance tests as parameters reflecting the cytoplasmatic redox potentials in the liver. Temporary elevations in blood lactate coupled with increases in blood L/P ratio was marked in cases where blood galactose retention was within the physiological limits. However in those cases where galactose retention was beyond the upper normal limit, no such salient elevations in blood lactate occurred, and the relevant changes in blood L/P ratio were inconsistent.
The results of the study described indicate that the galactose tolerance test will be useful in detection and estimation of the degree of hepatic dysfunction at, what we will call the “intrahepatic coenzyme level”. Diminution in blood NEFA levels following the galactose administration must be considered in relation to NADH metabolism in addition to the direct action of galactose.

View full abstract

Although changes of carbohydrate metabolism after total pancreatectomy have been widely investigated, changes after major pancreas resection have remained virtually unexplored. This study deals with observation on changes of glucose tolerance and endocrine functions of the pancreas after major resection of the pancreas.
Material and Methods: Adult mongrel dogs were used. After major pancreas resection without injury of the main pancreatic duct, intravenous glucose tolerance tests (IVGTT) were carried out before and every three weeks after the operation. Blood glucose and insulin level in the circulating plasma were measured. To test endocrine function of the pancreas remnant, plasma insulin and glucagon level in the pancreaticoduodenal vein were measured during or after intravenous infusion of arginine and histological sections were observed by Aldehyde-Thionin-Light-Orange, A zan and Gomori's Chrome-alum Hematoxylin Phloxine staining.
Results: Depending upon the extent of resection of the pancreas and upon time of onset of diabetes, changes of IVGTT after major pancreas resection were divided into 3 groups as follows. Group 1: Immediately after resection of 88% or more of the pancreas, hyperglycemia occured and plasma insulin level decreased below one third of the normal level. Group 2: After 70-88% pancreatectomy, IVGTT showed nearly normal curves for a short time, but hyperglycemia occured after 6 or more postoperative weeks. In so called Sandmeyer diabetes, which showed changes of IVGTT of this group, glucagon level in the pancreaticoduodenal vein rose promptly within 1 minute after arginine infusion, but the peak of insulin level was delayed. In histological findings, pancreas remnants of a Sandmeyer diabetes dog showed vacuolar degeneration in B cells and almost no changes in A cells. Group 3: After resection of 70% or less of the pancreas, IVGTT and circulating plasma insulin level were almost normal throughout the course of the observation.

View full abstract

Although pancreatitis is complicated with a derangement in carbohydrate metabolism, limited information is available as to the endocrine function of the pancreas. In this paper, 45 patients with chronic pancreatitis were studied to elucidate the endocrine function of the pancreas. In 42 out of 45 patients, pancreatolithiasis was proved and in the rest fibrosis of the pancreas was diagnosed.
Oral glucose tolerance tests revealed a diabetic curve in 28 patients and borderline with 12 patients, whereas only 5 patients showed a normal glucose tolerance. Of twenty seven patients in whom insulin response to oral glucose was studied, twenty patients showed a decreased insulin response, while a normal response was observed in four patients and a hyperresponse in three. When regular insulin in a dose of 0.1U/kg was injected intravenously in five patients, a fall of blood glucose was slightly decreased and delayed in comparison with healthy subjects. Five of six patients to whom tolbutamide was administered intravenously, showed a decreased insulin rise and a delayed fall of blood glucose. In five out of six patients who were infused with arginine, there was a decreased response of insulin and/or glucagon to arginine.
In comparison with primary diabetic patients with the same degree in glucose intolerance, a marked decrease in the response of insulin was observed in the patients with chronic pancreatitis.
The more the exocrine function of the pancreas was decreased, the more the blood glucose levels were elevated. However, no definite correlation between exocrine function and insulin response to glucose could be demonstrated.
An elevated fasting blood glucose and decreased plasma insulin were observed inthose patients with multiple small size stones compared to those with a single or a few large stones.
Diabetic retinopathy was proved in only three out of twenty five patients in this series of the study.

View full abstract

Gastrin levels in the sera of patients with diabetes mellitus, in one group up to 49 years of age and another group over 50 years of age, were higher than the corresponding healthy age controls.
The occurence of hypoacidity in both basal and tetragastrin-stimulated maximal acid output (MAO), showed a higher rate of incidence in diabetics than in tie age matched controls, and a significant negative correlation between MAO and serum gastrin level was seen in diabetic patients. The mechanism of hypergastrinemia in hypacidics can be explained by the lowering of the negative feedback mechanism between acidity and gastrin secretion.
Diabetic patients were divided into a normoacid and hypoacid group, and these were subdivided by the presence or absence of diabetic nephropathy. No hypergastrinemia was seen in normoacid cases without nephropathy, and higher gastrin levels than the normal control were seen in normoacid cases combined with nephropathy. The hypoacid group without regard to the presence or absence of nephropathy revealed high gastrin levels, however, the highest gastrin levels with mean values were observed in hypoacid cases with nephropathy. It was concluded from these facts that hypacidity and nephropathy were the main factors involved in the occurrence of hypergastrinemia in diabetics.
In order to clarify the mechanism of hypergastrinemia observed in diabetic nephropathy, the grade of degradation of gastrin by kidneys obtained from genetic diabetic mice (KKAy) in which glomerular lesions were histologically proven was compared with that of renal tissues obtained from normal control mice.
The investigation was made by incubation of ¹³¹I-gastrin with each renal tissue, development of the incubation medium with silica-G thin-layer chromatography, and by calculation of the radioactivities in ¹³¹I-gastrin and its degradation products.
The degradation products gradually increased in accordance with incubation time when ¹³¹I-gastrin was incubated with normal renal tissue, on the other hand, the grade of degradation was clearly decreased when the renal tissue from a KKAy mouse was used.
It was clear that a low metabolic rate of gastrin by the renal lesions would be the cause of hypergastrinemia in patients with diabetic nephropathy.

View full abstract

We present a patient with a so-called “insulin autoimmune syndrome”. A sixty year old man came to the hospital suffering from pronounced hypoglycemic attacks without apparent causes. These occurred only three times during the last week in April and the first week in May of 1968. He had never received any insulin injection or had contact with insulin until this hospitalization. He was suspected of having insulinoma because of the presence of Whipple's trias on admission.
The oral 50g glucose tolerance test (OGTT) was slightly impaired. Plasma immunoreactive insulin (IRI) measured by the two antibody method was over 1, 000μU/ml both at fasting and subsequent times in the OGTT or the intravenous 1g tolbutamide test. Concurrently in his plasma, an insulinbinding antibody which bound human and porcine insulins more than bovine insulin was detected. When we first measured the titer of the antibody after admission, it showed 58.3 mU/ml by the modified Wright's method. However, two subsequent values of the titer rapidly fell to 4.6 and 6.7 mU/ml for five months without any treatment.
Subjectively and objectively, he has been living with no complaints since discharge from the hospital. Our laboratory findings did not suggest any autoimmune diseases such as SLE or chronic thyroiditis. We can, however, still find an appreciable amount of the titer of anti-insulin antibody in this patien's plasma.
Consequently, we speculate that some autoimmune mechanisms must be working to explain the continuous presence of the autoanti-insulin antibody.

View full abstract

A 19 year old girl was admitted to the hospital unconscious. The patient had apparently been in good health until one day prior to admission. On admission, she was found to be comatose in acute distress, with involuntary and violent movements of the extremities and trunk. Only her tongue was markedly dehydrated. Laboratory studies revealed blood sugar 845mg/dl, positive urinary acetone, serum potassium 6.25 mEq/l and blood urea nitrogen 46.5mg/dl. An electrocardiogram taken at the time of admission showed findings of hyperkalemia. Shortly after taking of this electrocardiogram, her blood pressure was immeasurable and another electrocardiogramrevealed ventricular fibrillation, followed by ventricular tachycardia. An injection of adrenalin into the heart caused an immediate response, with a regular heart rate of 210 beats per minute and a slight elevation of blood pressure. However following electrocardiograms showed frequent appearances of ventricular fibrillation or ventricular tachycardia for the next hour. The hyperkalemic electrocardiographic findings turned rather rapidly to hypokalemic after insulin and fluid administration.
Following insulin treatment of one to two weeks, the patient developed transient episodes of hepatomegaly, edema on the feet and face, and frequent severe attacks of epigastric pain. The liver was palpated 3 fingerbreadths below the right costal margin, associated with elevation of SGOT, SGPT and SLDH levels. The liver was not felt 2 weeks later, with normal values of the serum enzyme activities. The edema appearing on the feet and face, was associated with decreasing urinary output. Levels of serum electrolytes, blood urea nitrogen and blood creatinine were within normal limits. This edema subsided within the next week. Frequent severe attacks of the epigastric pain was also noted. The pain occurred suddenly. The patient was given pentazocine in order to relieve the pain. Definite visceral lesions which caused such severe pain were not found. At the same time the patient complained of squeezing or painful sensations in the chest, numbness or tingling of the hands and feet, and tremors in the fingers. The epigastric pain and neurological abnormalities subsided spontanously over the next week.
The patient seemed to have slight character changes and her electroencephalogram showed slow %alpha; waves with sporadic 5 to 6 c/s θ waves. She was administered a daily dose of 100mg of diphenylhydantoin for lability of blood sugar, an abnormal electroencephalogram, and psychoneurotic symptoms. Her fasting blood sugar showed further elevation and wider fluctuations of the blood sugar occurred. Diphenylhydantoin was discontinued 3 weeks later.
The following various conditions were discussed, because these seem related to above mentioned symptoms of this patient: rapid changes of osmotic gradient between extracellular and intracellular compartment of the brain, electrocardiographic changes in hyperkalemia, glycogen deposition inthe liver after insulin treatment, insulin edema, insulin neuropathy, neuropathy after diabetic coma, abnormal electroencephalogram and character changes in brittle diabetes, and hyperglycemia due to inhibition of insulin secretion by diphenylhydantoin.

View full abstract

A case of lipoatrohic diabetes was reported with special reference to a plasma immunoreactive insulin (IRI) response to several stimulations.
The patient was a Japanese female, twenty five years of age, who had been noted to have no subcutaneous fat since the birth, and was found to have glucosuria at the age of twenty four. Physical examination showed prominant musculature with marked general lipodystrophy, acanthosis nigricans, hepatomegaly, peripheral neuropathy and diabetic retinopathy. Routine laboratory findings were normal except for glucosuria without ketonuria, and an abnormal glucose tolerance test (GTT). Serum lipid and BMR were normal on admission, and increased to abnormal levels thereafter.
To search for the cause of insulin resistance which was detected by the insulin tolerance test, insulin antagonist, insulin antibody and insulin as well as growth hormone response to several stimulations were studied. IRI response to oral GTT and intravenous injection of tolbutamide was high, but the glucose level was not decreased. Gelfiltration of plasma IRI was performed using Sephadex G-50, and a normal elution pattern was detected without any increase of higher molecular weight insulin. The insulin antagonist in urine, extracted according to Louis method, was negative. The plasma growth hormone level, stimulated by glucose, insulin, arginine and leucine, was not high. Insulin resistance was noted not only to endogenous, but also exogenous insulin, but there was no evidence of increase of insulin antibody (titer) in serum. Thus the only possible explanation for the insulin resistance in our patient was the total absence of adipose tissue as a target organ to be affected by insulin.
Then, insulin response was studied after treatment with chlorpropamide. Her fasting IRI level increased to as high a level as 80μU/ml after treatment with chlorpropamide, and IRI response to oral GTT was extremely high compared with the one before the treatment. But response to intravenous admnistration of tolbutamide did not change, suggesting that glucose and tolbutamide stimulate different points to secret insulin.

View full abstract