In 129 patients who recieved liver biopsy for pathological diagnosis, 15 clinico-laboratory parameters (age FBS, IRI, insulinogenic index, total bililubin, SGOT, SGPT, Al-p, LAP, γ-GTP, ICG, serum albumin, γ-globulin, serum total cholesterol and TG) were analyzed by principal component analysis. Four principal components; hepatic dysfunction, carbohydrate metabolism, lipid metabolism and chronic hepatic cellular damage, were derived by this analysis.
The scores for these 4 components in each patient were calculated and plotted graphically. The localization of the scores for patients with fatty liver, chronic acitve and inactive hepatitis, and liver cirrhosis were studied to test the correlation between their hepatic dysfunction and glucose intolerance along with examination of their characteristics with an ellipse of rejection at a risk level of 5%.
Although the scores for hepatic dysfunction in patients with chronic active hepatitis were high, the scores for glucose intolerance remained within the normal range. As a hypothetical explanation of the coexistence of hyperglycemia and hyperinsulinemia in patients with chronic active hepatitis, the presence of a peripheral tissue resistance to carbohydrate metabolism associated witha high NEFA level in the blood is proposed.
In liver cirrhosis, chronic inactive hepatitis and fatty liver, the correlations between hepatic dysfunction and glucose intolerance were found to be high.
To elucidate the development of fatty liver, it is concluded that additional factors suchas total caloric intake, daily intake of alcoholic beverages, and degree of obesity as well as serum lipid level, should be examined by multifactorial regression analysis.

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It has recently been indicated that glucagon plays an important role in metabolic regulation. However, the effects of physiological amounts of this hormone remain unclear.
The purpose of the present study was to evaluate the significance of glucagon in man and to determine the unique action of this hormone in metabolic and hormonal changes by comparing the responses to intravenous infusions of glucagon in normal subjects and patients with insulindependent diabetes mellitus and liver cirrhosis. Although the infusion of a high dose (50ng/kg per min) of glucagon in normal subjects resulted in rises in blood glucose, serum insulin and cyclic AMP, there was relatively little effect on them with a low dose (5 ng/kg per min) of glucagon. Glucagon infusion at 50ng/kg per min resulted in elevated blood lactate only in normal subjects and an increase in blood ketone body only in insulin-dependent diabetic subjects.On the other hand, elevation of serum cyclic AMP with the infusion of this hormone was observed in all subjects, although it tended to reach plateau values in normal subjects and patients with liver cirrhosis as compared to linear increases in insulin-dependent diabetic subjects.
It is concluded that 1) the changes in blood lactate following the administration of glucagon are dependent on the contents of glycogen in the liver, 2) the insulin: glucagon ratio in the blood plays an important role in the production of ketone body, and 3) the counterregulatory action between insulin and glucagon on the maintenance of euglycemia is mediated through cyclic AMP.

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We originally developed an artificial endocrine pancreas by combining a glucose infusion system with the artificial beta cell. This system was adapted to assist in the intravenous tolbutamide test and in the intraoperative localization of an occult insulinoma in a 45-year-old patient who suffered from hypoglycemic attacks several times within a year.
In this patient, the fasting plasma glucose concentrations were between 23 and 61mg/100ml, corresponding with insulin values of from 13 to 31μU/ml. In a 100g oral glucose tolerance test and a glucagon 1mg iv injection test, insulin secretion was markedly exaggerated. An intravenous tolbutamide injection test was performed under blood glucose control with the artificial endocrine pancreas since severe hypoglycemia was anticipated. With computer-operated glucose infusion, the blood glucose was maintained at levels of between 60 and 80mg/100ml, and then tolbutamideinduced hyperinsulinemia was proven by immunoassay.
Selective angiography of the celiac and superior mesenteric artery failed to demonstrate any tumor shadows. Percutaneous transhepatic portal and pancreatic venous catheterization revealed that the plasma concentrations of insulin were not unequivocally elevated in any sampling location.
Even though preoperative localization of the insulinoma was not successful, laparotomy was performed. During the operation, glycemia was monitored in continuously withdrawn whole blood, and glucose was infused to maintain the blood glucose concentration at a level of 80mg/100ml using an artificial endocrine pancreas with a closed loop that excluded its usual insulin delivery capability.
Inspection and palpation failed to reveal any tumors in the pancreas. Massage on the tail of the pancreas was then performed. After 10min, the blood glucose tended to decrease and the glucose infusion rate progressively increased. Massage of the head of the pancreas failed to increase the glucose infusion rate. The location of the insulinoma was thus decided to be the pancreatic tail. Eighty-five percent of the pancreas including the tail was removed, and the blood glucose then increased rapidly. Subsequently, this was confirmed directly by determination of the increment of insulin after pancreatic tail massage and reduction of insulin after pancreatic resection.
A single tiny (3mm) insulinoma was found in the resected portion of the pancreas. Following the operation, the hypoglycemic symptoms vanished completely.
The artificial endocrine pancreas thus facilitated not only the blood glucose control during insulin secretion stimulation tests and pancreatic resection, but also the intraoperative localization of an occult insulinoma.

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Two patients showing development of glucagon binding antibodies without previous immunization with glucagon or insulin are described. Case No. 1 was of diabetes mellitus and case No. 2 was of suspected Cushing's syndrome but showed normal glucose tolerance. Both patients had never received glucagon or insulin injections. In both cases, serological tests for syphilis, in particular the Treponema Pallidum Hemagglutination Test (TPHA) and Fluorescent Treponemal Antibody Absorption test, were positive, but no abnormalities were observed in other serological tests. The other clinical finding common to these patients was severe hypoglycemic fits during insulin sensitivity tests.
Plasma immunoreactive glucagon in each patient could not be determined using native plasma, since a substance was present which bound ¹²⁵I-glucagon and interfered with glucagon radioimmunoassay. This ¹²⁵I-glucagon-binding substance was detected by the polyethylene glycol method. The values expressed as bound % were case No. 1 =30.1%(control=7.4%) and case No. 2=22.9% (control =9.1%). Such high binding could be displaced only by porcine glucagon insofar as presently examined, and was dissociated at acidic pH. The binding substance was found in the plasma protein fraction on gel filtration and was proved to belong to γ-globulin (IgG, light chain; κ type dominant) by agarose electrophoresis and specific double antibody radioprecipitation.
Another 8 patients without insulin treatment, who had high glucagon binding in their plasma, also had positive TPHA. However, all of the positive TPHA found in 33 patients could not be correlated to high glucagon binding in their plasma.
Although the mechanism of antibody development towards glucagon and its clinical significance are at present unknown, we propose a new syndrome involving antiglucagon antibodies in the plasma associated with positive TPHA.

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The direct effects of ethanol on insulin and glucagon secretion were studied using isolated and perfused rat pancreas. Two series of experiments were performed. In one, the ethanol concentration in the perfusate was maintained at 21.7 mM, and in the other at 65 mM. The 65 mM ethanol suppressed more markedly both the first and second phases of insulin release induced by 16.7 mM glucose, compared to 21.7 mM ethanol. The 21.7 mM and 65 mM ethanol showed the same extents of inhibition of insulin and glucagon release to 6.4 mM arginine in the presence of 5.5 mM glucose.
These findings suggest that ethanol exerts a direct inhibitory effect on the secretion of insulin and glucagon, and that ethanol inhibits glucose-induced insulin release in a dose-related manner.

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The incidence of overt diabetes in patients with hyperthyroidism has been reported to be 2 to 3 %. Only a few cases of coexisting diabetic ketoacidosis and clinical hyperthyroidism have been reported in Japan.
We describe two young female patients who developed diabetic ketoacidotic precoma after longterm preexisting hyperthyroidism. Case 1: The patient, a 25-year-old female, developed hyperthyroidism at the age of 18 yrs, but had been incompletely treated. She was admitted to our clinic complaining of sudden onset of thirst, general malaise and somnolence. Physical examination on admission revealed a dehydrated lady in somnolence with struma (grade 2), dry skin and mucous membrane. The laboratory data were: urinary glucose and ketone bodies, strongly positive; blood glucose, 636 mg/dl; arterial pH, 7.236; PCO₂ 20.9 mmHg; base excess (BE)-17 mEq/l; HCO₃^-8.5 mEq/l; Ht 48%; T₃RU 51.5%; T₄ 17.4 μg/dl; T₃ 270 ng/dl; TSH below 1 μu/ml; thyroid and microsome tests, both positive. Case 2: The patient, a 37-year-old female, developed hyperthyroidism at the age of 23 yrs, but had received only occasional therapy as in Case 1. She was transferred to our clinic because of vomiting, palpitations and somnolence. Physical examination on admission revealed somnolence (severe), sinus tachycardia (154/min), dry skin and mucous membrane. Goiter was not found. The laboratory data were; urinary glucose and ketone bodies, strongly positive; blood glucose, above 400 mg/dl; arterial pH, 7.176; PCO₂ 17.5 mmHg; BE -19.9 mEq/l; HCO₃^- 6.4 mEq/l; Ht 53%; T₃RU 51.8%; T₄ 16.8 μg/dl: T₃ 280 ng/dl; TSH below 1 μu/ml; microsome test, positive.
Both patients recovered quickly from their impaired consciousness following intravenous administration of saline solution combined with insulin preparation. However, the daily insulin requirement had increased since the serum level of thyroid hormones was elevated during the hospital course until an antithyroid drug was administered. Antithyroid drug therapy resulted in a decrease of the insulin requirement, indicating that the hyperthyroid state had affected the glucose tolerance and actually precipitated diabetic ketoacidosis in these cases.
The present two cases appear to represent a clinical example of the ‘metathyroid diabetes’ proposed by Dr. Houssay. However, according to current concepts of autoimmunity, the possible mechanism common to the coexistence of insulin dependent diabetes and clinical hyperthyroidism may be involved in these cases.

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During 8 years from 1970, 22 patients were reported suffering from insulin autoimmune syndrome, associated with insulin antibodies without any previous known immunization. It was suspected that 5 of the cases were induced by drugs. In fact, 3 were found to be induced by 1-methyl-2-mercapto-imidazole, 1 by diphenylhydantoin and 1 by α-mercaptopropionyl glycine. The present patient who visited our hospital is a second case of induction by α-mercaptopropionyl glycine administration.
In Jan. 1979, a 71-year-old Japanese man was admitted to Yatsushiro General Hospital suffering from an attack of hypoglycemia which caused unconsciousness. The patient had suffered from chronic hepatitis for a long time, but he had no complaints untill receiving α-mercaptopropionyl glycine during a 3-week period. It was also discovered that he had received this drug 6 months previously for a period of 1 month.
Large amounts of insulin binding protein were found in his serum which belonged to IgG, and its light chain types consisted of the kappa-type. Measurements of blood glucose levels, total immunoreactive insulin, free immunoreactive insulin, ¹²⁵I-insulin binding capacity, and C-peptide reactivity in 50 g glucose tolerance tests were made in Jan., Feb., May and Sept., 1979. They showed the characteristic changes of the syndrome. High glucagon levels were recognized but glucagon antibodies were negative. A 9, B 15 and B 40 were found in the typing of HLA.
This patient was a medical orderly during his youth, and it was discovered that he had administered insulin injections to his diabetic mother for 2 years prior to her death. He was capable of injecting himself with insulin, but strongly denies that he ever did.

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Fasting plasma adenosine 3', 5'-monophosphate (cAMP) levels in diabetics without ketoacidosis were measured, and the relationships between the fasting plasma cAMP levels and fasting blood glucose (FBS), plasma immunoreactive glucagon (IRG), mode of therapy, onset and duration of diabetes mellitus were investigated.
There was no correlation between plasma cAMP levels and FBS, plasma IRG, onset and duration of diabetes mellitus. No significant difference in fasting plasma cAMP levels was found among diet-, drug-, insulin-treated diabetics and control subjects.
The fasting plasma cAMP levels in insulin-treated diabetics whose onset was before 39 years old, were significantly lower than those in control subjects. This finding is in agreement with the studies of other investigators.

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The reliability of a “Hemascope^TM System” was tested using venous blood samples obtained from diabetics. The following results were obtained.
1) The blood sugar levels determined with this system were significantly correlated to those obtained with an Autoanalyzer (r=0.93, p<0.001).
2) The influence of time of exposure to the blood sample on the blood sugar values was also studied. In order to obtain exact blood sugar values, it was necessary for the exposure time to be just for 60 sec.
3) The blood glucose levels determined with this system gradually declined after washing out a strip. However, the decline in blood sugar values was not significant when they were measured within 20 sec after washing out the strip.
It is concluded that the “Hemascope^TM System” represents a simple and reliable method for the measurement of blood glucose levels if the procedure is performed accurately.

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