Vitreous hemorrhage as a complication of diabetic retinopathy was examined in a total of 1, 962 diabetics who visited our Diabetes Center from November 1966 through December 1977.
The results obtained were as follows.:
1. Out of the 1, 962 diabetics, there were 60 patients with vitreous hemorrhage. Among these 60 patients, 32 (53.3%) already had vitreous hemorrhage at the first visit to our Center, and during one year from the first visit, another 13 patients (21.7%) who had not revealed vitreous hemorrhage at the first visit, developed vitreous hemorrhage.
2. The average duration of diabetes before vitreous hemorrhage was 11.9±1.2 years in males, and 8.1±1.2 years in females. It was thus significantly shorter in females.
3. Vitreous hemorrhage was found in males at a rate of 2.3% and in females at 2.2% after one year, at the first visit to our Center. These frequencies were thus almost equal.
4. There was a significant increase in the incidence of vitreous hemorrhage according to extension of the duration of diabetes.
5. There was no difference in the duration of diabetes before the first occurrence of vitreous hemorrhage or in the frequency of vitreous hemorrhage between the two groups in which the diabetes was treated or not treated, nor according to the method of treatment of the diabetes.

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Four “brittle” diabetic patients were given intravenous insulin infusion with our original artificial endocrine pancreas system and with a preprogrammable insulin infusion system, and subcutaneous insulin infusion with the latter system. Their blood glucose regulation as assessed from the mean blood glucose, M-value, mean amplitude of glycemic excursions, and frequency of occurrence of hypoglycemia was compared with that of conventional insulin therapies.
1. The artificial endocrine pancreas which we developed originally, was capable of restoring the circadian blood glucose profile of brittle diabetics to within the physiological range without demonstrating hypoglycemia.
2. Thereafter, one patient was given intravenous insulin infusion for 24 hr with a preprogrammable insulin infusion system. Insulin in an amount and in an infusion pattern corresponding to the daily insulin requirement determined with the artificial endocrine pancreas, was infused. By the intravenous infusion of insulin, near normal blood glucose fluctuations could be achieved in a brittle diabetic patient.
3. Brittle diabetic patients were then treated by subcutaneous insulin infusion with the preprogrammable insulin infusion system at a constant basal rate supplemented with the pulse-dose exponential decrement mode at meal time. The insulin infusion amounts were 1.0 to 1.5 timesas much as the insulin determined with the artificial endocrine pancreas. However, the glycemic control expressed as MAGE was not improved and unpredictable swings in blood glucose were observed. The efficiency of the subcutaneous insulin infusion treatment inbrittle diabetic patients corresponded to that of subcutaneous treatment consisting of two dailyinjections of intermediate-acting insulin (Insulin Rapitard).
The present findings suggest that, as compared to an intravenous route, subcutaneous insulin injections either by insulin infusion with a preprogrammable insulin infusion system or conventional therapies, may contribute to variability in insulin absorption and consequent lability of metabolic control. For better control and a more stable pattern of blood glucose in brittle diabetics with conventional insulin treatment, it is important to determine the appropriate doses for each type of insulin preparation on the basis of results obtained with the artificial endocrine pancreas system.

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We compared the incidence of familial diabetes in patients with type I (insulin-dependent) and type II (insulin-independent) diabetes. In type II patients, we also analyzed the familial incidence with reference to the maximal past body weight index and the number of children.
Full pedigrees of first-degree relatives were recorded in 671 patients with definite diabetes. The family history of diabetes was judged as positive when either of their parents, siblings or children had diabetes. The occurrence of diabetes in other relatives was disregarded. Among 229 insulintreated patients, 48 cases who appeared to be absolutely insulin-dependent were classified as type I diabetics. Among diet-, SU-, and insulin-treated patients, 580 were classified as type II and the remaining 43 cases as being of unknown type.
The overall incidence of familial diabetes was 42%(282/671), which represented the highest figure in the Japanese literature. The incidence of familial diabetes in type I diabetes (12/48=25%) was significantly lower than that in type II diabetes (251/580=43%)(p<0.02). The incidence was 44%(19/43) in patients with diabetes of unknown type. It was 27% in type I and 48% in type II (p<0.01) in patients with diabetes onset before the age of 50 years.
Type II diabetic patients with more marked obesity in the past had a lower incidence of familial diabetes. The highest incidence was observed in non-obese, type II diabetics of young onset. In females who developed type II diabetes after 40 years old, the frequency of diabetes in the parents and siblings did not differ significantly with the number of children.These data not only confirm the previously known higher incidence of familial diabetes in type II than in type I, but also demonstrate that this difference is not confined to young-onset diabetes.
Genetic factors seem to play a more important role in the pathogenesis of type II diabetes than that of type I diabetes. Excessive obesity is apparently so strongly diabetogenic as to induce diabetes in subjects with lesser genetic disposition for diabetes. Pregnancy is probably less important than obesity as a factor inducing diabetes.

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Series of 7-wk male and female DBA/2 N mice were infected intraperitoneally with 0.5 ml of M variant of encephalomyocarditis (EMC) virus with a titer of TCID₅₀, 10³/0.1 ml.
Glucose tolerance tests in fasting mice were performed by intraperitoneal injection of glucose, 2 mg/g body weight. The fasting IRI concentrations of male mice were determined at 0, 3, 7, and 14 days after inoculation. Histological examinations with H-E staining were performed on pancreatic tissues of male mice at 3, 7, and 14 days after inoculation. The specific binding of 125I-insulin to insulin receptors was observed by radioreceptor assay using liver particulate membrane of fasting mice at 0, 1, 3, and 7 days after inoculation.
The fasting blood glucose of infected male mice remained normal at the 1st and 3rd day, but elevation of fasting blood glucose appeared at the 7th day and continued for 7-14 days after inoculation. Elevation of blood glucose after glucose load appeared at the 3rd day after inoculation and maximal blood glucose elevation was observed at the 7th day. The glucose intolerance continued for 5 months, although the severity of glucose intolerance showed a decline. The glucose intolerance of female mice remained milder than that of male mice at the same period.
Changes of fasting IRI concentrations in infected male mice were not observed at the 3rd and 7th day, but a remarkable decrease in IRI concentrations was observed at the 14th day.
Histological alterations of the islets of Langerhans became evident at the 3rd day. Disruption of the overall architecture of the insular tissue, degeneration and pyknosis of the insular cells, and proliferation of blood vessels were observed, but infiltration of mononuclear cells did not appear unitl the 14th day after inoculation.
The specific binding of ¹²⁵I-insulin to insulin receptors of infected mice remained unchanged at the 1st day after inoculation, but was markedly decreased at the 3rd day. The binding returned to a normal control value at the 7th day in infected female mice. Scatchard analysis revealed that there was no change in the affinity constant of high affinity-low capacity component for 1-7 days after inoculation, but the affnity constant of low affinity-high capacity component was significantly decreased at the 3rd day and returned to a normal control value at the 7th day after inoculation. The numbers of insulin receptors in infected mice decreased slightly at the 1st day after inoculation, showed a minimum value at the 3rd day, and then returned to a normal control value at the 7th day.
It is considered that glucose intolerance at the early stage of virus-induced diabetes mellitus is due to impairment of insulin receptors, and that glucose intolerance at the late stage is due to hypoinsulinemia resulting from pancreatic damage.

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The effect of human insulin antibodies on insulin receptor was investigated using human placental membrane particulate. The following experiments were performed.
Group 1: ¹²⁵I-insulin was preincubated with insulin antibodies for 90min, and insulin receptor was then added to the incubation material. The mixture was incubated for 120min.
Group 2: ¹²⁵I-insulin, insulin antibodies and insulin receptor were incubated together for 120 min.
Group 3: ¹²⁵I-insulin was preincubated with insulin receptor for 120min, and insulin antibodies were then added to the incubation, material. The mixture was incubated for 90min.
Group 4: Insulin receptor was preincubated with insulin antibodies for 30min, the incubation material was washed once, and the mixture was then incubated with ¹²⁵I-insulin for 120 min.
¹²⁵I-insulin binding to insulin receptor was inhibited by insulin antibodies in groups 1, 2 and 4, but was not inhibited in group 3. The inhibition rate was positively correlated to the titer of insulin antibodies. There were different inhibition rates among groups 1, 2 and 4, and different inhibition rates were also observed with different insulin target organs: human placental insulin receptor, and hepatic and renal insulin receptor of the guinea pig, respectively.Insulin antibodies obtained in the insulin resistant period showed the most remarkable inhibition. However, insulin antibodies obtained from insulin resistant diabetics in the remissive state and from patients with steroid induced diabetes, exhibited decreased inhibitory activities. The dissociation rate of ¹²⁵I-insulin from the insulin receptor was increased by insulin antibodies. Scatchard analysis revealed that the affinity constants of insulin antibodies were increased in the insulin resistant period, but the affinity constants in the remissive state were significantly decreased. Scatchard plots for insulin receptor showed decreases of the affinity constants and numbers of insulin receptors by insulin antibodies.
Comparing the affinity constants between insulin receptor and insulin antibodies in the insulin period, the ratio of K₂ (low affinity-high capacity fraction) for insulin receptor to K₁ (high affinitylow capacity fraction) for insulin antibodies was 1: 8.30, and the ratio of K₁ for insulin receptor to K₂ for insulin antibodies was 1: 0.058. In the remissive state, the ratio of K₂ for insulin receptor to K₁ for insulin antibodies was 1: 2.49, and the ratio of K₁ for insulin receptor to K₂ for insulin antibodies was 1: 0.032. Based on these findings, it is speculated that the binding inhibition of ¹²⁵Iinsulin to insulin receptor may be caused mainly by the high affinity-low capacity component of insulin antibodies and the main binding inhibition site is the low affinity-high capacity component of insulin receptor in the presence of insulin antibodies.

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The mechanisms underlying the beneficial effects of exercise in the treatment of diabetes are not well understood. The effect of exercise on ketone body (KB) production and utilization has also not been determined in intact man, although in severe diabetics, exercise resulted in more pronounced hyperglycemia and hyperketonemia. Six insulin-withdrawn (24 hr) insulin-dependent diabetics and 6 healthy controls were studeid at rest during and after 60 min of bicycle exercise (40% of Vo2 max). Catheter technique was employed to determine the splanchnic exchange of metabolites.
The basal arterial concentrations of glucose (258 ± 18 mg/dl), FFA (0.97 ± 0.15mmol/l) and KB (1.25 ± 0.27mmol/l) were significantly higher in the diabetic patients than in the controls. The arterial FFA level remained unchanged or increased slightly during exercise, rose distinctly 5-20 min after exercise and then decreased gradually. The concentration changes occurred in parallel for the two groups but the levels were 60-100% higher in the diabetics. The patients' basal splanchnic ketone production (SKP)(0.72 ± 0.07mmol/min) rost to 0.96 ± 0.17mmol/min during exericse and increased further to 1.18 ± 0.15mmol/min at 20 min after exercise. It remained unchanged or even increased for 60 min after exercise. The arterial KB levels were unchanged during exercise but rose to 2.02 ± 0.28mmol/l at 20 min after exercise in the diabetics. In contrast, the SKP in controls was 0.09 ± 0.02mmoles/min at rest, rose 3-fold during exercise, peaked at 10-20 min after exercise and then decreased gradually. It is concluded that the stimulation of KB production during exercise persisted during the post-exercise recovery period in the diabetics but not in the controls, probably as a result of insulin deficiency in the diabetics. These findings emphasize the importance of adequate insulin therapy in connection with exercise.

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Noonan's syndrome is characterized by clinical features which resemble Turner's syndrome and by a normal karyotype.
A 20-yr-old man was referred to us for short stature and thirst. His birth weight was 2500 g and his growth had been retarded. At the age of 12, he was diagnosed as having depression and was treated with antidepressants. At the age of 20, thirst, polydipsia, polyuria and emaciation developed. There was no family history of short stature and diabetes mellitus. Physical examination revealed short stature (148.5cm, 41.3kg), hypertelorism, epicantus, microphthalmus, low set hairline and shield chest. Heart murmur was not heard. Atrophy of the seminal vesicles and prostate was noted with a short penis and small testes. The full scale intelligence quotient (I.Q) was 48.
The karyotype was 46-XY. The human leukocyte antigen (HLA) type was A₉, ₁₀, BW₄₀, ₅₁. Dermatoglyphicfindings revealed a bridge type of simian-line and a high axial triradius, and the total fingertip ridge count exceeded 190. Thyroidal and adrenal functions were normal. The plasma testosterone levels before and after human chorionic gonadotropin administration were normal. The basal and stimulated levels of plasma follicle stimulating hormone (FSH) during the luteinizing hormone-releasing hormone (LHRH) test were high. A 100g-glucose tolerance test revealed a diabetic pattern of blood glucose and a low response of immunoreactive insulin (IRI). Growth hormone showed an exaggerated response by the arginine infusion test.
The association of Noonan's syndrome with diabetes mellitus is rare in the literature, although the reason for this is not known.
Mental retardation is often recognized in Noonan's syndrome, while depression, epilepsy and schizophrenia are occasionally found in the syndrome. It is suspected that these psychoses may represent one of the component features of the syndrome.

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We describe six cases of diabetic gangrene with special reference to the clinical pictures and to treatment involving prostaglandin E₁ infusion therapy. Four of the six patients were over the age of 60, ranging overall from 41 to 74 years, and five cases were female. In five of them, the duration of diabetes was over 10 years, ranging overall from 2 to 27 years. All cases were complicated with retinopathy and neuropathy, respectively. The predisposing causes of diabetic gangrene were trauma, self-mistreatment of trauma or bulla, and poorly controlled blood sugar. In all cases, the levels of plasma β-thromboglobulin, one of the indicators of platelet function, were higher than that in the control. In two cases, there was a remarkable elevation (166 ng/ml and 244 ng/ml). Intravenous infusion of prostaglandin E₁ in combination with conservative therapy, is expected to yield beneficial effects in the treatment of diabetic gangrene.

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Disopyramide (Rythmodan ®) is a new antiarrhythmic agent with quinidine-like actions. We report a 56-yr-old diabetic woman in whom a hypoglycemic effect of this agent was proved.
The patient was admitted to our hospital complaining of visual disturbance due to fresh hemorrhage into the vitreous body of the right eye. On the 22nd hospital day, her electrocardiogram revealed ventricular extrasystoles. She was administered 300 mg/day of disopyramide and the ventricular extrasystoles disappeared. Prior to disopyramide therapy, the fasting blood glucose level was 215 mg/dl. On the 8th day after administration of the agent, while she was treated with 16 units of lente insulin and a 1400 Cal diabetic diet regimen, the fasting blood glucose level was 147 mg/dl and on the 14th day the fasting blood glucose level decreased to 85 mg/dl. From the following day, the dosage of lente insulin was reduced. Her blood glucose levels were controlled with 6 units of lente insulin. After the patient was discharged on the 67th hospital day. the blood glucose levels were not elevated. The fasting blood glucose level was 111 mg/dl. Since an electrocardiogram had revealed no ventricular extrasystoles, disopyramide was withdrawn. The blood glucose increased again to a level of 195 mg/dl even with 12 units of lente insulin. During this course, she received no other hypoglycemic agents and her body weight and renal function tests revealed no changes. A 50 g OGTT during treatment with disopyramide, demonstrated an improvement of glucose intolerance compared to that prior to disopyramide therapy and showed a normal response of C-peptide immunoreactivity. After withdrawal of the agent, a 50 g OGTT revealed a severer diabetic pattern and a lower response of C-peptide immunoreactivity. It is suggested therefore that the hypoglycemic effect of disopyramide may be due to increased insulin secretion of pancreatic beta cells.

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