Five patients with diabetes mellitus who had stiffness of hands were reported.
The patients, 3 males and 2 females, ranged in age from 47 to 60 years. Duration of diabetes mellitus was from 7 to 22 years. Their diabetic conditions were poorly controlled although four of them received 28 to 40 units of insulin daily and one oral medication.
Four patients had interphalangeal joint pain. Symptoms, including pain, swelling and motor disturbance were observed predominantly in the proximal interphalangeal joints. Two patients developed transient bilateral “claw hand” appearance with flexion contractures of the proximal interphalangeal joints. There was no accumulation of joint fluid. Hand stiffness, which was the most prominent after rising in the morning and improved gradually in the afternoon. However, sometimes it might persist throughout the day. Grasping power of the hands decreased in the patients with severe hand stiffness. All five patients revealed diabetic neuropathies of a greater or lesser degree. Electromyography of the median nerve of the patients showed reduced motor and sensory nerve conduction velocity. However, hand stiffness was not necessarily correlated with the degree of neuropathy. Latex test and C-reactive protein were always negative in the patients. There were no immunological abnormalities, nor hyperuricemia. Roentgenological findings of the finger bones showed slight osteoporosis, small cystic changes of bones or periarticular cortical erosions. Stiffness of the hands improved concomitantly with improvement of the diabetic condition.
This diabetic hand stiffness seems to be caused by diabetic neuropathy as well as osteoarthritis of the interphalangeal joints or other neuroskeletal abnormalities of the upper extremities.

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Deliveries of pregnant diabetics in hospitals with more than 200 beds throughout Japan during 1971-1975 were surveyed by means of questionnaires.
In 1975, the number of deliveries by diabetics was 157 out of 100, 431 total deliveries, thus makingthe incidence of delivery by diabetics 0.15%.
Out of 364 diabetic females, 377 deliveries (378 off-spring) were reported during the 5 years of the survey, showing a yearly increase. The mean duration of diabetes before delivery was 3.9 years. During pregnancy diabetics, were treated with insulin in 32.4%, oral hypoglycemic agents in 5.6%, and diet alone in 25.2% of the cases. Untreated patients accounted for 3.7%, mixed treatment for 31.8% and unknown for 1.3%.
Perinatal mortality was 10.8% or 41 of 378 fetuses or newborns, with the highest incidence, 35.7%, in the untreated group, 18.8% in the oral hypoglycemic agent group, 13.9%, in the insulin group and 3.4% in the diet group.
Congenital malformations in fetuses and newborns were found in 21 of 378 babies (5.7%). This incidence was highest in the untreated group and lowest in the diet group concerning malformations. There was no significant difference in incidence between groups treated with insulin and oral hypoglycemic agent concerning congenital malformations.
Concerning complications in newborns, hypoglycemia appeared in 13.6%, respiratory distress syndrome in 9.6%, hyperbilirubinemia in 2.5% and hypoglycemia in 1.1%.
The high incidence of perinatal mortality and congenital malformation in untreated groups during pregnancy emphasizes that strict control of diabetes mellitus is very important for pregnant diabetics.
The survey did not give results indicating that the oral hypoglycemic agents were teratogenic.

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In the previous study, we found that a dose response relationship after intravenous injection of 1.0, 0.1 and 0.01 mg of glucagon existed concerning insulin secretion, but not concerning hyperglycemic response. In the present investigation, the effect of intramuscular injection of 3 different doses of glucagon on hyperglycemic response and insulin secretion was studied in 20 normal subjects to compare with the previous results. For this purpose, 1.0, 0.1 and 0.01 mg of glucagon (Novo) or 2 of these 3 doses were administered to each subject within a week after overnight fasting and serum glucose and insulin concentrations were estimated during a period 2 hours.
1. A dose response relationship was observed concerning hyperglycemic action. The maximum increment of serum glucose was 48.7 ± 3.3 mg/dl with 1.0 mg, 22.5 ± 3.9 mg/dl with 0.1 mg (p< 0.005 vs 1.0 mg), and 4.7 1.2 mg/dl with 0.01 mg (p<0.005 vs 0.1 mg), respectively. When we injected 1 mg, the peak value was obtained after 30 min., and the hyperglycemic response lasted for 2 hours. The peak value and glucose area during the 2 hour period were found to be higher than those in intravenous injection of 1 mg glucagon. The peak time occurred earlier and the duration of hyperglycemia became shorter as the doses decreased. 2. Insulin secretion after glucagon injection, like the hyperglycemic response, decreased as the doses decreased. The Maximum serum insulin (IRI) increment was 44.9±6.9μu/ml with 1.0 mg, 15.7±2.2μu/ml with 0.1 mg (p <0.005 vs 1.0 mg), and 2.5±0.8μu/ml with 0.01 mg (p <0.005 vs 0.1 mg), respectively. When 1 mg of glucagon was administered, the peak value was obtained at 30 min. after injection and the secretion lasted for 2 hours. Although the duration of insulin secretion is found to be longer than that of intravenous injection, the peak value is higher in intravenous injection. The peak time became earlier and the duration of insulin secretion became shorter as the doses decreased.
These and the previous data indicate that intramuscular injection of 1 mg glucagon is best for recovery from the hypoglycemic state. Intravenous administration of 1 mg glucagon is recommended to obtain maximum release of insulin releases.

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A simple in vitro method for detection of igE insulin antibody using the principle ofradioallergosorbent test (RAST) is described.
In 6 patients with insulin allergy, the RAST values were higher than those of normal persons or insulin-treated diabeatic patients without insulin allergy. No difference was observed between normal persons and insulin-treated diabetic patients without insulin allergy.
One patient with insulin allergy showed a gradual decrease of the RAST value corresponding to IgG insulin antibody and clinical allergic syndromes after treatment with Monocomponent insulin.
This method, though it is slightly inhibited by non-IgE insulin antibody and issemi-quantitative, is reproducable and simple. It is, therefore, useful for the detection of IgE antibody against insulin

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The effects were studied of dietary lipid, dietary cholesterol and abministered insulin on 3-hy- droxy-3-methylglutaryl Co. A. reductase activity and serum cholesterol level in normal and alloxan diabetic rat liver.
The normal rats had been maintained on 0%, 5%, 10% or 20% fat-diet for 5 days. The amount of diet fed was adjusted so that each animal was given 60 calories daily. The enzyme activity was stimulated even with the feeding of a 5% fat-diet. The highest activities were obtained with the 10% and 20% fat-diets. The content of fat in the diet apparently regulate the level of the reductase activity, and 10% fat in the diet seems to be enough to achieve the maximum response of this enzyme.
The administration of insulin caused marked and rapid response of HMG-CoA reductase in normal and diabetic rats fed 0% or 10% fat-diet. However the stimulated activities of reductase were higher in animals maintained on 10% fat-diet than in those on 0%. The effects of dietary lipid and insulin administration on the reductase activity were shown to be additive.
On the other hand, the stimulatory effect of dietary lipid on reductase was completely blocked when cholesterol was added to the diet. This result suggests that cholestrol exerts its effect on the reductase activity at the more basic point of regulatory mechanism.
While producing widely different reductase activities, a number of dietary and hormonal manipulations produced no change in the level of serum cholesterol except in a group of diabetics on cholesterol diet. Despite its low activity of the reductase, the serum cholesterol level was slightly increased. This result strongly suggests that hepatic cholesterogenesis is not the sole determinant of serum cholesterol level and that other factor (s) such as catabolism of cholesterol may influence it.

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The progression of diabetic retinopathy in 397 diabetic patients was observed for five years. During this period the eye-grounds were examined periodically.
The results are as follows: 1. The percentage of patients whose conditions of ocular fundus progressed to retinopathy more severe than Scott IV during the five year period was 0.4% in the Scott 0 group, 3.1% in the Scott Ia group, 10% in Scott II group and 23.8% in Scott Ma group, thus increasing together with the development of diabetic retinopathy.
2. The occurrence of diabetic retinopathy in the first year after the beginning of diabetic treatment was significantly higher than that in the second and the following years. The rate of progression of diabetic retinopathy was highest in the first year following the beginning of diabetic treatment, and the difference in the rates of progression between the first year and the third and the following years was statistically significant.
3. The rate of progression of diabetic retinopathy in five years was significantly higher in the group with initial fasting blood sugar of more than 180 mg/dl it was that in the group with less than 139 mg/dl.
Furthermore, the rate of progression of diabetic retinopathy in patients whose retinopathy had progressed in the previous year was higher than that in patients whose retinopathy had shown no progression in the previous year.
4. The progression of diabetic retinopathy in the first year was significantly higher in cases with poor control of diabetes than in those with good control. Moreover, the progression of diabetic retinopathy in the group with initial fasting blood sugar level of more than 180 mg/dl was significantly higher than that in the group with less than 179 mg/dl irrespective of the control of diabetes.
5. In patients whose diabetic retinopathy had progressed remarkably during the five year observation period, such progression occurred during the first year after beginning of therapy in 10 of 22 cases.
6. In the study of the duration of diabetes till first examination, in 22 cases with prominentlyprogressed diabetic retinopathy, the duration in 8 of 10 patients whose retinopathy developed remarkably in the first year after the beginning of treatment was less than five years, and in patients whose retinopathy developed in the second and the following years, those whose duration of diabetes was less than five years were 3 of 12 cases, and their difference was significant.

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In 160 cases of hyperosmolar nonketotic diabetic coma reported in Japan, 28 cases were accompanied by various renal complications. The mortality rate in the cases with renal complications was extremely high. The 28 cases can be divided into two main categories according to serum sodium concentrations: hypernatremia and hyponatremia. The mean serum sodium concentration of the 10 cases in the former group was 165.1 mEq/l. Nine cases in this group died the coma. The main autopsy finding was glomerulosclerosis. The mean value of the serum concentrations of the 16 cases with hyponatremia was 123.1 mEq/l. In addition to hyperglycemia, hyperosmolarity and elevated blood urea nitrogen, the cases in this group showed hyperkalemia and a decrease in plasma bicarbonate and blood pH, which are findings suggestive of metabolic acidosis. Renal complications in the patients of this group were acute or chronic renal failure, glomerulosclerosis, lupus nephritis and various renal infections including renal abscess, pyelonephritis, and necrotizing papillitis. 13 casesdied while in the coma. It is supposed that such patients suffered severe renal complications, before their death. Peritoneal dialysis or hemodialysis were performed on six patients with signs of acutely developed renal failure during the coma and three of them recovered from the coma. It is thought that these therapeutic procedures might be attempted in cases with acute renal failure. Two cases with normal serum sodium concentrations recovered from the coma though they had renal complications.
Six cases with hyponatremia but no renal complications were present in the 160 cases with hyperosmolar non-ketotic coma in this series. They showed a lower level of serum urea nitrogen than the cases with renal complications. There were no deaths in this group.

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As an approach to prediabetes, glucose tolerance and insulin response was studied in 55 “nondiabetic” relatives of a juvenile diabetic patient, whose disease was discovered at the age of 3 years and 3 months.
1) Glucose intolerance was found in 14 of these 55 cases (25.5%), an extremely high frequency The frequency was slightly higher in closer relatives of the first to fourth degree, Group I, than in less close relatives of the fifth degree or over. Especially, in the age group 0-19 years, 2 out of 7 subiects had glucose intolerance. No significant difference was, however, observed between the two groups in the mean serum glucose level of the OGTT except the youngest age group, 0-19 years.
2) The insulin response of the two groups was compared in 35 relatives with normal glucose tolerance. Group I, which was closely related to the patient, had a lower insulin response and lower insulin area/glucose area ratio, than had Group II, which was less closely related.
It was obvious that the insulin response was decreased in close relatives of the juvenile diabetic patient, implying a decreased sensitivity of the pancreatic beta cells to glucose in prediabetes.

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The diameter and internodal length of myelinated nerve fiber were studied in alloxanized diabetic rats, using the teased fiber method after sural nerve biopsy. These biopsy specimens were fixed with 2 % glutaraldehyde solution at pH 7.4 and after osmication with 1 % osmium tetroxide, and were then macerated in 60% glycerol in water. The alloxanized diabetic rats were divided into five groups according to the course before and after administration of alloxan, that is, before administration and 1 week, 2 weeks, 3 weeks and 4 weeks after administration.
There was a positive statistical correlation between fiber diameter and internodal length in the untreated groups control and in the 1 week and 2 weeks groups, but not in the 3 week and 4 week groups.
All the internodes of the untreated control, The 1 week, and the 2 week groups had approximately the same length.
There were variations of node length along the same diameter in the 3 and 4 week groups.
In the 3 and 4 week groups of alloxanized diabetic rats, the main changes observed in the sural nerve were the large diameter and the internodal length, particularly in the distal portion.

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A soluble muscle enzyme which preferentially degrades insulin has been isolated from the supernatant of pig skeletal muscle centrifuged at 100, 000×g. This enzyme was purified 3521-fold by fractionation with (NH₄) ₂SO₄, Sephadex G-200 column chromatography and Ca₃ (PO₄) ₂ gel adsorptionelution. The enzyme was shown to be located mainly in the soluble fraction of the cell. The molecular weight of the enzyme was estimated to be about 140, 000 by its behavior on the Sephadex G-200. The enzyme exhibited a relatively narrow pH range with the optimum activity occuring at pH 7.O. The Km for insulin degradation was estimated to be 112 nM. Marked specificity for insulin degradation was found, and the degradation of insulin was shown to be proteolytic. The enzyme activity was independent of dithiothreitol, whereas N-ethylmaleimide was shown to be a potent inhibitor. These data suggest that a sulfhydryl group in the enzyme molecule is necessary for its activity. Thus, the enzyme could be verified as different from glutathione-insulin transhydrogenase and insulin-specific protease by their, enzymatic characteristics, and from cathepsins by their enzymatic characteristics. Therefore, the enzyme seems to be established as a unique insulin degrading enzyme.
In order to clarify the correlation between the enzyme activity and blood levels of insulin, changes in the activities of the enzyme partially purified from rats under various dietary conditions were observed. The enzyme activity correlated positively only with IRI (r=0.631, p<0.01), and not with body weight and blood glucose. Changes in the enzyme activity were shown to be well correlated with changes in the IRI level, while the increase in the enzyme activity was shown to be inhibited by actinomycin D. These data suggest that the enzyme activity may be regulated with its induction by available insulin.
From the results of the studies on the insulin degrading enzyme and its correlation with blood levels of insulin, it may be concluded that the enzyme degrades insulin with marked specificity and, with its optimum pH in the physiological range, ensures this one enzyme to be the insulin degrading enzyme. Its biological significance is that this enzyme may be one of the factors which regulates the blood levels of insulin.

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Continuous low-dose insulin was infused intravenously into nine patients with diabetic coma (one with hyperosmolar nonketotic coma), and it's effectiveness was evaluated. The amount of insulin infused varied from 5U/h to 10U/h, and the initial blood sugar levels of diabetic patients were from 368mg/dl to 1179mg/dl.
The results are as follows:
1) The insulin in the saline was not adsorbed to the polyethelene syringe used for continuous insulin infusion when the concentration of insulin was 2 or 4U/ml.
2) Similar outstanding improvement of high blood sugar and metabolic derangement was found with continuous low-dose infusion of 5 or 10U regular insulin/h whether or not the serum of patients contained insulin antibody or not.
3) The mean amount of insulin used until the level of blood sugar reached 250mg/dl was 36U, the mean decrease of blood sugar was 124mg/dl/h, and the volume of infused fluid was 2022m1.
4) The total amount of insulin by the old conventional combined IV and SC method in fifteen patients with diabetic coma was on average of 460U.

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Although tolbutamide, a typical oral hypoglycemic drug, is widely used for the treatment of diabetes mellitus, the mechanism of the hypoglycemic effect and the side effects of the drug have not yet been entirely clarified. The author attempted to clarify the distribution of ¹⁴C-tolbutamide in rats after oral administration of the drug by using a whole-body autoradiographic procedure.
Male Wister rats weighing about 100 g were subjected to autoradiography and following results were obtained.
1) ¹⁴C-radioactivity in the duodenum and the colon reached the highest value after three hours and thereafter decreased gradually. In contrast, radioactivity in the cecum and in the rectum increased again after five hours. The radioactivity in the bile duct was very high. Judging from the fact that the concentration in the rectum was far lower than that in the cecum, the major portion of¹⁴C-radioactivity must be reabsorbed between the cecum and the rectum. A small portion of the¹⁴C must be excreted in the feces.
2) The highest concentration of ¹⁴C in the whole body throughout the eight hour observation was in the bone marrow and in the lymph vessels.
3) Radioactivity in the lungs, liver, kidney and thyroid gland was high. Radioactivity in the heart, pancreas, adrenal glands and spleen was also high, but not as high as that in the former group. The radioactivity in adipose tissue and in muscle tissue was very low. The radioactivity in urine bladder was very high, suggesting that the major portion of the ¹⁴C was excreated via the urine.
Judging from above data, the extra-pancreatic effect of tolbutamide may be located in the bone marrow, lymph vessels, lung, kidney, liver and thyroid gland. The effect of tolbutamide o these tissues remains to be elucidated. It is also possible that tolbutamide may have some effect on the heart, spleen and abrenal glands. As the concentration of tolbutamide is very low in adipose tissue and in muscle tissue, the effect of the drug on these tissues may not be present in vivo.

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To evaluate the glucose tolerance and insulin secretion, intravenous high-dose glucose load and oral glucose tolerance test (GTT) were performed in patients with thyrotoxic and idiopathic periodic paralysis.
Blood sugar, serum insulin, and serum electrolytes were determined in twelve male patients with thyrotoxic periodic paralysis and in three male patients with idiopathic periodic paralysis who were subjected to intravenous infusion of 500 ml of 50% glucose solution in 60 minutes and to oral GTT.
Blood sugar levels on intravenous high-dose glucose load and on oral GTT were remarkably increased in the two patient groups compared with the results in normal subjects.
Serum insulin levels on intravenous high-dose glucose load were significantly lower in both patient groups than in the control. A significant increase in the insulin levels on oral GTT was observed in the female group with hyperthyroidism in comparison with the male group of hyperthyroidism, idiopathic periodic paralysis group and normal subjects. Serum insulin levels in patients mith thyrotoxic periodic paralysis were similar to those in the female group with hyperthyroidism. The values of ΔIRI/ΔBS (30 minutes) in patients with idiopathic periodic paralysis were lower than those in normal subjects and the female group with hyperthyroidism.
It may be concluded that there is decreased glucose tolerance in patients with thyrotoxic and idiopathic periodic paralysis, and decreased insulin secretion in patients with idiopathic periodic paralysis. Insulin secretions in patient with thyrotoxic periodic paralysis has a significantly low response to intravenous high-dose glucose load, and very high response to oral GTT.

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A 60-year-old diabetic woman had been treated irregularly with insulin for 15 years. She was admitted to our hospital in March 15, 1974, because of chills and headaches. Further evaluation disclosed bronchopneumonia, hypertension and severe diabetic complications. The symptoms subsided following adequate antimicrobial agent and insulin therapy. On March 8, 1975, intravenous urography was performed. Immediately following the dye injection, the patient became dysuric.
Urine output increased to 2000 ml per day after large doses of diuretics. On the 8th day after the excretory urography, she began to have chills, high fever, macroscopic hematuria and oliguria. Peritoneal dialysis was performed in addition to daily vesical lavage.
She died of terminal uremia which failed to respond to therapy. Autopsy revealed chronic pyelonphritis, severe nephrosclerosis, diabetic intercapillary glomerulosclerosis and an extensive gross bilateral renal medullary necrosis involving all papillae.
In the present case, the arteriosclerotic changes of the cortical glomeruli were more prominent than those of the juxtamedullary glomeruli. In addition to the severe sclerotic changes of the intrarenal arteries and arterioles, it is reasonable to assume that the ischemic necrosis of renal papillae was precipitated by the excretory urography.
Although the currently used contrast media are generally considered safe, careful considerations must be given to the diagnostic usefulness of excretory urography in diabetic patients.

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Twenty-nine unrelated Japanese patients with insulin dependent diabetes mellitus with juvenileonset (JOD) were HLA typed with special reference to family history.
The following results were obtained.
1) The frequency of BJW 22-2, a Japanese specific subclass of BW 22, was significantly (x²y= 20.7) increased in JOD, as a whole, compared with the control group.
2) The frequency of B 5 was significantly (x²=16.4) decreased in JOD as a whole.
3) Of twenty-nine JOD patients, twelve had a family history of maturity-onset diabetes (MOD), and seventeen had no apparent family history of diabetes mellitus. Among JOD patients with a positive family history of MOD, two with an insidious onset and one with a history of obesity before the onset were found. The incidence of ketonuria and emaciation was less frequent in this group than in the group without a positive family history of MOD.
4) In the group with a positive family history no difference in phenotype frequencies of HLA was found when compared with a control.
5) In the group without a family history, the frequency of BJW 22-2 was significantly (x²=19.7) increased and no patient had B 5. The frequency of a positive response in the leucocyte migration inhibition test, using mitochondrial fraction of islet cell as an antigen, was significantly higher in this group than in the group with a family history.
These results suggest a genetical as well as clinical heterogeneity of so-called JOD.

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