In pursuing the pathogenesis of diabetic optic neuropathy, the optic nerve of congenitally diabetic KK mice was observed with an electron microscope As a control, nondiabetic DDY mice with similar weight and age were used. The results were as follows.
1) Disorders of the myelin sheath, edematous change in the axon and the tendency oi enlargement and destruction of mitochondria were recognized.
2) In findings concerning the optic capillaries, the authors observed the thickening of the basement membrane and the reactive changes of the endothelial cells.
3) Glial cells and pericytes of the capillary wall did not show notable changes.
The authors presumed that the thickening of the basement membrane in the retinal and tntraoptical capillaries must play an important role in diabetic microangiopathic eye disease.

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The influences of free fatty acids (F.F.A.) on the uptake of glucose into muscle, adipose and liver tissues of rats were studied in vitro.
The extents of the influences were affected by the kind of the tissues, and the concentrations of glucose and administered F.F.A. in the medium.
When the F.F.A. concentration was equivalent to the normal plasma level of rats, suppression of glucose uptake into the muscle and liver tissues was observed under a condition where 200mg/dl of glucose existed in the medium. Under the same condition, glucose uptake was accelerated in the adipose tissue. When the administered F.F.A. concentrations increased, glucose uptake in the three tissues accelerated.
When a normal plasma level of F.F.A. was administered, suppression of glucose uptake into the muscle and adipose tissues and an output of glucose from the liver tissue were observed under a condition where 100mg/dl of glucose existed in the medum. When the administered F.F.A. concentration increased, suppression of glucose uptake into the muscle and adipose tissues was observed. In the liver tissue, the degree of the output of glucose from the tissue decreased.
When the administered F.F.A. increased, the triglyceride content of the liver tissue significantly increased under a condition where 200mg/dl of glucose existed in the medium.
The influences of the essential fatty acids such as linoleic and arachidonic acids on the glucose uptake were different from those of the other fatty acids.

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The incidence of diabetic gangrene is relatively uncommon in Japan. This paper deals with six patients with diabetic gangrene at the Hospital of the University of Nagoya and a review of 243 Japanese cases. The clinical picture of diabetic gangrene was follows:
1) In recent years this disorder has been reported with increasing frequency.
2) Three quarters of the patients were over the age of fifty, ranging from twenty to eighty years. Males predominated over females by a ratio of 2 to I.
3) In the majority of the cases, the duration of diabetes was over five years, ranging from newly diagnosed to 40 years. In eight cases the diagncsis of diabetes was made when the patients presented foot lesions.
4) Pred.sv.osing causes of this disease were burns, nailcut, trauma and trichophytosis etc.
5) In a high proportion of the patients (82%) fasting blood sugar was over 140mg/dl.
6) he most impressive was the frequent occurrence of an associated involvement of diabetic retinopathy (74%), nephropathy (61%) and coronary sclerosis (55%).
7) The majority of the patients (86%) had advanced diabetic neuropathy. These included pain, paresthesias, sensory impairment, weak or absent tendon reflexes and atonic bladder.
These results showed that diabetic angiopathy could play the most important part in the causation of diabetic gangrene, although the contribution of other various factors (e.g. infections and neuropathy) could not be excluded.

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Plasma immunoreactive glucagon and insulin levels were determined during and following the intravenous infusion of 1-arginine in normal non-obese and obese subjects, and patients with various endocrine diseases and chronic liver diseases. After overnight fasting and absolute bed rest for at least 30 min, patients and normal subjects received an intravenous infusion of 30g of 1-arginine over a period of 45min.
Blood was withdrawn before and then again 5, 10, 15, 20, 30, 45, 60, 90 and 120min after the start of the infusion. Plasma insulin was measured by the double antibody technique of Hales and Randle, and plasma glucagon was determined by the radioimmunoassay method of Sakurai and Imura, with antiserum 30K which is specific for pancreatic glucagon.
In normal subjects, plasma insulin rose significantly within the first 5min of the infusion period and the peak levels occurred at the end of the infusion; plasma glucagon also showed biphasic curves, with the first peak occuring within 10min and the second peak at 45min.
In obese subjects and patients with chronic hepatitis, plasma insulin and glucagon responses arginine to were significantly exaggerated. Patients with Cushing's syndrome, had elevated basal glucagon levels, an d their response to arginine was 300% greater than in normal subjects.
Hyperthyroid patients were characterized by low plasma insulin response and almost normal plasma glucagon response to arginine, whereas hypothyroid patients showed high insulin and glucagon responses.
The significance and pathogenesis of abnorma: plasma insulin and glucagon responses to arginine in these diseases are still obscure at present and must await further clarification.

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Since large doses of xylitol have been infused intravenously to provide calories for nutritional purposes, adverse effects in the clinical use have been reported, particularly that a large amount of xylitol produced lactic acidosis. In this paper, metabolic acidosis caused by lactate accumulation from xylitol, glucose or mannitol was investigated in anesthetized dogs with PCO₂ held constant.
Xylitol, glucose or mannitol were infused intravenously at a rate of 7.6mM/kg/h for 4 hours.
The infusion of xylitol produced a marked accumulation of lactate leading to a significant fall in bicarbonate concentration and in blood pH.
No significant fall in pH and bicarbonate occurred during glucose and mannitol infusion, although the infusion of glucose caused an increment of lactate levels.
It was explained that lactic acidosis caused by xylitol infusion was due to an increased NADH/NAD ratio as a result of the conversion of xylitol to D-xylulose.

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A new method for the quantitative measurement of the vibratory sense was studied.
The equipment consisted of an electrical vibrator with an amplitude measuring device fastened directly to the vibrator head. A determination using this equipment has three characteristic improvements as compared with the usual method, that is, it is capable of determining directly the vibration on the site examined in the body, determining exactly the change of the vibration by a vibration pick-up on the site examined and eliminating an unnecessary vibration using a pick-up filter. A measurement of the threshold was determined by the subject's response during the augmentation of the stimulus intensity on the finger tip.
Preliminary experiments showed that a frequency of 250c/s, weight of 250g on the skin and 28-32° skin temperature were optimal conditions. The thresholds of 119 normal subjects and 83 diabetics were studied and a distinct difference was observed between the two. Also observed was a rise in the threshold with age in both groups. Significant difference between the threshold and the duration of the disease was found statistically in the age group of less than 59 year-old. There was no statistical difference between the threshold and the duration in the age group of more than 60 year-old, FBS or the serum lipids.

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In order to clarify the relationship between the presence of diabetic retinopathy and serum immunoreactive insulin response, 100g oral glucose tolerance test was done to overt diabetic patients.
Blood glucose and serum immunoreactive insulin were determined.
The result is as follows:
The response of serum immunoreactive insulin after glucose loading in patients with diabetic retinopathy was significantly lower than in diabetics without diabetic retinopathy, although the change in blood level sugar was similar between them.

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To determine the direct effect of glybuzole upon the secretion of pancreatic glucagon, 100mg of glybuzole was infused for 10 minutes into the pancreatic artery of six anesthetized dogs.Blood glucose in the femoral artery decreased gradually 15 minutes and later following glybuzole infusion. Plasma insulin in the pancreatic vein rcse from a base line of 164.0±30.6 to a peak of 352.3±99.3μU/m/ at 3 minutes (p<.05). Plasma glucagon in the pancreatic vein de;reased promptly from a base line of 1.34±0.12 mpg/m/ and reached the nadir of 0.92±0.18 mpg/m/ at 6 minutes (p<.05). The glucagon level, however, returned gradually to the initial level after the withdrawal of the glybuzole infusion. To compare the effect of glybuzole with the other sulfonylurea drugs, glybuzole, tolbutamide and glibenclamide were infused successively for ten minutes into the pancreatic artery at 40-minute intervals in a group of three dogs. 100 mg of glybuzole induced a more marked decrease in the plasma level of glucagon compared with 200mg of tolbutamide or lmg of glibenclamide.
Pancreatic glucagon response to arginine infusion was investigated before and after the treatment with glybuzole in 5 diabetic patients. Approximately one month after glybuzole administration, blood glucose levels, either fasting or after arginine infusion, were significantly lower than those before the treatment. Plasma glucagon levels during arginine infusion tests were lower after the glybuzole treatment compared with those before the treatment. Significant changes in the plasma glucagon were observed before and 5 and 20 minutes after the start of the arginine infusion.
These results showed the direct effect as well as the chronic effect of glybuzole upon the alpha cell function of the pancreas.

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A considerably wide range of fasting plasma immunoreactive glucagon (IRG) values has been obtained in healthy subjects using a conventional radioimmunoassay technique even with antiserum 30K, specific for pancreatic glucagon. This wide variation appears, at least in part, to be caused by the presence of non-specific factors in plasma amples which interfere with the glucagon-glucagon antibody reaction and eventually give falsely high IRG values. A correction can be made for this adverse effect by subtracting correction factor (CF) from the “IRG values” of a given plasma sample read against a standard curve obtained by serial dilution of standard glucagon with veronal buffer containing bovine serum albumin. The CF is determined by reading apparent IRG values of glucagon free plasma (GFP) prepared for each sample against a standard curve.
This communication describes a simple and reliable method for the preparation of GFP. 1.5ml of a plasma sample and 60μl of veronal buffer are incubated with 150mg of cellulose powder MN 300HR for 1 hour at room temperature. The incubation is interrupted very 10min by complete mixing with vortex mixer. One ml of supernatant obtained with centrifugal separation at 2500r.p.m. for 20min is transfered to a tube containing 1000 K. I. U. of lyophilized Trasylol and stored at -20° until ssay.
Fasting 1RG levels in 14 healthy subjects determined with the present method using CF were 37±23 (mean±1S.D.) pg/ml, ranging 12 to 96 pg/ml, while the values without using CF were 223±154pg/ml, ranging 78 to 630pg/ml. Therefore, it seems to be quite reasonable to apply the present method to IRG determination.

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The correlation between the clinical-laboratory findings and the histopathological changes of renal glomeruli in forty diabetics of which renal biopsies were performed on 14 cases and autopsies on the remaining 26 cases was studied by the multivariate analysis such as principal component analysis, multivariate regression analysis and canonical correlation analysis.
I have proposed the grading system for the statistical analysis of pathological changes of the renal glomeruli. The abnormal morphological changes such as diffuse lesion, nodular lesion, and arteriolosclerotic changes were picked up in each photographic picture and points were given according to their severity.
Fourteen variables of clinical-laboratory findings such as age of patient, duration of diabetes mellitus, urinary protein, PSP test, edema, BUN, serum total protein, serum α₂-globulin fraction, serum A/G ratio, serum cholesterol, fasting blood sugar, retinal findings, systolic blood pressure and diastolic blood pressure were adopted.
Calculation for multivariate analysis was carried out with the computer NEAC 2200 model 500.Result:
1) Principal component analysis revealed that nine clinical variables (urinary protein, FSP test, edema, BUN, serum total protein, serum α₂-globulin fraction, serum A/G ratio, retinal findings and systolic blood pressure) had close relation to pathological changes of diabetic glomerulosclerosis.
2) The clinical-laboratory score of each patient in order to estimate the pathological changes of diffuse lesion, nodular lesion, and arteriolosclerotic changes respectively was calculated by multiple regression analysis. Multiple correlation ccefficient was.841 (p<.001) for a diffuse lesion, .904 (p<.001) for a nodular lesion, and. 752 (p<.05) for a arteriolosclerotic change respectively.
3) The canonical analysis for predicting pathological changes of renal glomeruli composed the following linear combination formula:
Clinical score=-(.046×age)-(.023×duration) + (.316×urinary protein)-(.717×PSP)-(.099×edema)-(.185×BUN)-(.238×serum total protein) + (.206×serum A/G ratio)-(.161×serum a2-globulin fraction) + (.054×FBS) + (.010×serum cholesterol) + (.323×retinal finiding) + (.114×systolic blood pressure)-(.131×diastolic blood pressure) Pathological score= (.343×nodular lesion) + (.791×diffuse lsion)-(.086×arteriolosclerotic change)
Pathological changes were found to be separated into the following three groups with the agreement of 92.5%:(1) slight to moderate diffuse lesion only, (2) diffuse lesion and slight nodular lesion, and (3) marked diffuse and nodular lesion.
These results show that multivariate analysis is useful in predicting the pathological changes of diabetic glomerulosclerosis and the prognosis of diabetics with nephropathy.

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A 49-year-old male, who had been known as a diabetic since 1966, was admitted to the Saiseika Kanakawaken Hospital on April 12, 1972, due to a mild fever and abdominal distension. On admission, he was noted to have bronchitis, chronic nephritis and liver damage, and he suddenly died of hematemesis on the 64th Lospital day. Autopsy revealed arteriosclerosis and hemorrhagic gastritis, and microscopical examination discicsed multiple necrotic foci and cryptococcus neoformans scattered diffusely in the lungs, liver, kidneys, spleen and pancreas. Most of the Langerhans' islets were damaged with the necrotic foci, although only a few foci were seen in the exocrine pancreas. Hyperglycemia of the patient was mild and was controlled with only dietary treatment.
The diabetes of the patient was thought to be associated with the damages in the islets caused by the cryptococcal infection.

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