We previously reported that heart rate (HR) variation during deep breathing was predominantly affected by the parasympathicus and that the maximum HR increase on standing was influenced predominantly by the sympathicus. According to these HR variation tests, 53 iabetic patients were divided into three groups-24 diabetics without autonomic neuropathy (group A), 13 diabetics with parasympathetic damage alone (group B) and 16 diabetics with both parasympathetic and sympathetic damage (group C). The changes of blood pressure (BP), HR, plasma epinephrine (PE) and norepinephrine (PNE) before and after standing were investigated in 53 diabetics and 15 healthy controls. The increments of BP, HR, PE and PNE after standing were calculated. 4 Systolic BP in controls and groups A, B, and C were +12.4, +3.3, ±0 and -21.5 mmHg, respectively.ΔSystolic BP values in three diabetic groups were all significantly lower than those in controls. Diastolic BP increased after standing in all four groups, but Δdiastolic BP values in groups B and C were significantly lower than those in controls. HR increased after standing in the four groups and ΔHR values in groups A an B were significantly greater compared with those in controls. PE concentrations were unchanged after standing in the four groups, whereas ΔPNE values were+0.253 ng/ml in controls, +0.232 in group A, +0.215 in group B and +0.072 in group C.ΔPNE in group C was significantly lower than the values in the other groups.
In order to clarify the pathogenesis of orthostatic hypotension, the changes of BP and HR in response to standing before and after administration of propranolol (12mg i. v.) were examined in 10 diabetics with orthostatic hypotension, who belonged to group B or C. After administration of propranolol, the diabetics in group C had more remarkable orthostatic hypotension, while orthostatic hypotension was improved in group B
These results demonstrate that abnormal orthostatic BP responses were found even in diabetics without autonomic neuropathy, who had compensatory orthostatic tachycardia, and that with the progress of autonomic neuropathy the compensatory orthostatic tachycardia decreased, producing orthostatic hypotension. Moreover it has been suggested that some diabetics with parasympathetic damage alone have orthostatic hypotension due to hyperfunction of the β-adrenergic system.

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In order to clarify the characteristics of cholinergic neurons in the CNS with respect to glucoregulation, various cholinergic agonists and antagonists were injected into the third cerebral ventricle and changes in hepatic venous plasma glucose, glucagon (IRG) and insulin (IRI) were studied.
Carbachol, muscarine, bethanechol, acetylcholine and methacholine injected into the third ventricle resulted in hyperglycemia. However, no hyperglycemic response was observed after nicotine and DMPP injection into the third ventricle.
The microinjection of neostigmine produced marked and sustained hyperglycemia dose-dependently (1×10^-9-1×10^-7 mole) associated with IRG elevation and relatively lower IRI secretion. Neostigmine-induced hyperglycemia was inhibited by bilateral adrenalectomy.
Coadministration of atropine with neostigmine into the third ventricle prevented glucose and IRG elevation, while hexamethonium did not modify the neostigmine-induced hyperglycemia.
These results suggest that the accumulation of endogenous acetylcholine in the CNS increases in hepatic glucose production through adrenal mechanisms and that the cholinergic receptor in the CNS is of the muscarinic type.

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In this study, we attempted to clarify the problem of discrepancies in interpretation of “good control” in treatment courses of diabetes among specialists in this disease by means of a researod technique never applied before. Data covering two-year treatment courses along with background factors from 279 patients with diabetes type II up to a moderate disease state who were on diet therapy alone or under additional treatment with hypoglycemic agents were submitted to each of the specialists in diabetes (9 persons), who were asked to evaluate the treatment conditions of each case in terms of satisfactoriness. The applied rating scale consisted of a contrasting “satisfactory-unsatisfactory” pair with continuous grading in between. The data from these ratings were then subjected to multivariate analysis and their relation to the examiners was also analyzed. The results showed that the specialists could be roughly divided into two groups: one showing a similarity in preference of items and the other providing similar distances (mildness or severity) of satisfactoriness rating. Out of eight specialists, three belonged to the first group and showed, at the same time, similar “distances”. These three belonged to different institutions than the rest of the examiners and had different clinical experiences. This demonstrates differences of evaluation standards even among specialists. Standardization was therefore felt necessary in evaluating good or poor control of diabetes. For the progress of diabetes treatment in the future, in our opinion, great importance must be placed on continued efforts to determine the goodness or poorness of diabetes control by collecting more data on clinical courses and at the same time by accumulating prognostic information in the long term.

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Leukocyte migration inhibition test (LMT) against a human pancreatic B-cell clone (JHP1-1) was performed in IDDM and NIDDM patients, and healthy controls. Subsequently th, -relationship between the migration index (M.I.%) of LMT and the presence of islet cell cytoplasmic antibody (ICCA) and islet cell surface antibody (ICSA) was examined in IDDM patients. The M.I. values in 17 healthy controls and 34 NIDDM patients were 100±8.5 and 98.3+7.9 (mean±SD), respectively. In contrast, the M.I. values in IDDM patients with and without the presence of ICCA and/or ICSA were 85.4+6.9 and 89.1±10.9, respectively. The M.I. values were more significantly decreased in IDDM patients than in NIDDM patients and controls irrespective of whether or not there were ICCA and/or ICSA in the patients, sera (p<0.01). No relation between the M. I. values and sex, age at onset and duration of diabetes was observed.
Our data suggest that the lymphocytes of IDDM patients might be sensitized by the antigen which was presented in pancreatic B-cells in the past, thus promoting leukocye migration inhibition. Our data also revealed no significant difference of M.I. in IDDM patients with or without ICCA and/or ICSA. These results suggest that humoral immunity may not always be related to cellular immunity.

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Multiple low-dose streptozotocin-induced diabetes in mice is thought to be a model of type 1 (insulin-dependent) diabetes mellitus because it is associated with insulitis. Several investigators have reported that cell-mediated immune response, especially thymic immunity, plays a critical role in the development of this type of diabetes. However, there are no reports concerning antibodydependent cell-mediated cytotoxicity (ADCC) or K-cells. Therefore, we investigated the ADCC of spleen lymphocytes from streptozotocin-induced diabetic mice and compared them with blood glucose levels and insulitis.
Eight-week-old male CD-1 +/+ mice and CD-1 nu/nu mice were studied. Among the CD-1 +/+ mice, increased ADCC and insulitis were found in multiple low-dose streptozotocin-injected mice before diabetes developed and the ADCC increased with the degree of insulitis. However, there was no insulitis or increased ADCC in single high-dose streptozotocin-injected mice or control mice. Among the CD-1 nu/nu mice, increased ADCC and high blood glucose levels were found but there was no insulitis in multiple low-dose streptozotocin-injected mice.
These results suggest that increased ADCC is connected with multiple low-dose streptozotocin injection and may play a pathogenetic role in the development of insulitis in the presence of thymic immunity. Our results also suggest that insulitis enhances the diabetogenic effect of streptozotocin.

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The influence of glucomannan (Konjac mannan) on the fecal bacteria was studied in eight healthy and eight non-insulin-dependent diabetic subjects. Healthy subjects were given isoenergetic diets (1, 955 kcal; mean energy for five days) in randomised order for the first five-days of the control period (six days), and consecutively for the first and last five days of a fiber enriched diet period (20 days; glucomannan 7.8g/day) and for the last five days of a final control period. Diabetic subjects were given a diabetic diet with glucomannan (7.9g/day) for 4 to 20 moths.
Throughout the isoenergetic diet period, the healthy subjects collected their feces in por-Aculture tubes. The diabetic subjects were divided into two groups. In one group, their feces were collected once a month for the first three months, in the other group, their feces were collected for four consecutive months selected between 11 and 25 months.
One gram of feces was mixed with 10 volumes of pre-reduced diluent. Serial dilutions of the specimens were prepared and seeded on plates of media for isolation of anaerobic (Bacteroidacea, B. fragilis, Bifidobacterium, clostridia Cl. Perfringens, Veillonellacea, Lactobacillus, Fusobacterium) and aerobic (streptococci, staphylococci, Enterobacteriacea, yeasts) organisms.
The results showed that no alterations in the flora occurred in either group of subjects.

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Granulocytic elastase (α₁ PI-EL) is a neutral protease contained in the lysosomes of granulocytes which is closely related to inflammation. In addition to its role as a factor in inflammatory diseases, it is suspected that granulocytic elastase has an antiatherogenic effect similar to that of pancreatic elastase.
We have measured plasma al PI-EL levels in 78 diabetic patients, who had no clinical signs or symptoms of inflammation, and the following results were obtained.
1)α₁ PI-EL levels in diabetics were significantly (p<0.001) higher than those in healthy individuals.
2) There was no relationship between α₁ PI-EL levels and other ihflammatory parameters.
3)α₁ PI-EL levels were significantly high in diabetics who had diabetic complications and longer durations of diabetes.
These findings suggest that granulocytic elastase is closely related to clinical aspects of diabetes mellitus, and is expected to become a new index which is available for evaluating diabetic complications.

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To clarify the significance of the parameters for detecting early diabetic nephropathy, urinary (u)-N-acetyl-β-D-glucosaminidase (NAG), u-total protein (TP), u-β₂-microglobulin (β₂MG) and serum (s)-NAG levels were determined in 61 type 1 diabetics who attended a summer camp and had no retinopathy or proteinuria, and in 19 age-, and sex-matched non-diabetic subjects.
1) U-NAG, u-TP and s-NAG levels were significantly higher in diabetics than in non-diabetic subjects, even though the duration of their diabeties was less than 2.5 years. No relation of any parameter with duration of diabetes was found. The incidence of patients having abnormal values was 42% for u-NAG, 27% for u-TP, 14% for u-β₂MG, and 8% for s-NAG.
2) The relationship of each parameter level to five glycemic indices at different periods was investigated. U-NAG was most significantly correlated with the antecedent mean blood sugar level over the previous 7 days (r=0.47), whereas both u-TP and u-β₂MG were most significantly correlated with urinary glucose level at the time of urine collection (r=0.77 for u-TP, r=0.37 for u-β₂MG). No correlation was found between any parameter level and stable HbAi. Multiple variant analysis showed that 32% of u-NAG, 61% of u-TP, 19% of u-132MG and 20% of s-NAG were explained by the five glycemic indices. No relation was observed between any parameter and insulin dose, urinary C-peptide excretion rate, lipid level and so on.
These data suggest that functional alterations in renal tubulus and glomerulus may already occur in diabetics before the development of structural alterations in the kidney, and these alterations appear to be affected by the more recent glycemic levels in different manners.

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The in vitro effect of glucocorticoid on insulin binding, insulin degradation, and glucose transport was studied using rat adipocytes. Isolated rat adipocytes were incubated with or without 0.70μg/ml (1.9μM) of hydrocortisone in TCM 199 medium at 37°C, 5 % CO₂/95% air (v/v), pH 7.4, for 2, 4, and 8 h, and then fat cell insulin binding, insulin degradation and insulin-stimulated 3-O-methylglucose transort were measured. Hydrocortisone did not affect insulin binding in terms of affinity or receptor number. Insulin degradation as determined with column chromatography, was also not changed by the treatment with hydrocortisone. Glucose transport in the absence of insulin was significantly decreased at the incubation time of 2 h and continued to decrease up to 8 h of incubation with hydrocortisone. Decreased insulin sensitivity of glucose transport (i.e., a right-ward shift of the dose response curve) was also demonstrated after 2 h incubation with hydrocortisone, and the ED₅₀ of insulin was maximally increased at 4 h or incubation (0.78 ng/ml for treated vs. 0.49 ng/ml for control cells). Maximal insulin responsiveness was also significantly decreased in treated cells after 8 h of incubation with hydrocortisone. When percentage maximum glucose transport was expressed relative to receptor-bound insulin, the ED50 values of treated and control cells were 10.5 and 7.2 pg of bound insulin, per 2×10⁵ cells, respectively. Thus, it was evident that glucocorticoid induced a post-receptor coupling defect in the signal transmission of insulinreceptor complex. Furthermore, degraded insulin or its degradation process appeared unrelated to insulin action.

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Esophageal candidiasis developed in two insulin-treated diabetics during antibiotic therapy.
Case 1: A 59-year-old female with a 15-year history of diabetes was treated with antibiotics for multiple subcutaneous abscesses. Twenty days after the beginning of the antibiotics treatment, the stool became positive occult blood. Esophago-gastroendoscopy revealed in the esophagus an erythematous mucosa covered with white elevated plaques which were easily peeled off. Smears of these plaques showed the mycelial form of a fungus which were consistent with candidiasis. One week after administration of amphotericin B syrup, endoscopic findings showed marked improvement.
Case 2: A 57-year-old male with a 10-years history of insulin therapy for diabetes complained of anorexia 10 days after the administration of antibitotics for bronchopneumonia. Since the endoscopic appearance was the same as that of case 1, the diagnosis of esophgeal candidiasis was established. After gradual tapering of antibiotic therapy, the bronchopneumonia improved. In spite of the fact that no antifungal agents were used, uniform disappearance of the candidal lesions was noted endoscopically.
Generally, diabetics are susceptible to infection by a variety of organisms including Candida species. Esophageal candidiasis can be a cause of serious and fatal complications such as bleeding, perforation and stenosis. Therefore, careful attention should be paid to this lesion in diabetics during long-term antibiotic therapy.

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A 29-year-old man with marked obesity, weighing 100kg, was admitted to our hospital in a stuporous state. In the last one month, he had complained of general fatigue and thirst. His vital signs were as follows: blood pressure 60/40mmHg, pulse rate 102/min, respiration rate 56/min with shallow breathing and tmperature normal. Laboratory data revealed a blood glucose level of 680 mg/dl, serum osmolarity 385 mOs/L, negative ketone bodies, Na 153 mEq/L, K 4.8mEq/L and Cl 120 mEq/L. Arterial gas analysis indicated a moderate metabolic acidosis with normal anion gap. He was diagnosed as a case of non-ketotic hyperosmolar diabetic coma (NHC) and was treated with a continuous intravenous infusion of Actrapid insulin and massive volume replacement by electrolyte fluids. However, the deterioration of acid-base balance continut d with progression of irespiratory failure and marked combined acidosis occurred. Positive end-expiratory pressure (PEEP) ventilation was immediately initiated. Improvement of acidosis was observed 1.5 h after the initiation of PEEP. Accordingly, the level of blood glucose was normalized. In this case, mechanical compression of the diaphragm by the marked obesity and gastrointestinal atony may have caused the ventilatory failure, thereby worsening the acidosis. Thus PEEP ventilation appeared to be effective in the treatment of NHC with respiratory failure. The levels of serum CPK and aldolase, which increased to 5040mU/In/ and 41.6mU/ml, respectively, on the first day of admission, gradually decreased and were normalized on the 15th day of admission. The mechanism of elevation of these enzymes was discussed.

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