In order to elucidate the effect of metabolic disorders of diabetes mellitus on ventricular function, examination was performed after an overnight fast at 8.00-9.00 a.m. before and after treatment. The echocardiogram (mitral valve), carotid pulse wave, phonocardiogram and electrocardiogram were simultaneosly recorded at a paper speed of 100mm/sec in 18 diabetic patients (7 men and 11 women, aged 40-65 years). They were classified into 3 groups, each of 6 patients: those given insulin therapy (I group), oral hypoglycemic drugs (Sugroup) and diet therapy (D group). From these tracings, QII, ET and IIA-MVO were measured, then PEP and ET/PEP were calculated. The values of PEP and ET were corrected for heart rate using the regression equations of Weissler et al. and were expressed as PEPi and ETi. At the same time, FBS, HbA₁, BP and HR were measured before and after diabetic treatment.
After treatment, FBS and HbA₁ fell markedly in all groups but HR and BP remained unchanged. ETi was increased in all groups, significantly in I group (p<0.01). PEPi was decreased in all groups, significantly in Su group (p<0.05). ET/PEP was increased in all groups, significantly in I group (p<0.05). IIA-MVO was shortened in all groups, significantly in I group (p<0.02).
Our results indicate that cardiac dysfunction (both systole and diastole) occurring in untreated diabetics may be reversed by treatment of diabetes mellitus.

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Fecal wet weight, fecal bile acid and hydroxy fatty acid were measured in 6 patients with diabetic diarrhea (one with pancreatic steatorrhea), 5 patients with simple diarrhea (diarrheal controls), 2 normal subjects with caster oil-induced diarrhea, and 13 healthy controls. Comparisons were made among these groups.
The average daily fecal wet weight of diabetics and diarrheal controls was 410 and 432g/day, respectively and both was significantly increased in comparison to the normal controls.
Average fecal bile acid excretion of the diabetics, normal controls and diarrheal controls was 1009, 305 and 298mg/day, respectively. On the other hand, the average fecal bile acid concentration of the diabetics was almost equal to that of normal controls, but decreased in the diarrheal controls.
Although steatorrhea was no found in the diabetics (in the patient with pancreatic steatorrhea the fecal fat was 23.4g/day, hydroxy fatty acid 13.8%, 3g/day), hydroxy fatty acid was significantly increased (13.4%, 0.21g/day) compared with the normal controls (1.5%, 0.02g/day).
The fecal hydroxy fatty acid excretion in the two normal subjects with caster oil-induced diarrhea was 19.5g/day (30%), and 14.9g/day (56%).
A high percentage of fecal hydroxy fatty acid output and moderate bile acid malabsorption observed in the patients with diabetic diarrhea suggested that there was bacterial overgrowth in the upper intestinal tract and ileal dysfunction.
We concluded that the cause of diabetic diarrhea was not explained by these substances only and in order to determine the pathogenesis of diabetic diarrhea, further investigations are necessary.

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We evaluated the urinary N-acetyl-beta-D-glucosaminidase (NAG) index, albumin (alb) index, β₂-microglobulin (β₂-MG) index, armicroglobulin (α₁-MG) index and serum Hb-A₁c in 29 insulindependent diabetics (IDDM) without proteinuria. We had follow-up studies on Hb-A₁c and the four factors (NAG, alb, β₂-MG and α₁MG) every one or two months for nine months. (1) The values (mean±S. E.) for the NAG index (U/g Cr) in IDDM patients and control subjects were 11.6±1.7 (at the first point) and 3.7±0.2; for the alb index (mg/g Cr), 2.62±0.27 and 1.93±0.20; for the α₁-MG index (mg/g Cr), 18.6±3.1 and 4.8±0.6, respectively. The values for the NAG index, alb index and α₁-MG index were statistically significantly high in IDDM patients (p<0.001, p<0.001 and p<0.05, respectively). The values (mean±S. E.) for the β₂-MG index (μg/g Cr) were 114.0±16.3 and 78.0±6.2. There was no significant difference between IDDM patients and control subjects for the β₂-MG index. (2) There was a statistically significant correlation between Hb-A₁c and urinary NAG index (r=0.66, p<0.001). (3) We classified these subjects into three groups; group I: Hb-A₁c≥7% at the first point and Hb-A₁c with no change or worsened; group II: Hb-A₁c≥7% at the first point and Hb-A₁c improved, group III: Hb-A₁<7% at the first point and Hb-A₁c always lower than 7%. The urinary β₂-MG index was almost within normal range and the urinary alb index was slightly high in the three groups. The urinary α₁-MG index was high in group I and almost within normal range in group II and III, The urinary NAG index was high and fluctuated in group I, in group II group was improved and in group III was almost within normal range.
This study suggests that urinary NAG index in IDDM patients without proteinuria in an important index in blood glucose control.

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In order to evaluate the in vivo effects of different insulin regimens, a glucose infusion test was performed for 24 hours on 23 diabetics; 10 cases were treated with continuous subcutaneous insulin infusion (CSII group), 5 cases with subcutaneous injection of intermediate-acting insulin in the morning (INT group), 5 cases with a mixture of intermedite-and short-acting insulin in the morning (Mix-I group) and 3 cases with a mixture of intermediate-and short-acting insulin in the morning and a mixture of long-and short-acting insulin in the evening (Mix-II group). Insulin effect was expressed in terms of metabolic clearance rate of glucose (MCRG).
In the CSII group, a rather sharp peak of MCRG was detected at 90 minutes after bolus injection.
Accumulated whole day MCRGs in the CSII group, INT group, Mix-I group and Mix-II group were 126.8±50.5, 64.1±27.1, 125.8±38.9 and 136.3±9.5ml/kg/min, respectively. Ratios of MCRG from the morning until midnight to those from midnight until the next morning in the 4 groups were 6.7, 3.9, 6.1 and 5.3, respectively.
In the CSII group, MCRG from 6: 00 to 7: 00 was 80.2% of that from 3: 00 to 4: 00, which was higher than those in INT group (68.4%), Mix-I group (72.0%) and Mix-II group (76.6%).
These results indicate that CSII supplies enough insulin in the daytime and morning, but not such an excessive level of insulin in the middle of the night compared with other insulin regimens.

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Drug compliance of oral hypoglycemic agents was investigated in 282 and 279 diabetic outpatients in 1983 and 1984, respectively. Compliance was estimated by interview and by pill count. When the patients took more than 95% of the prescribed dose, the compliance was evaluated as “excellent”, 75-94% as “good”, 50-74% as “fair”, and less than 50% as “poor”.
Of the patients, 86.2% and 74.8% were evaluated as “excellent” by interview and by pill count, respectively. It was shown that the patients tended to overestimate their own drug compliances.
No sex difference was observed in drug compliance. The “fair” group was older (mean age, 65.7 years old) than the “excellent” group (mean age, 60.2 years old). Drug compliance was best in the morning, more than 90% of the patients being evaluated as “excellent”, followed by the evening prescription, and was poorest at noon. The number of drugs did not affect the compliance. The duration of drug administration and that of diabetes showed no influence upon compliance, suggesting that the individual characters of the patients played an important role in the drug compliance.
Drug compliance for antihypertensive drugs was worse than that for oral hypoglycemic agents in diabetics to whom both kinds of drugs were prescribed.
No significant correlation was observed between the drug compliance and the fasting blood glucose or glycosylated hemoglobin values.
Drug compliances were comparable in 1983 and 1984 as a whole, but those of individual patients varied between years.

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The incidence of persistent albuminuria among diabetic patients who had negative or trace albuminuria at the baseline of the follow-up and associated risk factors were studied. The subjects studied were 1, 196 type 2 diabetic patients who were observed until the end of 1984, for a mean follow-up period of 10 years.
1) One hundred ninety-three (16.1%) patients developed persistent albuminuria with a mean period of 11.1±6.9 years after the onset of diabetes with a male preponderance. Among them, 66 (34.2%) died during the observation period, with mean period of 3.0 years after the onset of albuminuria. The prognosis of this group was extremely poor, since the mortality rate among the patients who did not develop persistent albuminuria was only 17.6%.
2) The development of persistent albuminuria was associated with age, durating of diabetes, systolic blood pressure, fasting plasma glucose, presence of diabetic retinopathy and type of treatment at entry. Patients with trace albuminuria had a significantly higher incidence of persistent albuminuria than those without albuminuria at the initial visit baseline.
3) The patients who developed albuminuria revealed a longer duration period, higher systolic blood pressure and plasma glucose level, higher prevalence of retinopathy and relatively higher frequency of treatment with oral hypoglycemic agents or insulin than that with diet.

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Celiac ganglia obtained at autopsy in three diabetics were studied and compared with control groups consisting of non-diabetic patients. In each case, the sections were stained with hematoxylin eosin and examined by light microscopy.
In the celiac ganglia from these patients, many satellite cells were hypertrophic due to accumulation of hyaline material in the cytoplasm; the nucleus in such cells was at the periphery. At this stage, the morphological change of the ganglion cell adjacent to the affected satellite cell was not obvious. With larger swelling, nuclear breakdown in the satellite cell and pressure against the adjacent ganglion cell were seen. As for the pressed ganglion cell, the following changes were found:(a) lipofuscin, (b) chromatolysis or local disappearance of Nissl bodies, which are arranged along the periphery of the nerve cell body under normal conditions, (c) dendritic swelling, and (d) deep penetration of the satellite cells into the cytoplasm of the ganglion cells. Particularly, lipofuscin and the local disappearance of Nissl bodies had a tendency to be observed in the only part adjacent to the swollen satellite cell. When the swelling of the satellite cell was striking, to the extent that the cytoplasm was sparse and scattered, the adjacent ganglion cell was flattened and appeared to be giant in the view from a certain angle. The final stage in the process was disappearance of the swollen satellite cell and the adjacent ganglion cell, leaving an empty and large space.
Though thickening of vessel walls was sometimes seen, neither endothelial proliferation nor vascular obstruction was found in the affected celiac ganglia. The swollen satellite cell was also observed near the vessel without morphological change. Generally, ischemic change of the satellite cell is mainly vacuolar degeneration. These facts give rise to the possibility that metabolic disorders play a more important role in the damage of the satellite cells than ischemic effect. Moreover, the local disappearance of Nissl bodies, in which protein synthesis takes place vigorously, suggests that transport of nutrients such as amino acids from the satellite cells to the ganglion cells is imparied because of damage of the satellite cells.
Because the neuropathological changes of the satellite cells preceded those of the ganglion cells, it is implied that the lesion of the satellite cells is profoundly related to the occurrence of diabetic autonomic neuropathy in celiac ganglia.

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In order to assess the changes occurring in the central nervous system function of patients with diabetes, the auditory brainstem response (ABR) was recorded. Interpeak latency (IPL) as well as new analyses for measuring the changes in the wave latencies under high power and low power stimuli were determined in order to evaluate the correlation between ABR and other complications of diabetes.
Fifty three diabetic patients (19 males, 34 females, mean age 41.9±9.8 years) and 35 age and sex matched healthy subjects with no hearing deficit were tested. The ABR was recorded by a DISA system 1500 elicited with binaural white click stimuli with a 10 msec analysis time set from 60 dB to 120 dB. The repetition rate was 10 Hz and ABRs were recorded from scalp electrodes placed on the vertex, with reference to the linked ears. The responses were summed 1000-2000 times on average.
1) In diabetic patients, the resolution of the ABR was poor, especially for low power stimuli more summation was needed than in normal controls.
2) The latency of the wave V was not significantly different between diabetic patients and normal controls for 120 and 110 dB stimuli. However, for 100-60 dB stimuli, the latency of the wave V in diabetic patients was rapidly prolonged in comparison with normal controls.
3) The difference in the latency of the wave V between 120 dB and 60 dB stimuli was 2.00±0.41 msec in diabetic patients and 1.52±0.29 msec in normal controls (p<0.001). It was prolonged significantly in patients with peripheral neuropathy, autonomic neuropathy, and a long history of diabetes in comparison with patients without these factors. A tendency of prolongation in patients with the proteinuria, retinopathy and poor blood sugar control was observed in comparison with patients without protinuria and retinopathy, and patients with good blood sugar control. However, in patients without peripheral neuropathy, proteinuria and retinopathy, and in patients with a short history of diabetes and good blood sugar control, the difference in the latency of the wave V between 120 dB and 60 dB stimuli was significantly prolonged in comparison with normal controls.
4) IPL of the waves I and V was 4.23±0.37 msec in diabetic patients and 3.95±0.32 msec in normal controls (p<0.001). IPL of waves III and V, and IPL of waves I and III were also prolonged in diabetic patients (p<0.005, p<0.05).
This new form of analysis for measuring the changes in the wave latencies under high power stimuli and low power stimuli in ABR was considered to be very useful for evaluating neurological abnormalities of the central nervous system in diabetic patients.

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In 388 type 2 diabetci patients who had not received any prior treatment up to their initial hospital visit, the relationship between diabetic retinopathy and clinical variables obtained at their first examination was analyzed.
At the initial examination, the prevalence of retinopathy was 15.2%(59/388). In the patients with retinopathy, the time interval between diagnosis of diabetes and initiation of treatment was longer and the sum of the blood glucose levels of the 50g oral glucose tolerance test (50g OGT) was higher than in those without retinopathy (the time interval; 3.63±3.27 yr vs. 1.64±3.01, p<0.001; the sum of blood glucose levels at 0 min, 60 min and 120 min. of 50g OGT; 951±234 mg/dl vs. 822±262, p<0.001). With respect to patients without retinopathy at the initial visit, the cumulative incidence of retinopathy after the initiation of treatment was analyzed by the life table method and Gehan test. In the patients who had a higher blood glucose level and/or longer time interval between diagnosis of dibetes and intiation of treatment, the incidence of retinopathy was significantly higher than in those who had a lower blood glucose level or shorter time intrval. In addition, the patients who were suffering from retinopathy at the time of analysis were thinner at the initial examination than those who did not suffer from retinopathy (% ideal body weight; 104±17.3% vs. 108±15.8, p<0.05). In the thinner patients at the initial examination (%, ideal body weight≤100%) who gained weight thereafter, in particular, diabetic retinopathy developed most easily. In contrast, diabetic retinopathy was not correlated to whether or not hyperglycemic symptoms, such as thirst, polydipsia and polyuria, were present at the initial hospital visit.
These data indicate that the patients whose blood glucose level was high, whose time interval between the diagnosis of diabetes and the initation of treatmept was long and whose body weight was low at the initial examination had a high risk of subsequent development of diabetic retinopathy.

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We injected female NOD mice with human interleukin-2 (IL-2) or mouse interferon γ(IFNγ) derived from recombinant DNA, or streptococcal preparation (OK-432), known to be a potent immunomodulator and used for human cancer immunotherapy in Japan, in order to observe the effects of these biological response modifiers (BRM) on the onset of insulin-dependent diabetes mellitus (IDDM).
Control (saline-treated) NOD mice showed massive glycosuria after 10 to 14 weeks of age and approximately 80 to 90% of the mice developed diabetes before 24 weeks of age. In the IL-2 or IFNγ-treated female NOD mice, the time of onset of diabetes was delayed as compared with that of the control NOD mice. On the other hand, mice that weekly received an intraperitoneal injection of 0.2 mg of OK-432 per mouse from 4 to 24 weeks maintained normoglycemia and did not develop diabetes until 24 weeks of age when the experiment ended.
Histologically, almost all the islets in the OK-432-treted NOD mice were intact or only mildly infiltrated with mononuclear cells, whereas all the islets showed severe insulitis in the control mice. Natural killer cell activity assayed as one of the markers of cellular immunity recovered in the OK-432-treated NOD mice to the level of age-matched ICR mice used as a control. Body weights of the OK-432-treated NOD mice were not different from those of the control mice before the onset of diabetes.
These results indicate the possible effects of BRM in the prevention of human IDDM.

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We report a 42-year-old diabetic patient with alcoholic cirrhosis who exhibited severe insulin resistance. He was admitted to our university hospital in a decompensated state of cirrhosis in August 1984. He had been hospitalized four times previously because of alcoholic liver injury and had been diagnosed as diabetes mellitus at the age of 37. Since then he had had good glycemic control with diet and/or oral hypoglycemics.
On admission, hyperglycemia was noticed, and insulin treatment was begun soon. Even after his liver function became well-compensated in several weeks, the hyperglycemia was unresponsive to large doses of subcutaneous insulin, whicn reached more than 200 U per day. In an attempt to clarify the mechanism of insulin resistance, we examined this patient in several ways, obtaining the following results. Anti-insulin anti-bodies were not detected in his serum. Of all hormonal insulin antagonists, plasma glucagon and growth hormone levels were increased, but within the range commonly seen in cirrhotic patients. Serum insulin degrading activity was shown to be temporarily increased, corresponding to the time course of his insulin resistance. Insulin binding to erythrocytes was almost normal. No anti-insulin receptor antibody was found. Euglycemic clamp study revealed a shift of the insulin dose-response curve, indicating a marked decrease in insulin responsiveness. In addition, the calculated metabolic clearance rate (MCR) of insulin was increased.
These data suggest that, in this patient, the main cause of the insulin resistance was postreceptor defects. However, an activated degradation of insulin in the tissues as suggested by the increased MCR of insulin may be an additional factor responsible for the massive insulin requirement in this patient.

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The effects of gliclazide on the oxidative phosphorylation of isolated rat liver mitochondria were studied using an oxygen electrode. Addition of gliclazide to medium caused uncoupling of the mitochondria, and complete uncoupling occurred at the concentration of 140 mg/dl. It has been reported that diabetic patients receiving 160 mg of gliclazide orally showed 5 mg/dl concentration in the peripheral venous blood, 3.6% of the complete uncoupling dosage of the drug (140 mg/dl). Addition of 0.5 g or 0.05 g of albumin in the medium partially restored the complete uncoupling of rat liver mitochondria induced by 140 mg/dl of gliclazide.
Since gliclazide found in the blood is mostly in albumin-bond form, the present results indicate that gliclazide administered orally does not reveal its uncoupling action in vivo.

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Many reports have shown that vagal neural efferent pathways affect the secrtion of insulin and glucagon. However, afferent pathways that might affect this system have received little attention. The present study was carried out to examine the role of the hepatic branch of the vagus nerve, which is composed mostly of afferent fibers in the rat and is a major afferent pathway between the liver and the medulla, in the secretion of insulin and glucagon after the intraperitoneal injection of arginine (1g/kg body weight) in rats. Measurements were made one week after section of this branch. Intraperitoneal arginine enhanced both plasma insulin and glucagon concentrations more in hepatic-vagotomized than in sham-vagotomized rats.
The results suggest that inhibition of the secretion of insulin and glucagon after arginine stimulation is mediated by the hepatic branch of the vagus nerve. The existence of “sensors” in the liver for arginine is proposed as an explanation for the inhibition of the secretion of insulin and glucagon by the hepatic vagus nerve.

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