The 24-h urinary excretion of glucosylated albumin (GA) as well as serum GA levels were estimated in 10 normal subjects (N), nine patients with hypertension (H), four patients with asymptomatic hematuria (AH), and 24 patients with diabetes mellitus (DM). GA was determined by the TBA method and expressed as nmol 5-HMF/mg albumin. The urinary GA/serum GA ratio in N averaged 7.7±4.4 (SD), indicating that GA was selectively excreted in the urine. Urinary protein was not found by routine urinalysis in 24 diabetic patients. Nevertheless, the ratio was decreased to 2.2±1.5 in these patients, probably because of the charge selectivity defect due to the glucosylation of the glomerular basement membrare. The urinary GA/serum GA ratio in H and AH did not differ significantly from that in N. The results suggest that the decreased selectivity of urinary excretion of GA may be a specific phenomenon in the early stage of diabetic nephropathy.
The decrease in the urinary GA/serum GA ratio in DM was not elevated to the normal range by treatment for two or three months. It returned to near the normal range when patients' HbAi and serum GA became nearly normal following treatment for one year or more. It was concluded that control of the blood glucose level is important in preventing the initial events in diabetic nephropathy.

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Serum fructosamine (FRS) levels in diabetics were measured by the RocheR “Fructosamine” test. The average basal FRS level was 2.56±0.23 (m±SD) in the healthy controls (n=395) 3.37 0.42 in one group of diabetics (HbA1<10%, n=120) and 4.42±0.64 mmol/L in another group of diabetics (HbA₁>10%, n=50). The differences between the three groups were highly significant (p<0.001). FRS correlated with fasting blood sugar (r=0.643) and HbA₁ (0.825). Clinical observations in the diabetics including diabetic coma and unstable diabetes revealed that FRS reflects the average blood glucose levels of approximately two weeks preceding its determination. Slight diurnal, postoprandial variations of FRS levels were observed in some cases, although rather inconstantly. FRS was significantly elevated in the presence of high serum creatinine (>2.5mg/dl) or bilirubin levels (>3.0mg/dl), while it was significantly low in the presence of hypoalbuminemia (<3.0g/dl). The explanation for these observations awaits further study.
It was suggested that FRS determination may be more useful in monitoring short-term, i.e., approximately two weeks, blood glucose control than HbAi. The test is simple to perform and the results can be obtained quickly. The combination of FRS and HbAi provides useful information regarding the efficacy of therapy, particularly in patients with unstable diabetes.

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A total of 1, 939 non insulin dependent diabetic patients (1, 200 males and 739 females) who were first seen between 1960 and 1979 at our hospital were followed until the end of 1984, a mean observation period of 9.4 years, and their prognosis and associated risk factors were studied.
The mortality rates per 1, 000 person-years during the observation period were 31.35 for males and 21.99 for females, and they tended to increase with age. The O/E ratios, a ratio of observed number of deaths over expected number of deaths, computed based on the mortality statistics from Osaka Prefecture during the study period, were 1.69 and 1.74 for males and females, respectively, increasing as age at entry into the study became younger
The mortality rates and O/E ratios in the age group under 35 years improved markedly during the past 25 years. The mean age at death and the mean duration from onset to death also revealed an apparent improvement during the same period.
It was found that albuminuria was a common risk factor to the mortality of the patients of all age groups, in addition to fasting glucose level and type of treatment for those under 45 years at entry; age, sex, systolic blood pressure, retinopathy, and fasting glucose level for those 45-64 years; and age and sex for those 65 years or older.

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A total of 1, 939 non-insulin dependent diabetic patients (1, 200 males and 739 females), who were first seen at our hospital during 1960-1979, were followed up until the end of 1984, with a mean observation period of 9.4 years, and the causes of death in 503 patients who died were analyzed.
Cerebro-cardiovascular and renal disease accounted for about half of total deaths: among them heart disease was the cause of death in 19.5%, cerebrovascular disease in 16.7% and renal disease in 13.1%. Malignant neoplasms accounted for about a quarter of all deaths. The O/E ratio, or ratio of observed over expected number of deaths, which was computed based on the general population in Osaka, was highest for renal disease, 13.81, and was also elevated for ischemic heart disease. 3.08.
Deaths from renal disease were most prevalent in subjects with an age at onset less than 45 years. On the other hand, the percentage of deaths from ischemic heart disease, cerebrovascular disease and malignant neoplasms increased as age at onset advanced. During the study period, a remarkable increase in deaths from ischemic heart disease was observed, from 8.9% in 1960-1974 to 15.2% in 1980-4984.
The relationship between the baseline characteristics and causes of deah was analyzed. Patients dying from renal disease were characterized by a younger age at onset, a younger age at death and poor control, compared with those who died from ischemic heart disease or cerebrovascular disease.

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The purpose of the present study was to clarify the significance of low serum C₄ levels in the acute stage of IDDM in children. Twenty-one patients whose onset of disease was less than one year ago, were chosen for the study. Of these patients, 11 were ICSA-positive and the remaining 10 were negative for ICSA. Serum C₃ level (63.6± 8.9 mg/dl) and serum C₄ level (20.5±5.3 mg/dl) of the ICSA-positive IDDM patients (n=11) were significantly lower than those (C₃: 83.5 ±25.2 mg/dl; C₄: 33.5±7.0 mg/dl) of control subjects (n=10)(p<0.02, p<0.005)
Serum C₃ levels (77.5±14.1 mg/dl) and serum C₄ levels (33.5±10.1 mg/dl) of the ICSA-negative IDDM patients (n=10) were significantly higher than those of the ICSA-positive IDDM patients (n 11)(p<0.02, p<0.005).
Serum C₄ levels (17.9±4.3 mg/dl) of the ICSA-positivelDDM patients with disease of five or fewer months' duration (n=7) were significantly lower than those (25.3±3.4 mg/dl) of IDDM patients with disease of 6-12 months' duration (n=4)(p<0.02).
Serum C₃ levels were also lower, though not significantly so.
ICSA-positive patients with IDDM of five or fewer months' duration (n=7) had significantly lower mean serum C4 (22.4±4.0mg/dl)(p<0.005) and C3 (73.1±8.6 mg/dl)(p<0.05) levels initially than 1 year later.
These findings suggest the possibility that serum C₄ levels in the acute stage of IDDM in children is determined not only by genetic factors but also by the decrease of serum C₄ levels due to activation of the classical complement pathway.

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Diabetic patients with autonomic neuropathy often show delayed gastric emptying. Delayed emptying of gastric contents may lead to delayed postprandial increase of blood glucose level. In this study, we examined the relationship between gastric emptying time and postprandial insulin requirement (PIRR) as determined by artificial pancreas (Biostator®) during feedback control of blood glucose level, and the possibility of improved blood glucose contorol by the recovery of gastric emptying time.
Gastric emptying time was determined by ^99mTC-Tin-colloid labeled scrambled egg meal served with 2 slices of toast and 200 ml of milk, (590 kcal). PIRR was calculated from infused insulin doses during a 2-hour period after the meal under the artificial pancreas.
Patients without gastropathy had a PIRR of 11.7±5.3 units (M±SD), whereas those with gastropathy had a PIRR of 5.6±2.1 units (during the 2-hour period after the meal, p<0.05). There was a highly negative correlation between the isotope remaining teh stomach and PIRR during the 2-hours after the meal (r=-0.84, p<0.005). Blood glucose control of diabetes was significantly improved by the recovery of gastric emptying time.
Abnormal gastric emptying is an important factor in unstable diabetes mellitus. Normalization of gastric emptying time may be useful in blood glucose control.

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To determine whether normalized glycemic response or normalized insulinemic response is the major factor responsible for maintaining B-cells in a “resting” state in non-insulin-dependent diabetic patients, a series of glucose clamp techniques with simultaneous insulin infusions were conducted.
In healthy subjects, plasma CPR responses against 0.3 U/kg insulin injection or oral glucose load with exogenous insulin infusion were similar to those against 0.1 U/kg insulin injection or oral glucose load without insulin administration, respectively, when plasma glucose concentrations were made identical by glucose clamp techniques. In non-insulin-dependent diabetic patients, hyperglycemia induced identical endogenous insulin secretion, even though the plasma insulin profiles were hypoinsulinemic, normoinsulinemic, or hyperinsulinemic. Normoglycemia suppressed endogenous insulin secretion in both normoinsulinemia and hypoinsulinemia.
These results indicate that in diabetic patients plasma CPR response is dependent on glycemic excursion but not on plasma insulin profiles and that the most crucial factor responsible for suppressing endogenous insulin secretion is establishing the normalization of plasma glucose response.

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A 60-year-old man with advanced chronic complications of diabetes was found to have an elevated serum creatine kinase (6867 IU/l, MM 100%) level during an episode of systemic edema caused by diabetic nephrotic syndrome. There were no myogenic changes causing enzymes to leak from the muscle in electromyogram and muscle biopsy, though slight muscle atrophy and neurogenic changes were found. The patient had neither hypothyroidism nor diabetic ketoacidosis. Therapy for the nephrotic syndrome had not only decreased his body weight and edema, but also the serum creatine kinase and aldolase levels. Although these enzymes increased when he again suffered systemic edema, they decreased to normal levels after normalization of his circulating blood plasma volume by hemodialysis. It is postulated that subclinical neurogenic muscle changes with excess interstitial edema caused the elevation in serum creatine kinase.

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Gangrene of the ear lobes and nose tip developed in a 44-year-old diabetic woman. She had been cooling her forehead and temples with ice, because she was suffering from fever due to pneumonia. A few days later, she found that her ear lobes and nose tip had become black and necrotic, but there was no pain. Diabetic treatment was changed from oral hypoglycemic agents to insulin. Futhermore, local debridement and antibiotics were used. This case suggests that factors such as local cooling or local pressure can cause diabetic gangrene in areas other than the foot.

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We explored whether camostat mesilate, a potent protease inhibitor, could change the blood glucose level in insulin-treated diabetic patients. Administration of camostat mesilate in a dose of 800 mg for one week caused a significant decrease in the basal and maximal level of blood glucose in response to arginine infusion. Camostat mesilate also decreased the maximal level of blood glucagon in response to arginine infusion, while its basal level was not changed by the same drug. Neither the basal level nor maximal response of blood C-peptide was changed by camostat mesilate. It is concluded from the present data that camostat mesilate may be an efficient drug in decreasing the basal and amino acid-induced level of blood glucose in insulin-treated diabetic patients; the latter reaction is attributed, at least in part, to a decrease in the blood glucagon level, but not the blood insulin level, while the former does not depend on these two endocrine factors.

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The purpose of this study was to analyze the cardiac function of diabetic patients. The cardiac index, using the CO₂ rebreathing technique, was determined at rest and after exercise in 20 diabetic patients (NIDDM: 17 males and three females) and in five healthy volunteers as a control (five males). No abnomalities on the electrocardiogram were found in any of the patients either at rest or after exercise.
The results were as follows: 1) In comparison with the control group, there was a significant reduction of the increase in the ratio of the cardiac index in diabetics. 2) This reduction of the increase in the ratio of the cardiac index was recognized in diabetics without any other diabetic complications. 3) These phenomena were in accordance with the degree of diabetic retinopathy.
In conclusion, cardiac dysfunction of diabetic patients during exercise was recognized even in the early stage of diabetes mellitus. This was thought to reflect a decrease in cardiac reserve. Cardiac dysfunction is considered to occur as a result of the following factors: a) abnormalities of contractile protein of the heart muscle; b) metabolic disturbance and c) the structural abnormalities of capillaries in the human diabetic heart as we have already reported.

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The Adhoc Committee on Diabetic Twins was organized in the Japan Diabetes Society in 1984 to collect data on diabetic twins in Japan. During past 3 years, the Committee collected data on 87 pairs of twins, one or both of whom had diabetes mellitus or glucose intolerance. Among them, 63 were monozygotic and 24 were dizygotic twins. Probands, who are defined as those who developed diabetes or glucose intolerance earlier, included 21 patients with IDDM, 56 with NIDDM, one case with diabetes of unknown type, and 9 with borderline glucose intolerance. Physicians in charge of diabetic twins were asked to fill out a form for detailed informations and some additional examinations when necessary. These data were gathered and analyzed by the Committee. The Committee ended the term in 1987 after 3 year's activity, and reports on main results obtained so far.
(1) Concordance rate for diabetes in monozygotic twins was 45%(5/11) in IDDM and 83%(38/46) in NIDDM cases. In dizygotic twins, concordance rate was 0%(0/10) in IDDM and 40 %(4/10) in NIDDM cases. It was significantly higher in NIDDM than in IDDM, and in monozygotic than in dizygotic twins.
(2) Concordance rate was higher in patients with the onset of diabetes above the age of 20 years than in those whose age of onset was below 20 years.
(3) The period of diacordance was not shorter in discordant pairs than in concordant pairs.
(4) In IDDM cases, about 90% lived together at the onset of diabetes, while more than 80% of twins lived separately in NIDDM pairs at the time of onset. This was independent of zygosity and whether they are concordant or discordant for diabetes. It is probably due to the difference of the age of onset of IDDM and NIDDM.
(5) The frequency of positive family history and the prevalence of diabetes in parents and siblings other than co-twins were higher in NIDDM than in IDDM cases, irrespective of whether they were concordant or discordant.
(6) The presence or absence of various complications agreed in 68-97% of concordant diabetic pairs. There were a few pairs discordant for the severity of retinopathy. In these pairs the difference in the duration of diabetes or in the degree of hyperglycemia would explain the difference in severity of retinopathy.
(7) Glucose tolerance test in 6 co-twins of discordant pairs of IDDM revealed that 4 had normal glucose tolerance and 4 had normal insulin response. In 8 co-twins of discordant pairs of NIDDM, normal glucose tolerance was found in only 2 cases and normal insulin response also in only 2 cases.
(8) The thyroid autoantibodies were more frequently positive in IDDM than in NIDDM patients, and the positive and negative tests agreed well between monozygotic twin pairs irrespective of concordance for diabetes. Data on islet cell antibody and HLA antigens were obtained in too few twin pairs to draw any substantial conclusions. All of IDDM patients who were tested for HLA antigens had HLA DR 4.

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