An abnormal cardiovascular response to deep breathing and standing in diabetics with autonomic neuropathy was obtained on evaluation of the “R-R interval variation” in ECG findings.
Fourteen diabetics with autonomic neuropathy showed a significantly lower R-R interval variation both in resting (p<0.02) and during deep breathing (p<0.001) compared to 8 controls who were age-matched.
Furthermore, the “30: 15 ratio”(length of the R-R interval at beat 30 divided by the length of the R-R interval at beat 15) was significantly lower (p<0.001) in diabetics with autonomic neuropathy (0.97±0.05) compared to normal controls (1.16±0.11). The “30: 15 ratio” in 8 diabetics without autonomic neuropathy was slightly lower (1.07±0.07), but not significantly so, compared to normal controls.
A postural fall in blood pressure was noted in the diabetics with autonomic neuropathy, but was independent of the R-R interval variation and “30: 15 ratio”.
Measurement of the R-R interval at beat 30 and 15 can be easily performed and may be employed as a test for autonomic function in diabetes.
Since autonomic neuropathy in diabetes appears to be related to the occurrence and development of diabetic microangiopathy, follow-up studies are considered important.

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We previously investigated the serum immunoreactive insulin response in diabetics with and without diabetic retinopathy. This prompted us to study the relationship between the response of immunoreactive insulin and the development of diabetic retinopathy. A 100g oral glucose tolerance test was performed in 58 cases where the grade of diabetic retinopathy was Scott III a or Scott III b at the time of well controlled diabetes. They still maintained good control of diabetes for one year thereafter. The responses of blood glucose and immunoreactive insulin to 100g oral glucose loading were compared between the groups with and without development of diabetic retinopathy during the one year observation period. The results is obtained were follows.
1) The blood glucose levels after glucose loading in patients with further development of diabetic retinopathy were higher than the levels in patients without development of diabetic retinopathy. A significant difference was found at the 2-hr point after glucose loading. The response of serum immunoreactive insulin after glucose loading was lower in the former than in the latter patients.
2) The ΔIRI/ΔBS ratio at 30 min after glucose loading in the patients with further development of diabetic retinopathy was lower than that in those without development of diabetic retinopathy. The proportion of patients whose ΔIRI/ΔIBS ratio at 30 min after glucose loading was less than 0.1 was 100% in the patients with development of diabetic retinopathy and 31.6% in the patients without development of diabetic retinopathy.
3) The ΣIRI/ΣBs ratio after glucose loading in the group with progression of diabetic retinopathy was lower than that in the group without progression of diabetic retinopathy. The proportion of patients whose ΣIRI/ΣBS ratio was less than 0.1 was significantly higher in the former than in the latter group.

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The relationship between electrocardiographic changes and serum potassium and plasma cAMP levels during insulin-induced hypoglycemia was investigated in 6 normal (group N) and 27 diabetic subjects. Electrocardiograms were recorded, and the blood sugar, serum potassium and plasma cAMP were measured before and at 20 (blood sugar alone), 30, and 60 min after the intravenous injection of 0.05 U/kg of body weight of MC Actrapid insulin. The diabetic subjects were classified as follows: Group D-I consisted of patients who had hypoglycemic symptoms or whose blood sugar decreased to less than 50 mg/dl (N=14), while group D-II consisted of patients who had no hypoglycemic symptoms and whose blood sugar did not decrease to less than 50 mg/dl (N=13).
The fasting blood sugar levels in N, D-I, and D-II were 85.7±3.2 (M±SE), 95.2±4.2, and 137.4±3.2 mg/dl, respectively. The nadir of blood sugar after the insulin injection was 38.2±4.3 mg/dl at 20 min in N, 46.2±2.3 mg/dl at 30 min in D-I, and 96.8±10.2 mg/dl at 60 min in D-II. The T-wave height in the leads I, II, and V5 decreased in all groups. However, the decrease in T-wave height in D-II was smaller than those in N and D-I. The fasting serum potassium levels in N, D-I, and D-II were 4.3±0.2, 4.0±0.1, and 4.2±0.1 mEq/l, respectively. The decreases in their serum potassium levels after the insulin injection were comparable at both 30 and 60 min. The fasting plasma cAMP levels in N. D-I, and D-II were 21.4±1.1, 19.3±1.0, and 20.7±1.7 pmol/ml, respectively. After the insulin injection, the plasma cAMP increased significantly in N and D-I, but did not change significantly in D-II. The peak values in N and D-I were 43.5±7.3 pmol/ml at 30 min and 30.3±2.9 pmol/ml at 60 min, respectively. There was no significant correlation in any group between the decrease in serum potassium and the percentage (%) change in T-wave height in lead V₅ at 30 and 60 min. However, a significant negative correlation was observed between increase in the plasma cAMP and % change of the T-wave height in lead V5 at 30 min in N and at 60 min in D-1.

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Abdominal pain and tenderness are common features in diabetic ketoacidosis, and serum amylase activity is abnormally raised in more than 50% of such episodes. To elucidate the origin and nature of hyperamylasemia in diabetic ketoacidosis, measurements of amylase activity by the Caraway method and analysis of its isoenzyme by cellulose-acetate gel electrophoresis were made in 10 episodes of diabetic ketoacidosis. The transition of amylase activity before and during treatment with small intravenous insulin boluses was investigated. The following results were obtained.
1) The serum amylase activity in each episode was low before treatment. The isoenzyme study revealed that pancreatic-type amylase was particularly decreased.
2) In 3 of 10 episodes, the amylase activity was abnormally raised during treatment with insulin. Isoenzyme analysis demonstrated that salivary-type amylase and not pancreatic-type amylase was responsible for the rise in these 3 episodes. No correlation was observed between abdominal pain and amylase activity.
3) Raised salivary-type amylase returned to normal during the initial 3 days of treatment. The amylase/creatinine clearance ratio was not increased in the 3 hyperamylasemic episodes. There was no clinical manifestation of abnormal salivary glands.
4) These findings demonstrate that pancreatitis is not usually the origin of the increase inamylase activity in diabetic ketoacidosis.
It is suggested that salivary-type hyperamylasemia in diabetic ketoacidosis is most often caused by acute changes of carbohydrate metabolism.

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When the bed-side type of artificial pancreatic beta cell system developed originally by us was applied to diabetics whose insulin sensitivity was low or supernormal, it proved necessary to change parameters manually in order to decide the insulin infusion rates for adaptive control of blood glucose.
In the present study, a computer algorithm for self-adaptive control was establisehed. Firstly, the projected rate of change in blood glucose [ΔBGp (t)] calculated from the relationship between the rate of change in blood glucose concentration and blood glucose concentration during declines from the peak values after 50 or 100 g oral glucose loads in normal subjects, was put into the program. Under blood glucose regulation with the artificial pancreatic beta cell, the real rate of change in blood glucose concentration in each subject [ΔBG (t)] was calculated, and the index of insulin sensitivity was then estimated from the difference between [ΔBG (t)] and Δ(t). According to the calculated insulin sensitivity, the computer automatically changes the parameters which regulate the insulin infusion rate.
Validation of this algorithm was performed in depancreatized dogs which were made ketoacidotic by 3-hydroxybutyric acid infusion or made hyperepinephrinemic by epinephrine infusion. On application of this algorithm, adaptive control of blood glucose in the insulin resistant dogs was carried out by infusing insulin at 2.8 times or 2. 2 times the insulin doses required when 3-hydroxybutyric acid and epinephrine were not infused, respectively.
This artificial pancreatic beta cell system with a computer algorithm for adaptive control represents a suitable research tool for investigating the insulin sensitivity of diabetics or for analyzing the blood glucose regulatory mechanism.

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The ultimate goal of artificial beta cell systems is to control the patients' blood glucose over long periods of time. In view of the difficulties encountered in the development of a portable glucose sensor, a small (15×12×5 cm) and light (700 g) Pre-Programmable Insulin Infusion System was devised for long-term clinical use and applied to 7 diabetics who had to begin insulin therapy. With this system, a microcomputer could memorize the duration and rate of insulin infusion for 24 hr which were obtained by using our bedside-type artificial beta cell. The plasma glucose, immunoreactive insulin (IRI), immunoreactive glucagon (IRG) and immunoreactive Cpeptide response (CPR) to iv insulin by the system were compared in each patient with sc regular insulin given 3 times a day, or with sc intermediate-acting insulin injection once a day on 3 consecutive days. In each patient, the insulin dose per day was set to be the same.
The intravenous insulin provided by the system produced adequate homeostasis and IRI responses, which were almost identical to those of normal subjects. With sc intermediate-acting insulin injection (mean dose, 0.66 U/kg/day), the. IRI profile was monophasic and the IRI peak was found to be only 35μU/ml, indicating that this administration method supplemented only the basic insulin secretion, and marked postprandial hyperglycemia was noted. Although with sc regular insulin injections 3 times a day both the M value by Schlichtkrull and the MAGE index by Service were almost the same as in iv insulin infusion by the system, the number of hypoglycemic episodes amounted to 7 times in 7 patients.
The IRG levels tended to be lower when the plasma glucose response and IRI were normalized by the system than when insulin was injected subcutaneously.
In all 7 patients whose CPR was elevated when the plasma glucose concentration was high with sc intermediate-acting insulin injection, the CPR was kept in the lowest concentration during iv insulin infusion, indicating that the beta cell function was maintained in a resting state.
Thus, as an alternative to the artificial beta cell alone, a combination of an artificial beta cell with a Pre-Programmable Insulin Infusion System was shown to be capable of restoring the circadian blood glucose profiles of diabetics to within the physiological range. This combination is thought to be useful for the long-term treatment of ambulant diabetic patients.

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Although there have been many reports enumerating the various causes of death in Japanese diabetics, we have found few investigations actually dealing with the mortality of Japanese diabetics. To clarify the mortality of Japanese diabetics and the relationship between clinical findings in diabetic patients and their prognosis, we undertook a prospective follow-up study of 1, 629 diabetic patients (898 males, 731 females) who had visited our Diabetes Center during the 12-month period from January through December, 1976. In this paper, we describe the results of this one-year follow-up study, especially regarding the mortality and causes of death in the diabetics.
During the one year follow-up study, only one case dropped out within one year from the start. The death of 31 cases (23 males, 8 females) among the 1, 629 was confirmed at the end of the one-year follow-up study. The mortality of the diabetic patients at our clinic was 1.91%(2.56% in males, 1.09% in females) and was a little higher than that of membets of the general population matched by sex and age, which was 1.63%(2.00% in males, 1.18% in females).
Although the mortality in patients who showed no neuropathy, retinopathy or proteinuria was0%(0/401), the mortality in patients with all of these three diabetic complic tions was 5.91%(12/203).
The main causes of death in the diabetics in this study were myocardial infarction (7 cases), malignant neoplasm (7 cases), diabetic nephropathy (4 cases), cerebrovascular disease (3 cases), and others (10 cases). An increase in myocardial infarction as a cause of death in Japanese diabetics was shown.

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An insulin suppository, has been prepared which is effective in reducing the plasma glucose levels of normal dogs at a dose as little as 2 U/kg. To evaluate its clinical usefulness, alloxandiabetic dogs with a fasting plasma glucose level of above 200mg/100ml were treated by rectal administration of the insulin suppository at a dose of 20 or 50 U per body twice a day for 6 to 9 days. The results obtained were as follows.
1) In dogs whose mean fasting plasma glucose levels were below 300mg/100ml before treatment, a significant reduction in fasting plasma glucose was observed at a dose of 20 U per body, accompanied by a significant decrease in daily urinary glucose excretion. In dogs whose mean fasting plasma glucose levels were above 300mg/100ml, 50U of insulin suppository were effective in reducing daily urinary glucose excretion. In these dogs, however, the decrease in fasting plasma glucose was not remarkable, although these differences were statistically significant.
2) In a few dogs examined for day-to-day variations in plasma glucose and insulin concentrations in response to rectal administration of the insulin suppository, postprandial hyperglycemia was markedly reduced with a coefficient of variation of 13 to 15%, although the peak values of insulin varied day to day between 50 and 130 μU/m/(the coefficients of variation were 30 to 35%).
3) Quantitative estimates suggested that the effectiveness of about 2 or 5 U/kg of insulin suppository was comparable to that of subcutaneous injection of Actrapid Insulin at a dose of 0.2 or 0.5U/kg.
he above results indicate that the insulin suppository is more effective in lowering the plasma glucose and urinary glucose levels than previously reported oral insulin preparations such as W/O/W insulin emulsions or micelles.

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A 60-yr-old woman with diabetic ketoacidosis and with a markedly increased level of serum creatine phosphokinase (CPK) is described. She had been treated with insulin after a diagnosis of diabetes mellitus had been made at the age of 49. On January 12, 1979, she experienced thirst, polydipsia, and polyuria. Two days later, she became somnolent. On January 15, she was admitted to hospital due to loss of consciousness. On admission the patient was in a state of shock. Her blood pressure was 55/30 mmHg, and she had cold extremities and a pulse rate of 116 per min. The body temperature was under 35°C. Respiration was rapid and deep at 24 per min. The blood glucose level was 1672 mg/dl, and the serum Na, K, and Cl values were 124 mEq/L, 7.1 mEq/L, and 81mEq/L, respectively. Serum ketone bodies were positive. Being diagnosed as having diabetic ketoacidosis, she was treated with a continuous low-dose intravenous infusion of Actrapid insulin at 6 U per hr and infusion of saline. The next morning, her consciousness became clear. On January 16, the serum CPK increased to 1710 IU/L despite its having been normal on admission. Two days later, it attained a peak value of 2888 IU/L, and thereafter gradually declined to the normal range by the 12th day after admission. The serum GOT, GPT, and LDH had peak values of 180 IU/L, 96 IU/L, and 768 U, respectively. Electrocardiograms taken during and after the treatment for diabetic ketoacidosis revealed no changes suggestive of myocardial infarction. Examinations for CPK isozymes showed an increased percentage of the MM type (97%) with a small percentage of the MB type (1-2%), As myositis, trauma, and intramuscular injection could be excluded, we concluded that the increase in serum CPK resulted from abnormalities of the muscle cell membrane. The mechanisms governing an increase in serum CPK in diabetic ketoacidosis are discussed.

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