Organ homeostasis in humans is maintained by the “auto-regulatory system.” Although this biological regulatory system is regarded as complicated and difficult to analyze, with the aid of control theory it has become possible for us to construct a mathematical model. To date we have created models for waterelectrolyte balance and glucose metabolism. The validity of these models has been evaluated by simulation study. As a clinical application of the model, we have successfully developed an artificial pancreas system for the treatment of diabetic patients. Through this system, we have made many contributions to the study of clinical nutrition and we feel that this has initiated a new era in this field. In order to make further progress in this field, it will be necessary to take a new dynamic and systemic approach.
To investigate myocardial ischemia during exercise, submaximal exercise testing with electrocardiogram and thallium 201-myocardial scintigraphy was performed in non-insulin-dependent diabetics. The relationship between plasma atrial natriuretic polypeptide (ANP) levels in response to exercise and cardiac function assessed by echocardiography was also examined. The following results were obtained: 1) Twelve of the 66 diabetics (18.2%) had ischemic ST-segment changes in exercise ECGs, compared with 4 of 75 control subjects (5.3%)(p<0.05). Of the 12 diabetics with positive exercise ECGs, 10 were asymptomatic. 2) The washout rate in thallium-201 myocardial scintigraphy was significantly less in diabetics with positive exercise ECGs (36.5±4.1%) than in controls (51.9±2.8%)(p<0.05). 3) Although no difference in heart rate were observed between diabetics and controls, diabetic patients had significantly higher systolic blood pressure than controls during all stages of exercise and at maximal exertion. Rate pressure products in stages 1 and 2 were significantly higher in diabetics than in controls. 4) The increase of plasma ANP concentration during moderate exercise (VO2 max 60%) was significantly greater in diabetics than in controls (32.3±11.9 pg/ml vs. 15.0±1.7 pg/ml)(p<0.02). 5) There was a significant correlation between the increase in plasma ANP during exercise and the levels of left ventricular diastolic function (A/R:r=0.504, p<0.05, IRT:r=0.587, p<0.02), assessed by echocardiography, in diabetics. In conclusion, this study demonstrated that the frequency of asymptomatic myocardial ischemia during exercise was higher in diabetics than in controls. Furthermore, the exaggerated response of plasma ANP to exercise may be useful for the medical evaluation of diabetics in exercise therapy.
To evaluate the relationship between cardiac function at rest and the exercise capacity of diabetic patients, left ventricular function and exercise capacity were evaluated in 15 non-insulin-dependent male diabetic patients. Isovolumic relaxation time (IRT) and the PEP/LVET ratio were obtained by simultaneous echophonocardiograms, electrocardiograms, and recordings of the carotid arterial pulse. VO2 at anaerobic threshold was obtained from a cycle ergometer exercise test with expired gas analysis. Patients were divided into two groups: those with IRT<90 msec (Group 1) and those with IRT≥90 msec (Group 2). Group 2 patients had a lower VO2 at anaerobic threshold than Group 1 (Group 1:17.4±3.6, Group 2:12.9±2.5ml/min/kg; M±SD, p<0.05). There was a good correlation between the IRT at rest and ΔHR, defined as the change in heart rate from rest to anaerobic threshold (r=0.666, p<0.01), and between ΔHR and the beat-to-beat variation in R-R interval at rest (r=0.637, p<0.02). There was also a good correlation between VO2 at anaerobic threshold and IRT (r=0.555, p<0.05), and between VO2 at anaerobic threshold and ΔHR (r=0.858, p<0.01). Our data suggests that both left ventricular diastolic function and cardiac sympathetic nervous system reflexes, reflected by ΔHR, may affect the exercise capacity of diabetic patients. Thus, IRT obtained by a non-invasive method may provide a useful index for cardiovascular response to exercise in diabetic patients without coronary artery disease.
For perfect glycemic control in diabetics, therapeutic modalities which enhance impaired hepatic glucose uptake seen in diabetics should be utilized. In animal experiments, we demonstrated that factors promoting hepatic glucose uptake are the glucose gradient between the central nervous system and the hepato-portal system, portal hyperinsulinemia and normal premeal glycemia. Therefore, we investigated both the effects of intensified insulin therapy and a single bout of exercise on hepatic glucose uptake by euglycemic hyperinsulinemic clamp combined with oral glucose loading. In 56 out of 77 patients, perfect glycemic normalization was established with mean regular insulin doses of 10, 7, 7 U at breakfast, lunch and dinner, respectively. The ratio of splanchnic glucose disposal to the amount of ingested glucose increased significantly from 19.0 to 42.1%. A single bout of exercise enhanced hepatic glucose uptake from 23.4 to 50.5%. Both strict glycemic regulation and exercise enhance hepatic glucose uptake significantly in non-obese diabetic patients.
Total body bone mineral content and bone mineral content in various body sites were measured by dual-photon absorptiometry in 103 patients with non-insulin-dependent diabetes mellitus (NIDDM) and the findings were compared with those for 214 non-diabetic control subjects matched for age and body weight. Neither total body bone mineral content (TBBM) nor the bone mineral density of the third lumbar vertebra (L3 BMD) in the diabetic subjects differed from the values in control subjects of either sex, but the values were significantly decreased in patients diseased for at least five years when compared with control subjects. Regional bone mineral measurement showed prominent bone loss in the truncal site, but no reduction in bone mass was found in the head, pelvis, arms, or legs in either male or female patients. These results suggest that reduced TBBM and L3 BMD are associated with duration of the disease and that a site-specific bone defect is present in NIDDM.
Calcium metabolism was studied in patients with diabetes mellitus. Information on the dietary intake of major nutrients was gathered from 23 non-insulin-dependent diabetic patients, 42 insulin-dependent diabetic patients and 245 nondiabetic patients under hemodialysis through a questionnaire. A calcium absorption test was performed, using an isotopic technique, in 11 non-insulindependent diabetic patients and 4 age-mathced healthy subjects. Parathyroid function was examined, using oral phosphate loading, in 6 diabetic patients and 6 age-matched control subjects. The daily dietary intake of calcium in the non-insulin-dependent diabetic patients (602±52mg) was up to the average daily nutritional requirement (600mg). The calcium absorption rate in these patients (54.4±13.9%) was similar to that in the healthy subjects (50.1±5.4%). The response of parathyroid hormone to phosphate loading was significantly reduced in the diabetic patients compared to the control subjects. The results suggest that calcium homeostasis in diabetic patients with normal renal function is almost conserved, despite the decreased response of parathyroid hormone to phosphate loading.
We examined changes in high density lipoprotein (HDL) metabolism during a very low calorie diet weight reduction program in 6 massively obese normolipidemic women. The diet protocol consisted of a 1st low calorie diet (LCD; 1440, 1280, and 880 kcal daily for 1 week, each, in succession), a 1st very low calorie diet (VLCD; 420 kcal daily for 4 weeks, using Optifast 70), intermission (880 kcal daily for 1 week), the 2nd VLCD (4 weeks) and the 2nd LCD (880 and 1280-1440 kcal daily for 1 week, each). Mean body weight reduction was 18.9 kg. HDL-cholesterol, more specifically HDL2-cholesterol, reduced transiently during the 1st VLCD, intermission, and 2nd VLCD periods, and tended to increase in the 2nd LCD. Apolipoprotein (apo) A-I showed a similar change to HDL-cholesterol. However, apo A-II decreased persistently throughout the weight reduction program, and the apo A-I/apo A-II ratio increased significantly in the later part of the program. Serum triglyceride, apo B, and lipoprotein lipase (LPL) activity in post-heparin plasma did not change. These data suggest that the observed decrease in HDL-cholesterol was not due to a reduction in very low density lipoprotein-derived HDL production or to an LPL deficiency, but was consistent with reduction in chylomicron-derived HDL formation following dietary fat restriction.
Total body and regional bone mineral density (BMD) and bone mineral content (BMC) in obese patients and healthy controls were assessed by dual-photon absorptiometry (DPA) in this study. In both men and women, BMD values in total body, pelvis, upper and lower extremities were significantly (p<0.05) higher in the obese group (body mass index>28) than in the non - obese group (body mass index<23). These BMD values correlated significantly with body weights and with percentages of body fat. In the obese group, 8 massively obese women were treated with an 8 - week very low calorie diet (VLCD), resulting in a 13.4kg of mean body weight reduction. Although BMC in total body and in pelvis were maintained, significant decreases of BMC in the upper (from 275±30 to 255±26 g) and lower (from 871±47 to 805±31 g) extremities were observed following the 8 - week VLCD treatment. These results suggest that body fat mass affects BMD and BMC preferentially in weight bearing bone, the changes of which are not always associated with changes in total body BMD or BMC.
We developed an in vivo ultrasonic attenuation measurement system with which we attempted to evaluate the degree of fatty infiltration in the liver. In an animal study, fatty liver was induced in rabbits, and ultrasonic radiofrequency waveforms from the liver were obtained using a 10 MHz A mode transducer. Frequency-dependent attenuation of the ultrasound, which was correlated with total lipid content, was calculated using a spectral difference method. In a human study, ultrasonic waveforms were obtained using a 3.5 MHz transducer. Frequency-dependent attenuation also showed a significant correlation with the grading of fatty infiltration of the liver. These results suggested that fatty infiltration of the liver could be evaluated quantitatively and noninvasively using frequency-dependent attenuation of the ultrasound.
Dipeptides injected intravenously or added to liver perfusion medium were hydrolyzed rapidly to amino acids. The clearance volumes per min of plasma Gly-Phe and Gly-Lys were 63% and 224%, respectively, of the total plasma volume. These values far exceed the blood flow in any single organ, suggesting that several organs must be involved in peptide assimilation. Intravenous administration of peptides increased the levels of their constituent amino acids in organs. Two possible explanations for this were assimilation of the peptides by the organs, and transport into the organs of the amino acids generated by extracellular hydrolysis of the peptides. The former possibility was tested by eliminating plasma lysine by enzymic degradation, so that the amino acid would accumulate only in the organs that assimilate lysine-containing peptides. Results showed that all organs tested, except the brain, had an intrinsic ability to assimilate peptides.
To determine the effectiveness of dietary protein restriction on proteinuria in patients with non-insulin dependent diabetes (NIDDM), 14 diabetic patients with overt nephropathy were placed on either a low protein diet (N=7) or conventional protein diet (N=7) for one month. After the study period, daily urinary protein excretion rates decreased significantly, from 3.2±0.4 to 1.9±0.4g/day, and serum albumin levels increased from 3.3±0.2 to 3.7±0.5 g/dl only in the low protein diet group, without any significant changes in either serum creatinine levels or creatinine clearance. These findings suggest that dietary protein restriction has a beneficial role in the treatment of NIDDM patients with overt nephropathy.
The mechanism by which resistance to 1, 25 dihydroxyvitamin D3 (1, 25-(OH)2D3) occurs in patients with chronic renal failure was studied. This agent induces differentiation and 1, 25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid-hormone receptor mechanism. HL-60 cells were cultured in RPMI 1640 medium supplemented with 10% normal or uremic serum. Treatment of these cells with 10-8M 1, 25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in a maturation of the cells amounting to 30.3 ± 18.7% (mean ± SD) and 32.5 ± 11.2%, as obtained by NBT reduction assay and NSE assay, respectively. These values were significantly lower than those obtained with 10% serum from 3 normal controls (66.6 ± 12.8%, 58.3 ± 10.9%, p<0.02). The treatment of HL-60 cells with 1, 25-(OH)2D3 in a mixture of 5% normal plus 5% uremic serum caused cell differentiation to an extent similar to that in 10% uremic serum, which suggests the presence of a substance(s) having 1, 25-(OH)2D3-inhibitory activity in the uremic serum. Exposure of HL-60 cells to uremic serum significantly impaired their responsiveness to 1, 25-(OH)2D3 as assessed by the induction of the cell's ability to hydroxylate the C-24 position of 1, 25-(OH)2 [3H] D3. The mechanism by which uremic serum confers an impaired cellular response to 1, 25-(OH)2D3 seemed to be due, in part, to a decrease in 1, 25-(OH)2D3 receptor levels. A significant positive correlation was observed between intracellular cAMP levels and 1, 25-(OH)2D3-induced HL-60 cell maturation. In summary, the mechanism by which uremic serum confers 1, 25-(OH)2D3 resistance upon HL-60 cells seemed to be due to the presence of 1, 25-(OH)2D3-inhibitory activity in uremic serum, which may modulate cellular responsiveness to 1, 25-(OH)2D3 by such mechanisms as reducing 1, 25-(OH)2D3 receptor levels in the cells, in part through alteration in cAMP metabolism.
Phosphorus (P) retention plays an important role in the pathogenesis of secondary hyperparathyroidism (2nd HPT) in chronic renal failure. In recent years, periodic intravenous or intermittent oral administration of high doses of 1, 25(OH)2D3 has been reported to improve severe 2nd HPT in hemodialysis patients. The present study was performed to determine the effects of dietary P restriction on 2nd HPT in hemodialysis patients treated with intermittent oral high-dose 1, 25(OH)2D3. A high dose of 1, 25(OH)2D3 was administered orally twice a week at the end of hemodialysis in 20 hemodialysis patients with 2nd HPT. Dietary P content was estimated from records of the patients' food intake, made twice during the treatment period. Based on this information, dietitians developed appropriate meal plans and instructed the patients. After 8 weeks of the treatment, serum c-parathyroid hormone (c-PTH) and alkaline phosphatase (ALP) levels decreased significantly, from 18.8±1.9 ng/ml and 347.1±30.7 U/liter to 9.4±1.2 ng/ml and 268.3±19.6 U/liter, respectively. Serum P levels increased gradually during the first 4 weeks of the treatment. Dietary P intake was reduced significantly, from 908±49 mg/day to 734±39 mg/day, after the nutritional instructions. As a result of the dietary P restrictions, serum P levels were significantly decreased in the 8th week as compared with those in the 4th week. Serum Ca levels remained unchanged throughout the observation period. There was a significant relationship between the mean values for serum P levels during the study and the percent suppression of serum c-PTH. These results suggest that dietary P restriction facilitates serum P control without increasing doses of phosphate binders, and that this ameliorates 2nd HPT during intermittent oral high-dose 1, 25(OH)2D3 treatment in hemodidalysis patients with this condition.
We investigated the relationship between bone mineral density loss and mean serum phosphate level for one year in 58 men on maintenance hemodialysis who were treated with 1α-hydroxycholecalciferol and calcium bicarbonate. Bone mineral density of the femur head and neck was measured twice, 8 months apart, by dual energy X-ray absorptiometry (Hologic QDR 1000). Patients were divided into two groups according to their mean serum phosphate level during the year of the study. Group A had almost normal serum phosphate levels (mean, <6.0 mg/dl) and group B had hyperphosphatemia (mean, ≥6.0 mg/dl). In group A, the mean bone mineral density was 0.825±0.122 g/cm2 at the beginning of the study and 0.828 ±0.118 g/cm2 8 months later. In group B, these values were 0.787 ±0.167 g/cm2 at the beginning and 0.762 ±0.171 g/cm2 8 months later. Bone mineral density did not decrease in group A, but it decreased significantly in group B (p<0.01). For all patients, the percent increase in the bone mineral density was inversely correlated with the mean serum phosphate value for the year of the study (r= -0.274, p<0.05). These results indicate the importance of serum phosphate control in patients on maintenance hemodialysis, even when they are being treated with 1α-hydroxycholecalciferol and calcium carbonate.
Knowledge of daily blood pressure profiles is now an important factor in the management of hypertension. We recently analyzed the relationship of casual blood pressure (CBP) to 24-hour blood pressure (24-h BP) in 9 hypertensive patients and 11 normotensive subjects. A 24-hour ambulatory blood pressure monitoring apparatus (24-h ABPM, A & D Co.) was used to monitor 24-h BP. Data were divided into daytime mean blood pressure (daytime mBP), night mean blood pressure (night mBP), and 24-hour mean blood pressure (24-h mBP). In each subject, the 24-h ABP pattern was highly reproducible. Analysis of CBP disclosed that both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) correlated more closely with 24-h mBP than with any other parameter. In view of the high incidence of cerebral infarction during night time or rest, prior knowledge of a blood pressure change pattern from daytime mBP to night mBP in individual patients is important in the prevention of this condition. The degree of decrease from daytime mBP to night mBP varied greatly among individuals, being higher in hypertensive patients than in normotensive subjects. The degree of this change in blood pressure was difficult to predict based on the CBP change pattern following postural change or 5-min rest. In some cases, 24-h ABPM data were within the hypertensive range (systolic > 160 mmHg, diastolic > 95 mmHg) for many hours, even though CBP was within the normal range. On the other hand, the duration of this sustained hypertensive level during 24-h ABPM was sometimes short, even in subjects with elevated CBP. To deal with such discrepancies between CBP and 24-h ABPM, the duration of the sustained hypertensive level during 24-h ABPM should be given high priority in assessing the severity and prognosis of hypertension.
The higher average age of employees, due to the advancement of the compulsory retirement age, and their sedentary lifestyle in automated environments, have become important issues in the workplace, as witnessed in increased incidence of adult disease and decreased physical fitness levels. The purpose of the present study was to evaluate the effects of a long-term corporate fitness program in helping employees to stay well. The fitness program consisted of medical checkups, physical fitness tests, and a physical training program, given on an individual basis. The medical checkups and physical fitness tests were evaluated in 1499 male employees, with the following results. 1) The incidence of obesity showed no significant change. 2) There were no significant changes in total cholesterol levels nor in the incidence of hypertriglyceridemia and hypercholesterolemia. 3) Physical fitness was markedly improved. 4) There was a decrease in the percentage of smokers. These results suggest that a long-term corporate fitness program is effective for improving the health and fitness levels of employees and for preventing the progression of adult disease.