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Pulmonary diseases, including chronic obstructive pulmonary disease (COPD), are major chronic diseases that result in decreased pulmonary function. Relationships between body composition and pulmonary function have been reported. However, few epidemiological studies have used the visceral fat area (VFA) to measure body composition. This study aimed to examine the relationship between body composition and pulmonary function. A cross-sectional study was conducted between 2015 and 2016, using data obtained from 1,287 residents aged between 19 and 91 years living in the Iwaki area of Hirosaki City, a rural region in Aomori Prefecture, Japan. Pulmonary function was evaluated using the forced vital capacity (FVC) as a percentage of the predicted value (predicted FVC%) and the ratio of forced expiratory volume in one second (FEV1) to FVC. The measurements for evaluating body composition included the body fat percentage (BFP) of the whole body and trunk, skeletal muscle index (SMI), body mass index (BMI), VFA, waist circumference (WC) at the navel level, and waist-to-hip ratio (WHR). To adjust for potential confounders, Spearman’s partial correlation analysis was used to examine the relationship between the measurements of body composition and pulmonary function. There were significant correlations between the predicted FVC% and the following parameters: BFP (whole body and trunk) in younger males; SMI in older males; WC, VFA, BMI, and SMI in younger females; and BFP (whole body and trunk) and VFA in older females. Contrastingly, WC and VFA in younger males and WC in younger females were correlated with the FEV1/FVC ratio. VFA was correlated with the FEV1/FVC ratio in younger males and predicted FVC% in older females. These findings suggest that visceral fat accumulation may increase the development of obstructive pulmonary disease in young males and accelerate the decline of pulmonary function (predicted FVC%) in older females.

Little is known about the relationship between polyunsaturated fatty acids (PUFAs) and reactive oxygen species (ROS) in the general population. Therefore this study aimed to describe the association of PUFAs with ROS according to age and sex in the general population and to determine whether PUFA levels are indicators of ROS. This cross-sectional study included 895 participants recruited from a 2015 community health project. Participants were divided into 6 groups based on sex and age (less than 45 years old (young), aged 45&ndash, 64 years (middle-aged), and 65 years or older (old)) as follows: male, young (n = 136), middle-aged (n = 133), old (n = 82), female, young (n = 159), middle-aged (n = 228), and old (n = 157). The PUFAs measured were arachidonic acid (AA), dihomo gamma linolenic acid (DGLA), AA/DGLA ratio, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ROS considered in the analysis were basal ROS and stimulated ROS levels. Multiple linear analyses showed: (1) significant correlations between PUFA levels, especially DGLA and AA/DGLA ratio, and neutrophil function in the young and middle-aged groups, (2) no significant correlations in old age groups for either sex. Because PUFAs have associated with the ROS production, recommendation for controlled PUFA intake from a young age should be considered.

A low-carbohydrate/high-monounsaturated fatty acid liquid diet (LC/HMD) was investigated for its role in long-term glycemic control in tube-fed type 2 diabetes patients who require insulin therapy.The study included 10 type 2 diabetes patients requiring insulin therapy who were being tube-fed with a high-carbohydrate liquid diet (HCD). With stable glucose control maintained, these patients were monitored for glucose levels for 4 consecutive days by using continuous glucose monitoring (CGM). The patients were continued on HCD during the first 2 days and were switched to an LC/HMD during the final 2 days. The patients were then continued on the LC/HMD, and seven of the 10 patients were monitored for glucose levels for 2 consecutive days by using CGM after 3 months of feeding with the LC/HMD. Insulin regimens used included basal-bolus insulin in five of these seven patients and intermediate-acting insulin in two patients.Based on CGM data, the indices for glucose variability, such as SDs of 288 glucose levels for 24 h, total area for the range of glucose variability, mean amplitude of glycemic excursions, and 24-h mean glucose levels were significantly decreased 3 months after switching from the HCD to the LC/HMD. Additionally, despite the significant decrease in required insulin dose, the hemoglobin A1c (HbA1c) values were significantly decreased 3 months after switching.Study results demonstrated that the LC/HMD not only narrowed the range of glucose variability, but also decreased the required insulin dose and HbA1c values in diabetes patients on tube feeding who required insulin therapy, suggesting the LC/HMD may be useful in long-term glycemic control in these patients.

In an earlier continuous glucose monitoring (CGM)-based study, we reported that sitagliptin not only reduced 24-h mean glucose levels but also suppressed postprandial glucose increases, thus reducing the range of glycemic fluctuations in type 2 diabetes patients. In this study, we investigated whether sitagliptin might provide similar benefits in type 2 diabetes patients receiving insulin therapy by using CGM.The study included a total of 13 type 2 diabetes patients in whom stable glycemic control had been achieved after admission for glycemic control. Insulin regimens used included long-acting insulin preparations once daily in four patients and biphasic insulin preparations twice daily in nine, with the daily insulin dose being 19.0±12.7 U. During the CGM-based study, the patients were given insulin therapy alone on Days 1 and 2 and were given sitagliptin 50 mg/day as add-on treatment on Days 3-6, with their daily insulin doses maintained.The add-on treatment with sitagliptin led to significant decreases in 24-h mean glucose levels and SDs of 288 glucose levels measured by CGM for 24 h, as well as in the indices for magnitude of glucose variability and proportion of time in hyperglycemia, compared with insulin therapy alone (P0.01), whereas there was no significant change seen in regard to the proportion of time in hypoglycemia with or without add-on treatment with sitagliptin.This CGM-based study clearly demonstrated that insulin therapy alone, whether with long-acting or biphasic insulin preparations, does not provide adequate glycemic control in type 2 diabetes patients. In contrast, add-on sitagliptin was shown to narrow the range of 24-h glucose fluctuations in these patients, suggesting that add-on treatment with sitagliptin is effective for postprandial glucose control in type 2 diabetes patients receiving insulin therapy.

This study compare the effect of various liquid diets on 24-h glycemic variability in diabetes patients on tube feeding.The study included type 2 diabetes patients in whom percutaneous endoscopic gastrostomy had been performed for dysphagia as a sequela of cerebrovascular disease and who had been put on tube feeding with a standard high-carbohydrate liquid diet (HCD). Once stable glycemic control was achieved, these patients were continuously monitored for glucose levels for 5 days on continuous glucose monitoring. Of the 14 patients included, seven were given HCD on day 1, a low-carbohydrate/high-monounsaturated fatty acid liquid diet (LCD) on Days 2 and 3, and a isoleucine-containing liquid diet (ICD), which is known to promote glycemic uptake by skeletal muscle, thus suppressing increases in glucose levels, on Days 4 and 5, with the remaining seven given the same diets but ICD given on Days 2 and 3 and LCD given on Days 4 and 5. All comparisons were made under the same caloric conditions (caloric intake, 800-1200 kcal/day).The 24-h mean glucose level was significantly lower with LCD and ICD than with HCD but was also significantly lower with LCD than with ICD. On the other hand, the SD of 288 glucose levels over a 24-h period, 24-h total area for glycemic fluctuations, and mean amplitude of glycemic excursion were significantly lower with LCD than with HCD or ICD, whereas they did not differ significantly between HCD and ICD.LCD and ICD led to significant decreases in mean glucose levels, compared with HCD. However, of the diets compared, LCD had the greatest effect on glycemic variability in these patients on tube feeding.

We compared the effects of miglitol as an add-on to bolus insulin and dose-intensified bolus insulin on postprandial glycemic excursions by continuous glucose monitoring (CGM).The glucose levels of 21 type 2 diabetes patients admitted for glycemic control were monitored for three consecutive days by CGM after stable glycemic control was achieved with bolus or basal-bolus insulin therapy. During the 3-day period, bolus insulin administration was continued in 11 patients on Day 1; the dose of bolus insulin in these patients was increased by 2 U before each meal on day 2, and on day 3, 50 mg of miglitol was administered before each meal in addition to the initial dose of bolus insulin given on Day 1. In the remaining 10 patients, the order of administration on Day 2 and Day 3 was reversed.Of the glycemic fluctuations observed during the 24-h period, postprandial glycemic excursions showed a greater reduction during treatment with dose-intensified bolus insulin and during treatment with miglitol plus bolus insulin than during treatment with bolus insulin alone; however, miglitol plus bolus insulin treatment had a more potent effect than treatment with dose-intensified bolus insulin on reducing postprandial glycemic excursions immediately after meals. Changes in area under the curve (ΔAUC) occurring within 1 h and 2 h after each meal were significantly smaller during treatment with miglitol plus bolus insulin than during treatment with dose-intensified bolus insulin, whereas ΔAUC within2 h after each meal, except dinner, was significantly greater during treatment with miglitol plus bolus insulin than during treatment with dose-intensified bolus insulin.Our findings suggest that miglitol as an add-on to bolus insulin in patients with type 2 diabetes may be one of the beneficial therapeutic options that provides a more rigorous postprandial glycemic control without increasing the risk for hypoglycemia before the next meal.

The number of patients with both hypertension and obesity has been increasing in Japan. Many of these patients may also have insulin resistance. Telmisartan, an angiotensin II receptor blocker (ARB), selectively activates peroxisome proliferatoractivated receptor (PPAR)-gamma, and this effect is considered to markedly improve insulin resistance in obese patients with hypertension. We compared the antihypertensive and insulin resistance-improving effects of telmisartan with those of candesartan and valsartan in this patient population. Twenty-eight elderly patients with an average body mass index (BMI) of 27.1 kg/m2 were enrolled in this 6-month study. Patients were randomly selected to either switch from candesartan or valsartan to telmisartan or to continue with their current ARB. A 75 g oral glucose tolerance test (OGTT) was performed before and after switching, and the effect of telmisartan on the insulin response to glucose loading was investigated. There was no significant difference in blood pressure between the two groups after drug administration, but glucose tolerance significantly improved in the telmisartan group. The hyperinsulin response to glucose loading also significantly improved in those taking telmisartan, as well as homeostasis model assessment of insulin resistance (HOMA-IR). These changes were not observed in the control group. In patients with hypertension and obesity showing insulin resistance, treatment with telmisartan significantly improved the hyperinsulin response to glucose loading. Telmisartan may therefore be beneficial in these patients.

summary Background & aims: In type 2 diabetic patients with dysphagia as a sequela of cerebrovascular accident, enteral nutrition tube feeding, especially with high-carbohydrate (CHO) standard formulas, may lead to acute glucose variation (GV). We assessed whether a low-CHO, diabetes-specific formula improves GV over 24 h using continuous glucose monitoring (CGM). Methods: Patients were fed either a low-CHO, diabetes-specific formula (henceforth, low-CHO formula) or a high-CHO standard formula (henceforth, high-CHO formula) for 2 days. Blood glucose (BG) was assessed by CGM throughout the observation period. Results: Ten patients who received enteral tube feeding with the low-CHO formula had significantly (p < 0.01) lower 24-h mean BG than patients fed a high-CHO formula (123.2 � 38.3 vs. 143.7 � 58.1 mg/ dL). Mean amplitude of glucose excursion was significantly (p < 0.01) lower in the low-CHO vs. high-CHO formula group, as was 24-h GV (p < 0.05). Percent period of hyperglycemia was significantly (p < 0.05) reduced when patients were fed low-CHO vs. high-CHO formula (16.8 � 31.5% vs. 37.9 � 33.0%); hypoglycemia was rarely observed. Conclusions: A low-CHO formula may enhance postprandial and fasting BG profiles and alleviate GV. It may therefore be useful for diabetic patients requiring enteral tube feeding.

Aim: Menopause is a risk factor for cardiovascular disease (CVD) in women because of the reduction in endogenous estrogen. Recently, single nucleotide polymorphisms (SNPs) of the estrogen receptor α (ESR-1) gene (c.454-397T>C) associated with the prognosis of myocardial infarction in postmenopausal women were identified; however, the mechanism by which genetic variation of ESR-1 contributes to the pathogenesis of CVD is unknown. Circulating levels of adipokines and inflammatory cytokines predict CVD risk; hence, this study aimed to investigate whether ESR-1 genotypes (c.454-397T>C) might influence circulating levels of adipokines and inflammatory cytokines in postmenopausal women with type 2 diabetes.Methods: Sixty-three postmenopausal women with type 2 diabetes were recruited. Serum levels of adiponectin, resistin, interleukin-6 (IL-6), and high-sensitive C-reactive protein (hs-CRP) were determined.Results: The genotype of ESR-1 was closely associated with serum adiponectin, which was decreased in subjects with the T allele and was lowest in those with the T/T genotype. Multiple logistic regression analysis revealed independent contribution of the homozygote for the T allele to low serum levels of adiponectin.Conclusion: The T allele of the c.454-397T>C SNP of ESR-1 is associated with low serum levels of adiponectin, which may lead to a high risk of CVD in postmenopausal women.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p /= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (>/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to lard on the development of hypertension and insulin resistance in Dahl salt-sensitive (Dahl-S) rats fed a high-sucrose diet (HSD), a model of salt-sensitive hypertension. After 16 weeks of treatment, the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test significantly increased in the HSD-EPA-E group compared with the HSD-water or -lard control group. The GIR was approximately three times higher in the HSD-EPA-E group versus the HSD-water or -lard control group, and it was about 70% of the rate in the calorically deprived control group fed a low-fat-high-fiber diet (LF-HFD). In addition, EPA-E significantly suppressed the elevation of plasma glucose and insulin levels after oral glucose loading. These results indicate that EPA-E prevents the development of insulin resistance in Dahl-S rats fed a HSD. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase in C18:2, C20:5, and C22:5 components in the HSD-EPA-E group and, conversely, a significant decrease in C16:0, C20:4, and C22:6. The present results indicate that the beneficial effect of EPA-E on insulin resistance in Dahl-S rats fed a HSD is likely dependent on the modification of phospholipid components in the skeletal muscle membrane. These findings suggest that EPA-E might prevent the development of insulin resistance in dietary obesity. In addition, the HSD-EPA-E group showed a significant increase in the level of uncoupling protein (UCP) in brown adipose tissue as compared with the HSD-water or -lard control group. However, EPA-E had no effect on the development of hypertension and obesity in Dahl-S rats fed the HSD.

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to the effects of lard, olive oil, safflower oil, or distilled water as the control on the development of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) with obesity. After 17 or 18 weeks of treatment, the glucose infusion rate (GIR) in the euglycemic insulin-glucose clamp test only showed a significant increase in EPA-E-treated rats compared with control rats given distilled water alone as the vehicle. The GIR in EPA-E-treated animals was approximately three times greater than in the controls. This is the first report to display the influence of various fatty acids on the development of insulin resistance in OLETF rats. We demonstrated that EPA-E prevents the onset of insulin resistance, whereas olive oil and safflower oil have no effect and lard exacerbates insulin resistance. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase of the C18:2, C20:5, and C22:5 components in EPA-E-treated rats and, conversely, a significant decrease in C20:4. In addition, EPA-E-treated rats showed a significant increase in GLUT4 mRNA in skeletal muscle when compared with control rats. Our results indicate that the beneficial effect of EPA-E on insulin resistance in OLETF rats is likely to be dependent on modification of the phospholipid components of the skeletal muscle membrane. These findings suggest that dietary fatty acids may play a key role in the development of insulin resistance in patients with NIDDM.

The prerequisite of problem-solving is consciousness of the problems that exist in a service system where a person supports others. In order to provide better services and improve the current situation, it is very important to determine the structure of problem consciousness and how critical thought can be applied to it. In this paper, the authors attempt to systematize, using the KJ method, the Confucian thought relating to a strong active problem-consciousness collected in the Analects of Confucius. The authors suggest that the problem consciousness structure of Confucianism comprises four elements: objective responsibility, wisdom (information and knowledge), and judgment based on the results of systematizing the Analects of Confucius using the KJ method.

Though an inverted pendulum is one of the typical examples of nonlinear control systems, it is shown that the inverted pendulum is not feedback linearizable. Saeki proposed a new method to design a backstepping-like controller. This paper presents a swing up controller by combining Saeki's method with the energy function method. First, we give the control input of the cart to cancel the effect of the pendulum and then design the input that guarantees the convergence of the acceleration of the cart to the desired value. Next, regarding the acceleration of the cart as the input of the pendulum, we design the swing-up control law using a energy function. Moreover, we propose another nonlinear state feedback control law that converges to a homoclinic orbit. Finally, the MATLAB simulations are performed to demonstrate the validity of the proposed control laws.

Liraglutide was examined for its effects on 24-h glucose fluctuations in Japanese type 2 diabetes patients as well as for its differential effects depending on glucose tolerance status after favorable glycemic control was obtained in these patients.In this prospective open-label pilot study, a total of 20 type 2 diabetes patients hospitalized for glycemic control were given liraglutide 0.3 mg, followed by liraglutide 0.6 mg and 0.9 mg, with each given at 1-week intervals. The patients were continuously monitored for their 24-h glucose levels before treatment and during the course of treatment with liraglutide 0.3 mg, 0.6 mg, and 0.9 mg, respectively, using continuous glucose monitoring (CGM). At the start of treatment with liraglutide, 12 patients were on diet therapy alone, of which six were drug-naive, and eight were being treated with glimepiride.Liraglutide not only significantly reduced 24-h mean glucose levels but also significantly improved all the indices for glycemic variation evaluated, which included SDs of 24-h glucose levels, mean amplitude of glycemic excursions (MAGE), and total area under the glucose fluctuation curve (AUC) for 24 h. The study showed a significant negative correlation for mean glucose levels, SD, and AUC immediately before treatment versus their changes with liraglutide. A 75-g oral glucose tolerance test (OGTT) was given in 11 patients treated with liraglutide monotherapy once favorable glycemic control was achieved. The OGTT revealed that of these, six were found to have normal glucose tolerance, four had impaired glucose tolerance, and one had diabetes, and that of the six drug-naive patients, five patients were found to have normal glucose tolerance, and one had impaired glucose tolerance.Study results showed that liraglutide is expected not only to reduce mean glucose levels but also to improve 24-h glucose fluctuations, including postprandial glucose excursions, with its effects being particularly conspicuous in patients with early-stage type 2 diabetes.

This study was performed to examine the efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes using continuous glucose monitoring (CGM) of 24-h glycemic changes.The study was a prospective open-label pilot study in patients with type 2 diabetes who were admitted to our hospital and treated with sitagliptin alone or concomitantly with another oral hypoglycemic drug. CGM was performed for 2 days before sitagliptin administration and for another 2 days after administration. The average 24-h blood glucose level, SD of the 24-h blood glucose level, 24-h glycemic fluctuation range, mean amplitude of glycemic excursions (MAGE), and hyperglycemic and hypoglycemic time periods were compared before and after administration.Sitagliptin administration alone and with a concomitant drug decreased the average 24-h blood glucose level, SD of the 24-h blood glucose level, 24-h glycemic fluctuation range, MAGE, and hyperglycemic time, compared with these parameters before administration. There were significant correlations between the average 24-h blood glucose level before administration and the decrease in the average 24-h blood glucose level after administration and between MAGE before administration and the decrease in MAGE after administration.Sitagliptin decreased the average glycemic level and also improved 24-h glycemic fluctuation, including postprandial hyperglycemia.

The objective of this study was to evaluate the effects of the α-glucosidase inhibitor acarbose on glucose fluctuations in patients with type 2 diabetes using continuous glucose monitoring (CGM).CGM was performed for 4 days (72 h), and acarbose at 300 mg/day was administered on two of these days but not on the other two days. The effects on blood glucose fluctuations were evaluated.We recruited a total of 10 patients (five men and five women) with a mean ± SD age of 63.1 ± 12.1 years, body mass index of 22.6 ± 5.4 kg/m(2), and glycohemoglobin of 9.9 ± 1.9%. During treatment with acarbose, significant decreases in median (range) SD of 24-h mean blood glucose (22.48 [6.39-47.22] mg/dL vs. 32.78 [18.83-58.93] mg/dL, P = 0.004), 24-h blood glucose fluctuations (453.27 [128.51-903.94] mg·h/dL vs. 677.05 [358.03-1,234.57] mg·h/dL, P = 0.002), and mean amplitude of glycemic excursions (65.00 [18.17-117.50] vs. 97.09 [53.00-166.67], P = 0.010) occurred compared with no treatment.Acarbose reduced excessive blood glucose fluctuations.

We report the case of a 62-year-old woman who was admitted to our hospital with diabetic ketoacidosis. Her urinary C-peptide was 3.5 micrograms/day, HLA typing was DR9, and serum was positive for islet cell antibodies. There was no significant increase in the major viral titer. Pancreatic head tumor was suspected, and pancreaticoduodenectomy was performed. The pathology of this tumor was polycystic adenoma. We examined the surgical specimen from around the tumor histologically. The pancreatic islets had decreased in number. The immunohistochemical staining of islets for insulin, glucagon and somatostatin showed that the number of B cells had decreased remarkably, while A and D cells were preserved. Marked lymphocytic infiltration was observed in the islets. The majority of lymphocytes were helper/inducer and suppressor/cytotoxic T cells, which did not express HLA-DR antigen or interleukin-2 receptor. No NK cells were present in the islets. The present case, which was examined histologically in detail, is consistent with the previously proposed hypothesis that autoimmunity might play an important role in the pathogenesis of insulin-dependent diabetes mellitus.

We examined the effect of 1 alpha-OH-D3 on diabetic osteopenia in spontaneously-developed diabetic WBN/Kob rats. Diabetic male WBN/Kob rats aged 12 to 15 months were randomly divided into 1 alpha-OH-D3-treated group (n = 6) and control group (n = 5). 1 alpha-OH-D3 was administered 3 times a week at an oral dose of 0.1 microgram/kg and triglyceride was administered in the control group during the observation period of 12 weeks. Although plasma Ca level decreased significantly in the vehicle-treated group, there was no significant change in plasma Ca level in the 1 alpha-OH-D3-treated group. Urinary Ca excretion significantly increased in the 1 alpha-OH-D3-treated group compared with that in the vehicle-treated group. As for plasma vitamin D metabolites levels after the 12 week-treatment, although there was no significant difference in plasma 25-OH-D and 24,25(OH)2D levels, plasma 1,25(OH)2D level was significantly increased in the 1 alpha-OH-D3-treated group compared with that in the vehicle-treated group. There was no significant difference in plasma bone-Gla protein level between 1 alpha-OH-D3-treated and vehicle-treated groups. As for bone mineral content (BMC) in the femur measured by a dual energy absorptiometer, BMC was significantly increased in the 1 alpha-OH-D3-treated group compared with than in the vehicle-treated group. In conclusion, 1 alpha-OH-D3 ameliorated diabetic osteopenia in WBN/Kob rats through the normalization of vitamin D metabolism.

The development of ocular, renal, and neural lesions was examined in male diabetic WBN/Kob rats with endoexocrine pancreatic insufficiency. As for the ocular lesions, around 15 months of age, opacity of the lens began to appear. Opacity was first observed in the periphery of the lens, and then increased rapidly in severity, extending concentrically and centripetally, until total cataracts developed. The incidence of cataracts in male rats was gradually increased and reached almost 100% at 24 months of age. As for renal lesions, the 24-h urinary total protein began to increase at about 13 months of age and reached 50-300 mg/24 h at 13-28 month of age, which was significantly higher than in age-matched male Wistar rats (15-25 mg/24 h). Electrophoretic analysis revealed that the urinary protein was almost all albumin. Morphologically, an increased GBM thickness and glomeruli with segmental or global enlargement of mesangial areas were observed. As for neural lesions, a reduction in motor nerve conduction velocity was demonstrated electrophysiologically, and a marked decrease in density and diameter of myelinated fibers in the sciatic nerves were observed morphometrically. In conclusion, the WBN/Kob rat strain with slowly developing but severe lesions associated with pancreatopathy presents a suitable model for human diabetic complications.

The early morning hyperglycemia of diabetic patients has been commonly referred to as the "dawn phenomenon". Recently the nocturnal surges of growth hormone (GH) have been suggested as an important factor in the pathogenesis of the dawn phenomenon. In order to reassess the role of the nocturnal GH secretion in the dawn phenomenon, seven C-peptide negative diabetic patients were studied during 48hr-feedback control using a closed-loop insulin infusion device (Biostator). They received oral sleeping medication only on the first night (control) and sleeping medication with anticholinergic agent (pirenzepine 75mg) on the second night, and blood glucose, insulin requirements, GH and cortisol concentrations during 0000hr and 0700hr were measured. The peak of sleep-induced GH secretions was markedly suppressed by pirenzepine in comparison with the control night (19.8 +/- 3.7 vs. 3.0 +/- 1.2ng/ml; p less than 0.05). Insulin requirements during 0500hr and 0700hr were suppressed significantly by pirenzepine (3.0 +/- 0.2 vs. 2.0 +/- 0.2U/2hr; p less than 0.05). Insulin infusion ratio, i.e. insulin requirements during 0500hr and 0700hr divided by those during 0000hr and 0200hr, was decreased by pirenzepine (2.2 +/- 0.3 vs. 1.5 +/- 0.2; p less than 0.05). There were no significant differences in blood glucose and cortisol concentrations whether or not the anticholinergic agent was given. In conclusion, these results have shown that an anticholinergic agent may be useful in the management of insulin-treated patients with marked dawn phenomenon.

Background Glycated albumin (GA) has been utilized to monitor mid-term glycemic control, and reflects the status of blood glucose more rapidly and effectively than hemoglobin A 1c (HbA 1c ). To examine the relationship between GA level and structural changes or glycation sites of albumin, we analyzed pre- and post-treatment samples from a diabetic patient with extraordinary increase of GA. Method A female diabetic patient with poor glycemic control had a GA > 94% and was treated with intensive insulin therapy to decrease blood glucose. We analyzed changes in fluorescence derived from tryptophan (Trp) and advanced glycation end product (AGE) of albumin isolated/purified from pre- and post-treatment samples. To determine the sites of glycation of albumin, samples were carboxymethylated and digested by Glu-C endoprotease, and peptides were analyzed using liquid chromatography/mass spectrometry. Results GA level decreased almost linearly and reflected the improved glycemic state well. Trp-related fluorescence of pre- and post-treated samples did not change while AGE-related fluorescence increased depending on GA level. Ten major glycation sites were detected in the pre-treatment sample, while 3 major glycation sites were detected in post-treated samples. Conclusions GA level reflects the status of blood glucose more rapidly than HbA 1c . Since GA level was related to AGE-related fluorescence and number of glycation sites, it might be a good marker for not only glycemic control of diabetic patients but also structural and functional changes of albumin.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p0.001 vs. baseline). The summation operator CPR in the Ins group was unchanged. Among the SU group, 30% of subjects (9/30) progressed to IDDM, while 8.3% of Ins group subjects (2/24) progressed to IDDM (p = 0.087). With regard to the subjects who had a preserved C-peptide response ( summation operator CPR/= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is characterized by (1) late age of onset, with initial features of NIDDM and subsequent progression to insulin-dependent stage; (2) high predictive value of autoantibodies against glutamic acid decarboxylase (GADAb) and islet cell antibodies (ICA) for progression of beta cell failure; (3) less predominant T cell response, which may attack and eventually destroy beta-cells in affected pancreas. These findings may suggest a rationale for intervention to prevent slowly progressive beta cell dysfunction in this type of diabetes. We identified three independent risk factors for progression of beta cell failure in SPIDDM: (1) sulfonylurea treatment; (2) ICA-positive periods; and (3) initial body weight. We hypothesized that removal of the risk factors for further progression of beta cell dysfunction will have beneficial effects on intervention strategy in treating SPIDDM. In our pilot study, we used a small dose of insulin instead of sulfonylurea in the early stage of treatment of patients with SPIDDM. Insulin-treated SPIDDM patients had a sustained C peptide response (CPR), while most of sulfonylurea-treated patients progressed to an insulin-dependent state. We organized a randomized multicenter clinical trial to study early treatment to prevent the progression of beta cell dysfunction in SPIDDM (the Tokyo Study). It was demonstrated that early intervention with insulin therapy is an effective treatment modality in the early stage of SPIDDM patients who had preserved beta cell function at entry (integrated value of serum C peptide values at 0, 30, 60, 90, and 120 minutes; Sigma CPR >or= 10 ng/mL) and high GADAb (>10 U/mL). Preventive insulin treatment was ineffective in the patients who had diminished insulin reserve at entry (Sigma CPR < 10 ng/mL). Insulin intervention to preserve beta cell dysfunction in SPIDDM is effective and safe in patients with preserved beta cell function and high GADAb titers at the initiation of insulin.

Monotherapy with sulfonylurea may result in the exhaustion of pancreatic beta-cell function, fat accumulation, and dyslipidemia. We examined the possibility of dose reduction by administering sulfonylurea together with troglitazone, and investigated changes in insulin secretion and fat deposition. Seventy-eight patients with type 2 diabetes adequately controlled with glibenclamide were randomly allocated to a troglitazone (400 mg/d)-added group (n = 40) or a control group without placebo (n = 38) and monitored for 24 weeks. The daily dose of glibenclamide was adjusted to maintain stable HbA(1c) levels. Fat accumulation to the liver and thigh muscle were measured in mean Hounsfield units determined on computed tomography (CT) scan. Visceral fat accumulation (V), subcutaneous fat accumulation (S), and the V/S ratio were also determined by CT scan. The daily dose of glibenclamide and serum fasting insulin level in the troglitazone-added group significantly decreased (from 4.05 +/- 2.50 mg/d to 1.84 +/- 1.65 mg/d and from 8.47 +/- 4.62 microU/mL to 6.49 +/- 3.28 microU/mL, respectively) during the observation period compared with the control group (P < .01 and P < .01, respectively). Serum triglyceride and homeostasis model insulin resistance index (HOMA-R) in the troglitazone-added group decreased significantly in comparison to the control group (P < .05 and P < .01, respectively). The mean Hounsfield units of liver significantly decreased in the control group compared with the troglitazone-added group (P < .05). Visceral fat area and the V/S ratio significantly increased in the control group compared with the troglitazone-added group (P < .01 and P < .01, respectively). Glibenclamide monotherapy resulted in fat accumulation accompanied by dyslipidemia. An alternate conclusion is that troglitazone reversed type 2 diabetes (not sulfonylurea)-associated fat accumulation. The addition of troglitazone decreased daily doses of glibenclamide, preserved fasting insulin secretion, improved fat accumulation in liver, and prevented dyslipidemia.

OBJECTIVE: Troglitazone was recently reported to specifically promote the differentiation of pre-adipocytes into adipocytes in vitro in subcutaneous fat only, indicating a relation to insulin-resistance-improving action of troglitazone. To expand on this finding, we investigated at the clinical level how long-term administration of troglitazone influences the body fat distribution in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Troglitazone (400 mg/day) was administered for 6 months to 30 type 2 diabetic patients whose glycemic control was poor. A total of 18 patients received diet therapy alone (in the single-treatment group, BMI 26.0 +/- 4.6, HbA1c 8.2 +/- 1.7%), and 12 patients concomitantly received glibenclamide (1.25-7.5 mg/day) (in the concomitant sulfonylurea group, BMI 25.4 +/- 4.7, HbA1c 9.2 +/- 1.2%). BMI, HbA1c, serum lipid level, and body fat distribution, which were determined by computed tomography (CT) scan at the umbilical level, were measured and compared before and after troglitazone treatment. RESULTS: During the 6-month troglitazone treatment, HbA1c levels decreased and BMI increased in both groups. As for body fat distribution in the single-treatment group, visceral fat area (VFA) decreased (from 118.3 +/- 54.3 to 101.1 +/- 50.8 cm2; P < 0.001), and subcutaneous fat area (SFA) increased (from 189.7 +/- 93.3 to 221.6 +/- 101.6 cm2; P < 0.001), resulting in a decrease in visceral/subcutaneous (V/S) ratio (from 0.74 +/- 0.48 to 0.50 +/- 0.32; P < 0.001). In the concomitant sulfonylurea group, VFA was unchanged (from 108.1 +/- 53.5 to 112.5 +/- 59.9 cm2), while SFA increased (from 144.6 +/- 122.0 to 180.5 +/- 143.5 cm2; P < 0.01), thereby decreasing the V/S ratio (from 0.91 +/- 0.46 to 0.77 +/- 0.44; P < 0.01). The serum triglyceride level and the area under glucose curve during the 75-g oral glucose tolerance test decreased significantly in the single-treatment group. CONCLUSIONS: According to our data, troglitazone appears to promote fat accumulation in the subcutaneous adipose tissue rather than in the visceral adipose tissue in mildly obese Japanese people with type 2 diabetes. This shift of energy accumulation from the visceral to subcutaneous adipose tissue may greatly contribute to the troglitazone-mediated amelioration of insulin resistance.

OBJECTIVE To investigate the social and economic backgrounds of youth-onset insulin-treated diabetes mellitus in Japan. RESEARCH DESIGN AND METHODS We conducted a case-control study on 35 diabetic patients with age at onset of 19.5 ±; 5.1 yr and duration of diabetes 14.9 ±; 6.7 yr. Sex- and age-matched (within 5 yr) siblings were selected as control subjects. Thirty-five matched pairs were asked to complete a questionnaire, including employment status and educational achievement. RESULTS Overall, diabetic patients were more likely to encounter job refusal in their lives than sibling control subjects (20 vs. 0%), and most patients (6/7) who had an experience of job refusal told job interviewers about their diabetes. Although the full-time employment rate and unemployment rate did not differ significantly between patients and control subjects, income levels were lower among patients than in the sibling (1600 vs. 2500 thousand yen). A multivariate analysis indicated that patients had lower incomes than control subjects after adjusting for the effect of physical disability. Educational achievements in the patients were similar to those in the siblings. CONCLUSIONS These results suggested that diabetic patients had several social and economic problems in Japan. Further studies in more subjects are required to grasp the social and economic impact on diabetes precisely, and minimize the social handicaps on diabetic patients.

This paper presents a novel single sustain PDP with a high voltage address driver (Hi-AD) that has an address supply voltage equal to the sustain voltage and does not change wall voltage on the address electrode side during sustain periods. The Hi-AD system reduced the luminance degradation to only 1% after 1000 hours. A power consumption in an all black display condition for the Hi-AD system is 28 % less than that for a conventional dual sustain system.