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Background Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables. Methods This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG. Results Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700–1800 h), night-time (1800–0000 h), and bed-time (0000–0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment. Conclusions In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients. Trial registration Unique Trial Number, UMIN000005874 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929)

Objective: We investigated the relationship between insulin withdrawal (IW), endogenous insulin recovery, and concurrent SGLT2 inhibitor (SGLT2i) therapy. Patients and Methods: Of the 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment, 39 patients who had received intensive insulin therapy after admission were subjected to retrospective analysis. Of these, 26 patients in whom insulin withdrawal had been achieved during admission were divided into those who had received concurrent SGLT2i therapy (n=19) and those who had not (n=7). Insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h during the MTT was compared at admission and discharge. Results: 1) While there was no significant difference between those with IW and those without IW in their age, BMI, HbA1c, C-peptide index and urinary CPR excretion at admission, significantly more patients with IW had received SGLT2i than those without IW (P < 0.001). Again, ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h were significantly (p Conclusions: Study results confirmed that endogenous insulin secretion was significantly restored in those with IW and that the time to IW was significantly shorter in those with concurrent SGLT2i therapy than in those without, suggesting a role for SGLT2i in achieving IW. Disclosure M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None.

Objective: We investigated the effect of short-term improvements in glycemic control with SGLT2i therapy on insulin and glucagon secretion with or without concurrent DPP-4 inhibitor (DPP-4i) therapy. Patients and Methods: 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment were subjected to retrospective analysis. Of these, 41 patients were found to have received SGLT2i after admission, with 15 of these also found to have received concurrent DPP-4i. The patients were divided into those not receiving SGLT2i (n=37), those receiving SGLT2i without concurrent DPP-4i (n=26) and those receiving SGLT2i with DPP-4i (n=15) and were compared for changes in postprandial insulin and glucagon secretion. All patients were evaluated at admission and discharge for insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2h, and as well as for glucagon (G) secretion in terms of ΔG/ΔPG 0-30 min and AUC-G 0-2h during the MTT. Results: There was no significant difference between the 3 groups in their HbA1c, C-peptide index, and urinary CPR excretion at admission. With improvements in glycemic control, ΔCPR/ΔPG 0-30min and AUC-CPR 0-2h were significantly increased, and AUC-PG 0-2h were significantly decreased, in all groups. Again, with improvements in glycemic control, AUC-G 0-2h was significantly decreased in those not receiving SGLT2i, increased in those receiving SGLT2i without DPP-4i, and decreased in those receiving both SGLT2i and DPP-4i. Conclusions: Postprandial insulin secretion was shown to be restored after short-term improvements in glycemic control irrespective of SGLT2i or concurrent DPP-4i, while glucagon secretion was shown to be increased with SGLT2i without DPP-4i but decreased with combined SGLT2i and DPP-4i. Disclosure M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None.

Objective: Disparities were compared between flash glucose monitoring (FGM) sensor glucose (SG) and blood glucose (BG) values vs. between continuous glucose monitoring (CGM) SG and BG values to establish the accuracy of FGM SG values in patients with type 1 diabetes. Methods: FGM (FreeStyle Libre Pro; Abbott Japan) and a sensor-augmented pump (SAP) with built-in CGM (MiniMed 620G; Medtronic Minimed) were simultaneously put in place in 8 outpatients with type 1 diabetes receiving SAP therapy (Age, 50.9 ± 6.3 years; BMI, 20.4±2.6 kg/m2; HbA1c, 7.4±0.3%; urinary C-peptide excretion, 1.5±0.7 µg/day; duration of SAP therapy, 11.9±3.7 months; insulin dose, 34.2±14.5 U/day). SMBG BG values at 385 points registered on Minimed 620G for calibration purposes and CGM/FGM SG values at the same time points, were selected to examine the accuracy of FGM SG values. Both these devices were evaluated for accuracy in terms of 1) simple correlation coefficients between CGM/FGM SG values and BG values; and 2) mean absolute relative differences (MARD) in SG values of CGM/FGM relative to BG values as reference. Results: 1) A strong positive correlations were found between the CGM/FGM SG values and BG values (r = 0.984, p < 0.001 / r = 0.852, p< 0.001). 2) The MARD in CGM/FGM SG values were 5.81 ± 6.66% (0-39.4%) / 17.5 ± 24.8% (0-213.6%), and the frequency of MARD showing 10% or less accounted for 83% of all CGM SG values, and 48.3% of all FGM SG values. The relationship between the MARD of FGM SG values and the durations of FGM put in place varied depending on the number of days FGM put in place. Additionally, the disparity between the FGM SG values and the BG values varied greatly depending on the individual patient. Conclusions: While FGM represents an innovative device for glucose monitoring, there is a wide disparity between the FGM SG and BG values in some patients with type 1 diabetes, suggesting that FGM may be appropriately positioned as an adjunct, but not an alternative, to SMBG. Disclosure M. Tanizawa: None. H. Takahashi: None. Y. Mori: None. K. Utsunomiya: None.

Objective: Changes in C-peptide index (CPI) before and after hemodialysis (HD) were compared to explore factors associated with insulin resistance in diabetic patients receiving HD. Methods: Fasting blood samples were drawn from type 2 diabetic patients receiving maintenance HD but not insulin therapy at our clinic before HD on the first day of the week they went on HD (pre-HD) as well as on the next day (post-HD) and CPI was calculated. Results: The mean post-HD CPI was significantly lower than the mean pre-HD CPI (6.7 ± 2.7 ng/mL vs. 8.1 ± 3.3 ng/mL) in the 19 type 2 diabetic patients (men/women, 12/7) included in the study. The rate of decrease in CPI was strongly positively correlated with geriatric nutritional risk index (GNRI) (R2 = 0.692) in these patients, while it was not correlated with their glycoalbumin (GA) or fasting glucose values. Conclusions: Despite reports that HD leads to resolution of uremia and excessive fluid overload resulting in improvements in insulin resistance, to date, very few reports compared insulin resistance before and after HD. This study showed that the rate of decrease in CPI was not increased in patients with favorable glycemic control but significantly increased in those with favorable nutritional status, suggesting that the patient’s overall status may have a role to play in HD-mediated improvements in insulin resistance in the short term. Disclosure S. Funakoshi: None. J. Hashiguchi: None. M. Hayashida: None. R. Etoh: None. K. Sawase: None. Y. Mori: None. K. Utsunomiya: None. T. Harada: None.

Objective: To investigate oral health status in patients receiving maintenance hemodialysis (HD) and to examine the characteristics of diabetic patients receiving HD. Methods: A questionnaire survey was conducted in a total of 249 outpatients receiving HD using the Japanese Academy of Clinical Periodontology’s Self-administered Questionnaire on Periodontal Disease to compare oral/nutritional health status between diabetic and nondiabetic patients. Results: Of the patients surveyed, diabetic and nondiabetic patients totaled 83 and 166 (mean age, 64.3 ± 21.7 years and 73.9 ± 33.3 years), respectively. While there was no significant difference in the prevalence of periodontal disease between the diabetic and nondiabetic patients (26.5% and 34.9%), the diabetic patients had a significantly fewer number of intact teeth than the nondiabetic patients (14.9 ± 11.5 vs. 21.7 ± 12.9) as well as a lower geriatric nutritional risk index than the nondiabetic patients (85.7 ± 20.9 vs. 93.9 ± 27.4). Conclusions: While there was no difference in the prevalence of periodontal disease between the diabetic and nondiabetic patients among those receiving HD, the diabetic patients were associated with a fewer number of intact teeth as well as poorer nutritional status. Further study is required to investigate whether these may represent causes or consequences of diabetes and/or nutritional status. Disclosure S. Funakoshi: None. Y. Ohata: None. K. Fujimori: None. R. Etoh: None. K. Sawase: None. J. Hashiguchi: None. Y. Mori: None. K. Utsunomiya: None. T. Harada: None. M. Hayashida: None. M. Kawano: None.

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.

Angiotensin II type 1 receptor (AT1 receptor) blockers (ARBs) are one of the most popular anti-hypertensive agents. Control of blood pressure (BP) by ARBs is now a therapeutic target for the organ protection in patients with hypertension. Recent meta-analysis demonstrated the possibility that telmisartan was the strongest ARB for the reduction of BP in patients with essential hypertension. However, which molecular interactions of telmisartan with the AT1 receptor could explain its strongest BP lowering activity remains unclear. To address the issue, we constructed models for the interaction between commonly used ARBs and AT1 receptor and compared the docking model of telmisartan with that of other ARBs. Telmisartan has a unique binding mode to the AT1 receptor due to its distal benzimidazole portion. This unique portion could explain the highest molecular lipophilicity, the greatest volume distribution and the strongest binding affinity of telmisartan to AT1 receptor. Furthermore, telmisartan was found to firmly bind to the AT1 receptor through the unique "delta lock" structure. Our present study suggests that due to its "delta lock" structure, telmisartan may be superior to other ARBs in halting cardiovascular disease in patients with hypertension.

Angiotensin II receptor blockers as a class are reported to act as insulin sensitizers. Of these, telmisartan has been shown to have additional unique peroxisome proliferator-activated receptor-gamma-mediated, insulin-sensitizing properties. In this study, investigators explored the effects of telmisartan on glycemic control and lipid metabolism in hypertensive patients with type 2 diabetes who had switched to telmisartan from another angiotensin II receptor blocker. The study subjects were 42 hypertensive outpatients with type 2 diabetes who were being treated with candesartan 8 mg/d and who agreed to switch to treatment with telmisartan 40 mg/d. Relevant laboratory variables were measured 6 mo before treatment switching, at the time of switching, and 6 mo after switching. No significant differences were noted in blood pressure, body mass index, or glycosylated hemoglobin among subjects before and after therapy was switched. No adverse reactions such as edema or hepatic toxicity were noted. No significant changes in fasting plasma glucose, fasting insulin, HOMA-R (insulin resistance as measured by the homeostasis model), preheparin lipoprotein lipase mass, high-density lipoprotein cholesterol, and free fatty acids were noted. Triglyceride levels were significantly decreased, however, and adiponectin levels were significantly increased (8.1+/-3.1 microg/mL at switching; 8.6+/-3.0 microg/mL 6 mo after switching; P.01) after the switch to telmisartan therapy. Study results show that telmisartan did not affect glycemic control, but it improved lipid metabolism and adiponectin production in patients with type 2 diabetes, suggesting that AT(1)-receptor antagonism and selective peroxisome proliferator-activated receptor-gamma activation by telmisartan combine to account for observed effects on lipid metabolism and adiponectin production.

Objective We investigated the relationship between serum uric acid (SUA) and body fat area, serum lipid level, insulin resistance, and metabolic syndrome in Japanese men. Method We studied 508 Japanese man industrial workers who underwent an annual medical examination and agreed to participate in the CT scanning examination. Body fat area was measured at the umbilical level. Metabolic syndrome was defined by the presence of visceral fat Accumulation (≥100 cm2) accompanied by two or more disorders; dislipidemia, hypertension, and hyperglycemia. Results SUA was positively correlated with visceral fat area, subcutaneous fat area, serum total cholesterol level, serum triglyceride level, the Homeostasis Model Assessment index, and was negatively correlated with the high-density lipoprotein cholesterol level. In multiple regression analysis, the most influential factor for SUA was visceral fat area (p=0.0027), followed by the serum triglyceride level (p=0.0245). We clarified a higher SUA in the metabolic syndrome group as compared with the non-metabolic syndrome group: 6.67±1.14 mg, 6.09±1.14 mg, respectively (p

To elucidate the role of visceral fat accumulation in the metabolic syndrome, differences in the pathology of the metabolic syndrome with or without visceral fat accumulation were investigated. A total of 472 prediabetic Japanese men (mean age, 47.5±7.2 yr) with impaired fasting glycemia (IFG) levels of 110–125 mg/dL were eligible for participation in the study. The study subjects were divided into the following four groups, and intergroup comparisons were made: group I without visceral fat area [VFA]≥100 cm2 but presenting with fewer than two other risk factors (i.e., TG≥150 mg/dL, HDL-C

We investigated the role of hypoadiponectinemia in the metabolic syndrome (MS), as well as its association with post-glucose challenge hyper-free fatty acidemia in the clinical setting. The study subjects comprised 177 corporate employees shown to have a fasting plasma glucose (FPG) level of 125 mg/dL or less in a 75 g OGTT in the corporation's healthcare center. When divided into those who met the Japanese criteria for the metabolic syndrome (MS group; n = 45) and those who did not (Non-MS group; n = 132), the MS group was shown to have significantly lower adiponectin levels than the Non-MS group, and tended to show higher high-sensitivity C-reactive protein (CRP) values than the Non-MS group, while not achieving statistical significance. The MS group showed higher baseline glucose levels; higher baseline, 30-, 60-, and 120-min post-challenge insulin levels; higher 30-, 60-, and 120-min post-challenge free fatty acid levels than the Non-MS group. Additionally, there was a significant, negative correlation between adiponectin levels, area under the free fatty acid curve, and area under the insulin curve at OGTT (r = -0.24, p0.01; r = -0.21, p0.01, respectively). When the patients were divided by adiponectin level into four groups to examine the number of risk factors for MS detected per patient and the incidence of MS, the lower the adiponectin level, the more risk factors were found per patient, with 68% of patients with an adiponectin level of less than 4 microg/mL found to have MS. In those with an adiponectin level of less than 4 microg/mL, BMI values, uric acid levels, HOMA-R values, and the number of risk factors for MS involved per patient were shown to be higher than in those with an adiponectin level of 4 microg/mL or greater. Furthermore, the following risk factors for MS were more frequently found in those with an adiponectin level of less than 4 microg/mL than in those with an adiponectin level of 4 microg/mL or greater: VFAor = 100 cm2 (OR 12.8, p0.001); TGor = 150 mg/dL (OR 3.2, p0.05); HDLC40 mg/dL (OR 1.9, p = 0.29); BPor = 130/85 mmHg (OR 2.2, p = 0.15); and FPGor = 110 mg/dL (OR 1.9, p = 0.29). Again, the incidence of MS (OR 7.6, p0.001) by the ATPIII criteria, as well as that by the Japanese criteria (OR 8.6, p0.001), was found to be higher in those with an adiponectin level of less than 4 microg/mL than in those with an adiponectin level of 4 microg/mL or greater. Our study results suggest that adiponectin is closely associated with the multiple risk factors that go to make up the MS, suggesting a role for hypoadiponectinemia as a surrogate marker for the MS and further appear to suggest that post-challenge hyper-free fatty acidemia may account in part for hypoadiponectinemia in the MS.

We investigated the relationship between insulin reaction and glycemic control in a 75-g oral glucose tolerance test of lipid in the paraspinal muscles using computed tomography (CT). The subjects were 79 males aged from 30 to 60 years old whose body mass index (BMI) was 25 or more. Those who had already been diagnosed as having type-2 diabetes mellitus in a regular health check and whose fasting plasma glucose was 126 mg/dl or more were excluded. Abdominal CT scan at the umbilicus level was conducted, and the visceral fat area (VFA) and subcutaneous fat area (SFA) were obtained. As an index of the relative lipid content within muscle, the mean skeletal muscle attenuation (MA) was determined. The age-adjusted odds ratio caused by the MA size for each variable was calculated. Compared with those with smaller intramuscular fat volume, those with larger volume demonstrated 8.75 times higher BMI, 3.73 times higher VFA and 2.88 times higher HOMA-IR. A significant difference was observed between the groups with high and low lipid content in the muscle in the values of Age, BMI, VFA, Fasting immunoreactive insulin (IRI) and HOMA-IR. It was suggested that MA of the paraspinal muscles reflected fat content, and this regional body composition parameter was closely related to insulin secretion response and glycemic control.

Impaired glucose tolerance (IGT) represents a prediabetic state positioned somewhere between normal glucose tolerance and diabetes, which is also assumed to make individuals in this state highly susceptible to atherosclerotic disease. IGT also accounts for a highly heterogeneous population, with the condition varying from individual to individual. In this study, we stratified subjects with IGT by their insulin response and compare the pathology of IGT when it is associated with high or low insulin response to gain insight into the diverse pathology of IGT. Of the male corporate employees who underwent 75 g OGTT at the corporation's healthcare center, 150 individuals diagnosed with IGT (isolated IGT, combined IGT and IFG) comprised our study subjects. The study subjects were stratified into four quartiles by percentile AUC for insulin, and those in the 25th or less percentile were defined as the low insulin response group (n = 37), vs those in the 76th or greater percentile defined as the high insulin response group (n = 38), and these groups were compared. There was no significant difference observed between the two groups in regard to post-OGTT glucose response and area under the glucose curve. However, the high insulin response group was associated with higher BMI, subcutanesous fat area, uric acid levels, HOMA-beta cell values, and delta insulin/delta glucose (30 min) than the low insulin response group. The number of risk factors for the metabolic syndrome detected (as defined by the ATPIII diagnostic criteria) per subject was 2.84 +/- 0.17 and 2.08 +/- 0.20, respectively, in the high insulin response group and in the low insulin response group, with the number significantly (p0.05) higher in the high insulin response group. Furthermore, the incidence of the metabolic syndrome as defined by the ATPIII diagnostic criteria was 63.2% (24/38) in the high insulin response group vs 32.4% (12/27) in the low insulin response group, with the incidence significantly (p0.01) higher in the high insulin response group. Likewise, the incidence of the metabolic syndrome as defined by the Japanese diagnostic criteria was found to be significantly (p0.05) higher in the high insulin response group at 50% (19/38) compared to 27.0% (10/37) in the low insulin response group. Our study findings suggest that IGT subjects with high insulin response and those with low insulin response vary greatly in regard to the number of atherosclerotic risk factors complicated and the frequency with which they are associated with the metabolic syndrome. It is also shown in middle-aged Japanese males that of the two forms of IGT, IGT with high insulin response is more closely linked to the pathogenesis of atherosclerotic cardiovascular disease.

To investigate the relationship between insulin resistance, postprandial hyperglycemia, postprandial hyperlipidemia, and oxidative stress in type 2 diabetes, changes in postprandial glucose, triglyceride, and nitrotyrosine levels vs baseline after diet loading were examined in type 2 diabetic patients given pioglitazone (PG) or glibenclamide (GB). Twenty-four outpatients with type 2 diabetes treated with oral PG for 6 mo (BMI, 26.3 +/- 0.9; HbA1c, 8.2 +/- 0.2%) and 10 type 2 diabetic patients treated with GB (BMI, 27.4 +/- 1.6; HbA1c, 8.1 +/- 0.2%) at our institutions were compared. These patients were given meal tolerance tests (MTT; each consisting of energy 400 kcal, protein 8.7 g, fat 22.4 g, carbohydrate 41 g) before and 6 mo after administration of either agent. PG produced a significant decrease in FPG, HbA1c, HOMA-R, and TG levels in the subjects compared to baseline. In contrast, GB significantly decreased FPG and HbA1c levels, while not affecting HOMA-R and TG values. While PG produced a significant increase in LPL, HDL-cholesterol, and adiponectin levels, GB did not affect these values. At MTT 6 mo after PG administration, insulin levels before and 4 h after MTT, free fatty acid (FFA) levels 1, 2, and 4 h after MTT, glucose, TG, and RLP-TG levels before and 1, 2, 4, and 6 h after MTT were significantly decreased compared to baseline. At MTT 6 mo after GB administration, while a significant decrease in fasting and 2 h, postprandial glucose values compared to baseline MTT levels was observed, fasting and postprandial TG and RLP-TG levels remained unchanged compared to baseline. After 6 mo of PG and GB administration, serum nitrotyrosine levels before and after MTT were significantly decreased compared to baseline in both groups, while the decrease in nitrotyrosine levels before and after MTT was more marked in the subjects given PG. Our study results suggest that PG suppresses increases in postprandial glucose and TG levels, and improves insulin resistance; and, in addition, that PG may have a favorable impact on oxidative stress in type 2 diabetic patients.

We experienced a case in which 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (131I-adosterol) scintigraphy showed high uptake in the right adrenal gland. We diagnosed functional cortical adenoma because of the finding of 131I-adosterol scintigraphy. However, no positive findings for the existence of cortical adenoma were obtained in other examinations and we performed right adrenalectomy. Unexpectedly, pathological finding showed the right adrenal gland was occupied with a large ganglioneuroma. This is an instructive case in which 131I-adosterol scintigraphy showed abnormal high uptake in the adrenal gland, in spite of the fact that the adrenal gland was occupied by a tumor derived from adrenal medulla.

Our study evaluated the relationship between the pathologic changes associated with atherosclerosis, as primarily represented by postprandial remnant-like lipoproteins and carotid intima-media thickness (IMT), in type 2 diabetic patients. Meal tolerance tests (MTT) were performed in 68 patients with type 2 diabetes. The subjects were divided by pre-meal and 2-h postprandial triglyceride (TG) levels into the normotriglyceridemia (NTG) group; the postprandial hypertriglyceridemia (PHTG) group; and the fasting hypertriglyceridemia (FHTG) group. HOMA-R values were significantly higher in the FHTG group than in the NTG group, with the plasma pre-heparin LPL mass and serum adiponectin levels in the FHTG and PHTG groups significantly lower than in the NTG group. One- and two hour postprandial RLP-TG levels were significantly higher in the PHTG group than in the NTG group, while there was no significant difference in postprandial glucose levels between the two groups. The IMT values were significantly higher in both the FHTG and PHTG groups than in the NTG group. Logistics regression analysis of the 1- and 2-h RLP-TG values using IMT as an induced variable showed the odds ratio for high IMT values to be 5.17 (p0.05) for the 1-h RLP-TG values and 3.01 (p = 0.105) for the 2-h RLP-TG values. Our study results suggest that delayed TG metabolism leading to the retention of remnants in type 2 diabetic patients appears to be closely associated with atherosclerosis, and that postprandial hyperlipidemia is an independent risk factor for the early onset of atherosclerosis.

Objective: Short-term hypoglycemic effects of single-dose voglibose and nateglinide were compared after sucrose loading in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Materials and Methods: After a 17-h fasting period, the animals received 0.06 mg/kg of voglibose (VOG group, n=6), 50 mg/kg of nateglinide (NAT group, n=6), or 0.5% methyl cellulose (control group, n=6), immediately followed by 2.5 g/kg of sucrose. Results: Compared to control group values, glucose levels after sucrose loading were significantly decreased in the portal blood in the VOG group and in the peripheral blood in the NAT and VOG groups. The portal glucose AUC0−120 min was significantly lower in the VOG group than in the control and NAT groups, whereas the peripheral glucose AUC0−120 min was significantly lower in the VOG and NAT groups than in the control group. Portal insulin levels in the VOG group were significantly decreased compared to the control group. However, portal insulin levels in the NAT group were acutely increased, peaking 15 min after sucrose loading. Portal FFA levels were decreased in the NAT group 15, 30, and 60 min after sucrose loading; no FFA reductions were seen in the VOG group. Conclusions: Although both drugs produced similar hypoglycemic effects after sucrose loading in the peripheral blood, these drugs generated vastly different results in portal blood. Reduced FFA in the portal blood, observed after single administration of nateglinide, may have a favorable impact not only on glucose metabolism but also on lipid metabolism.

Bilateral symmetric striopallidodentate calcinosis, also known as Fahr's disease, is characterized by bilateral calcifications of the basal ganglia, thalami, dentate nuclei of the cerebellum, and the white matter of the cerebral hemisphere. Intracranial calcifications are easily visible as high-density areas on computed tomographic images. On magnetic resonance images, the calcifications exhibit different signal intensities. The differences in signal intensity are thought to be related to the stage of the disease, differences in calcium metabolism, and the volume of the calcium deposit. The moderate reduction of cerebral blood flow in bilateral thalami was also identified using brain SPECT.

The diagnostic potential of a new bone resorption marker, type I collagen-cross-linked N telopeptide (NTx), for bone metastasis of prostate cancer was evaluated. Ninty-one prostate cancer patients underwent bone scintigraphy, and urine NTx/creatinine (NTx/Cr) was measured. Urine NTx/Cr levels were compared with bone scintigraphic results. Urine NTx/Cr levels in the bone metastasis-positive group (n = 47) were 92.9 +/- 105.1 nmol/L of bone collagen, which is equivalent to per millimole of urinary creatinine (nmol/L BCE/mmol/L Cr), significantly higher than the level of the bone metastasis-negative group (n = 44) (59.0 +/- 41.6 nmol/L BCE/mmol/L Cr). When patients were classified by the extent of disease grade (EOD grade) nomenclature, the urine NTx/Cr level of the EOD (4+) group was 209.5 +/- 186.5 nmol/L BCE/mmol/L Cr. This level was significantly higher than those of the EOD (-) group (59.0 +/- 41.6 nmol/L BCE/mmol/L Cr), EOD (1+) group (59.0 +/- 47.8 nmol/L BCE/mmol/L Cr), and EOD (2+) group (81.1 +/- 41.3 nmol/L BCE/mmol/L Cr). However, no significant difference was observed between the EOD (-) and EOD (1+) groups. The mean change in urine NTx/Cr level 3 to 17 months after the first bone scintigraphy and urine NTx/Cr examination in the bone metastasis-progression group (n = 8) was 11.0 +/- 31.2 nmol/L BCE/mmol/L Cr, significantly higher than that in the bone metastasis-regression group (n = 15) (-26.8 +/- 40.7 nmol/L BCE/mmol/L Cr). In conclusion, urine NTx /Cr can be measured noninvasively and reflects the state of bone metastasis. However, the sensitivity of urine NTx/Cr is not as high as that of bone scintigraphy. Therefore, it may provide an auxiliary diagnostic index for bone scintigraphy.

99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) scintigraphy with Digirad 2020tc ImagerTM (2020tc), which was a multi-crystal scintillation camera with solid-state detectors was performed for patients with secondary hyperparathyroidism having autografts of parathyroid glands in the right arm. With the 2020tc camera, three abnormal accumulations were found in the right arm. The images obtained with this camera were superior in resolution to those obtained with a conventional NaI crystal gamma camera (ZLC7500, Siemens, Germany). The next day, resection of autografts of parathyroid glands was done. Four hyperplastic parathyroid glands were resected and all were hyperplastic in pathological findings.

We performed N-isopropyl-p (I-123) iodoamphetamine (IMP) single-photon emission computed tomography (SPECT) on 28 patients with severe cerebrovascular disease before rehabilitation, and compared the degree of redistribution and the assessment of activities of daily living (ADL). We calculated a redistribution (RD) ratio in the central and peripheral parts of the lesions: RD ratio (c) and RD ratio (p). We classified the patients into four groups based on the degree of redistribution: complete: both RD ratio (c) and (p)or = 75; peripheral: RD ratio (c)75, RD ratio (p)or = 75; incomplete: both RD ratio (c) and (p)75 and at least one of RD ratio (c) or (p)or = 25; no redistribution: both RD ratio (c) and (p)25. We assessed the ADL using the modified Barthel index (BI). deltaBI was defined as BI after rehabilitation-BI before rehabilitation (BIpost-BIpre). The deltaBI of the four groups were as follows: complete-redistribution group (40.8 +/- 22.8), peripheral-redistribution group (40.0 +/- 15.8), incomplete-redistribution group (27.2 +/- 22.6), no-redistribution group (8.8 +/- 12.3). The deltaBI of the complete and peripheral redistribution groups were significantly higher than that of the no-redistribution group. However, deltaBI was almost the same in the complete- and peripheral-redistribution groups. This suggests that the effect of rehabilitation might be closely related to the viability of the peripheral part of the lesion.

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 bone-seeking radiopharmaceutical Sr-89 has been used as a palliative treatment for patients with bone pain caused by bone metastases. The authors report the results of nine patients (three with prostate cancer, four with breast cancer, one with thyroid cancer, and one with lung cancer) who underwent therapy with Sr-89 chloride for painful bone metastases, and evaluate Sr-89 imaging with bremsstrahlung. Two levels of dosage (1.5 and 2.2 MBq/kg) were used. Sr-89 imaging was performed in seven patients 1 week after injection. Abnormal uptake was seen in all and was consistent with the results of Tc-99m HMDP imaging. Six patients were assessed at 3 months and three patients toward the time they were terminal; 78% (seven of nine) derived some benefit. Two patients had a favorable clinical response and showed improvement on Tc-99m HMDP imaging.

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.

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.

Three-phase bone scintigraphy has been used for the diagnosis of osteomyelitis in some regions of the body. However, its utility in patients with chronic osteomyelitis of the mandible (COM) has been reported only occasionally and the significance has not been fully examined. The aim of this study was to investigate what can be identified from each phase of the three-phase bone scintigraphy in patients with COM. Three-phase bone scintigraphy using 99mTc-labeled phosphonates was performed [96 s (phase 1), 5 min (phase 2) and 3 h (phase 3)] in 15 patients with COM. An increase in accumulation was regarded as a positive result in visual analysis. We investigated the positive ratio of each phase, including in the classification of the disease type, serum white blood cell count, C-reactive protein value and morbidity period. We also calculated the uptake ratio relative to the contralateral side using mean and maximum counts of the region of interest in semiquantitative analysis and investigated the correlation between the uptake ratios of each phase. The positive ratio of phases 2 and 3 was 100% and higher than that of phase 1 (33.3%, p = 0.0001). Almost all patients with a positive result in phase 1 had the osteolytic type (5/6). The extent of increased uptake on phase 3 images was similar to that of phase 2 images. The uptake ratio of phase 2 correlated with that of phase 3 (mean: r = 0.88, p

Childhood obesity is a medical and social problem in Japan. The number of obese children has been increasing steadily since 1980 according to a survey on school health statistics. However, more simple and reliable criteria for assessment of obesity in children are required. The aim of this study was to establish gender- and age-specific body mass index (BMI) cutoff values for evaluation of obesity in school-aged children. A total of 100,587 elementary school, junior and senior high school students, aged 6 to 17 years, comprised the study population, in whom BMI was measured. The BMI cutoff values were calculated by using the receiver operating characteristic (ROC) analysis in the degree of obesity of 20% or greater as definition of obesity. The validity of the determined cutoff values of BMI was then compared with the Rohrer index, the International Obesity Task Force (IOTF) data and the percentile method. The sensitivity and specificity of the BMI cutoff values were over 93% in both boys and girls of all ages, thereby providing criteria that are highly diagnostic in all ages. The Rohrer Index and BMI 95th percentile values tended to underestimate obesity, while the IOTF criteria tended to overestimate it. In conclusion, the BMI cutoff values determined in the present study enable us to detect obese individuals with extremely high precision, and thus may represent an instrument with superior diagnostic capabilities to those of the existing instruments currently being used for assessment of pediatric obesity.

To investigate changes in free benzodiazepine receptor density in response to repeated, long-term administration of diazepam in epilepsy, we assessed125I-iomazenil (125I-IMZ) binding in a mouse model. El mice were divided into two groups of 12 mice each which received either no diazepam (EI(D[-]) group) or 2 mg/kg of diazepam per week (EI(D[+]) group). Nine ddY mice were used as a control. Once each week from the age of 5 to 19 weeks, the El mice received stimulation to produce epileptic seizures 20 minutes after receiving intraperitoneal injections. At 20 weeks of age, a total dose of 0.37 MBq of125I-IMZ was injected in all mice and their brains were rapidly removed 3 hours later. The incidence of epileptic seizures at the age of 19 weeks and the autoradiograms of the brain were compared. The incidence of epileptic seizures in response to weekly stimulation was significantly lower in the E1(D[+]) group than in the E1(D[-]) group (p < 0.001). The percent injected doses of125I-IMZ per gram of tissue in the cortex, hippocampus and amygdala were significantly lower in the E1(D[+]) group than in the E1(D[-]) group (p < 0.05). The results suggest that diazepam binds competitively to125I-IMZ as an agonist to free benzodiazepine receptor sites in the cortex, hippocampus and amygdala and shows anticonvulsant effect in El mice.

Objective To investigate the influence of blockade of the renin-angiotensin system (RAS) on adipocytes, we compared the effect of telmisartan versus valsartan and amlodipine on adipocyte cellularity in the spontaneously type 2 diabetic, obese rat model. Methods Male Otsuka Long Evans Tokushima Fatty rats, 8-week-old, were divided into four groups as follows: valsartan (V) group (10 mg/kg, n = 12), telmisartan (T) group (5 mg/kg, n = 12), amlodipine (A) group (2 mg/kg, n = 12), and control (C) group (n = 12). Each drug was mixed with chow and given for 16 weeks. Results Although no significant differences were observed in the fasting plasma glucose level between the groups, the fasting plasma insulin level for group T was significantly lower than that for group C. Histopathologic examination showed that the ratio of small adipocytes in groups V and T was significantly higher than that in group C, with the ratio of large adipocytes and the mean adipocyte size shown to be significantly lower in groups V and T than in group C. Furthermore, group T was shown to have a significantly higher ratio of small adipocytes, a significantly lower ratio of large adipocytes, as well as a significantly lower mean adipocyte size, compared to group V. Conclusions Although both valsartan and telmisartan downsized adipocytes, adipocyte downsizing was significantly greater with telmisartan compared to valsartan. The likely mechanism for this difference was thought to be the PPAR-γ-mediated action of telmisartan.

Epidemiological and clinical studies on the lifestyle-related obesity have identified smoking, physical activity and alcohol intake as risk factors for obesity. However, no consensus has yet been reached on the effect of smoking on visceral adiposity. This study was designed to assess whether smoking is associated with the accumulation of visceral fat, glucose and lipid metabolism. The subjects were 450 males aged from 24 to 68 years old, who were examined at the health control center in the regular health check conducted by their company. A self-administered questionnaire was used to ascertain smoking status, daily physical activity and alcohol drinking. The number of Brinkman index as an index for smoking status was positively related to being visceral fat area (VFA). In smokers whose Brinkman index was higher, the percent of subjects with abnormal body mass index, VFA, triglyceride, high density lipoprotein-cholesterol, atherosclerotic index, plasma glucose, immunoreactive insulin, or homeostasis model assessment of insulin resistance (HOMA-IR) was higher than that in non-smokers. When evaluated in terms of age-adjusted odds ratios for incidence of a VFA of 100 cm(2) or greater, alcohol drinking was associated with the highest odds ratio. Smoking, physical inactivity and excessive alcohol drinking were associated with visceral adiposity, and smoking affected glucose and lipid metabolism. In conclusions, these findings suggest that smoking is a risk factor for visceral fat accumulation and deterioration of glucose and lipid metabolism.

In recent years, intra-abdominal visceral fat leads to obesity-related complications. A simple indicator that reflects the mass of visceral fat is also needed to enable practical screening of patients. The present study was designed to establish new body mass index (BMI) criteria of central obesity for male Japanese. The subjects were 516 men aged from 19 to 80 years old who were examined at the physical examination center in the regular health check conducted by their company. Correlations between visceral fat area (VFA) or subcutaneous fat area (SFA) and BMI in the subjects were investigated. Receiver Operating Characteristics (ROC) curve was used to find out the optimal cut-off values of BMI to predict central obesity. We compared the percentile ranks corresponding to VFA of 100 cm2, BMI of 25 kg/m2 and new BMI criteria to check to see whether the present BMI criteria classify correctly Japanese men as central obesity. Further evidence for the effectiveness of BMI for VFA is needed. The correlation coefficient between VFA or SFA and BMI was 0.59 or 0.67, respectively. At the cut-off for BMI that maximized sensitivity and specificity for predicting central obesity was 24 kg/m2. Moreover, the percentile value corresponding to VFA of 100 cm2, BMI of 24 kg/m2, and BMI of 25 kg/m2 was the 53, 50 and 61 percentile, respectively. It is necessary to lower a cut-off point for central obesity from BMI of 25 kg/m2 to 24 kg/m2.

The age-related changes in acute insulin response after glucose loading and the influence of suppression of body weight gain were investigated by using blood samples from portal and peripheral veins. We placed indwelling catheters in the portal vein of 12- and 24- wk-old Otsuka Long-Evans Tokushima fatty (OLETF) rats (n = 8, 12), and age-matched control Long-Evans Tokushima Otsuka (LETO) rats (n = 8, 6). To suppress the body weight gain, 6 out of 12 OLETF rats were fed chow containing 50 ppm voglibose (VOG) from 8 until 24 wk of age. After fasting for 17 h, rats underwent 1 g/kg oral glucose tolerance test (OGTT). Peripheral glucose levels after glucose loading were significantly higher in 12- and 24-wk-old OLETF rats than in the age-matched LETO rats. Values for delta insulin 15 min/delta glucose 15 min (delta I15 min/delta G15 min) in portal blood were 0.029 +/- 0.011 and 0.009 +/- 0.009 (12 wk of age) and 0.03 +/- 0.03 and -0.01 +/- 0.01 (24 wk of age) in the LETO rats and OLETF rats. At the age of 24 wk, the body weights in VOG-treated OLETF rats were significantly lower than those in the OLETF rats. And there was significantly greater acute insulin response to glucose in VOG-treated OLETF rats than in the OLETF rats. Acute insulin response to glucose decreased with advancing age and the suppression of body weight gain preserved the response in spontaneously type 2 diabetic rats with visceral fat obesity.

The effect of short-term bezafibrate (BF) administration over time on the expression of adiponectin mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into the high-dose (100 mg/kg) BF group (n=15), the low-dose (10 mg/kg) BF group (n=15), or the control group (n=15) and followed up for 14 d. Tri-glyceride and free fatty acid levels significantly decreased in a dose-dependent manner in the high-dose BF group. The insulin levels increased with time, although they were significantly lower in the high-dose BF group on d 3 and 7 than the control group. Adiponectin levels significantly increased in the high-dose BF group. On d 14 of BF administration, the levels of VLDL and chy-lomicron were significantly lower in BF groups, and adiponectin mRNA expression in the white adipose tissue was significantly higher in the high-dose BF group. Findings from this study suggest that in type 2 diabetes with insulin resistance, hypertriglyceridemia is closely linked to adiponectin.

The aim of the present study was to determine the effects of dietary diacylglycerol (DG) on the metabolism of lipids and glucose in type II diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats.In experiment 1, the rats were orally administered 10 mL/kg of a triacylglycerol (TG) or DG emulsion (15% [w/v] oil), and the subsequent changes in the serum lipid levels were compared. In experiment 2, the rats were fed diets containing 15% DG or TG oil. After 22 weeks, the serum levels of lipids, glucose, and cytokines were determined. In addition, an oral glucose tolerance test (OGTT) was performed on the rats.Administration of an oral fat load caused marked hypertriglyceridemia with a peak at 2 h. Oral DG loading reduced the serum TG increase; the difference between the groups was significant at 4 and 6 h (P0.05). Diacylglycerol also markedly reduced the serum free fatty acid concentration increase due to the fat load. After 22 weeks of feeding, dietary DG reduced serum TG levels in the non-fasting state. Moreover, an OGTT revealed enhanced glucose disposal in the DG-fed rats compared with the TG-fed rats. Serum levels of adiponectin, an important insulin-sensitizing adipocytokine, were higher in the DG-fed rats than in the TG-fed rats (P0.05). In addition, DG-feeding reduced serum levels of C-reactive protein, a cardiovascular risk factor (P0.05).These results suggested that dietary DG improves lipid metabolism and glucose tolerance, and retards the progress of diabetes mellitus in OLETF rats.

To elucidate the role of early insulin response in post-prandial hyperlipidemia, we examined triglyceride (TG) and remnant-like particle triglyceride (RLP-TG) levels, using a meal tolerance test (MTT) with or without the administration of nateglinide (NAT). The MTTs were performed 2 d apart in 36 drug-naive patients with type 2 diabetes who had been hospitalized for glycemic control while receiving diet therapy. Before the second MTT, patients were treated with 90 mg NAT. Treatment with NAT was associated with a significant increase in insulin levels in the treated patients 1 h after the test meal, compared to levels in non-treatment. NAT treatment was also associated with a significant decrease in the level of free fatty acids 1 and 2 h after the meal, and with a significant decrease in plasma glucose levels 1, 2, and 4 h after the meal, compared to those in non-treatment. During the first MTT with NAT non-treatment, 13 patients showed serum TG levels of 200 mg/dL or greater when measured 2 h after the meal. In these 13 patients, NAT administration produced a significant decrease in TG levels 1, 2, and 6 h after the meal, as well as a significant reduction in RLP-TG levels 1 and 2 h after the meal. NAT administration was also associated with significant reductions in area under the curve (DeltaAUC) for TG and RLP-TG. These results suggest that, in a clinical setting, the early insulin response is closely associated with both postprandial glucose and postprandial lipid metabolism in Japanese patients with type 2 diabetes.

The efficacy of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI)-guided surgery for detecting abnormal parathyroid glands in patients with secondary hyperparathyroidism (2-HPT) was evaluated and compared with the results from the same examination in patients with primary hyperparathyroidism (1-HPT). The results were also compared with those found by ultrasonography (US) and preoperative 99mTc-MIBI scintigraphy was also made. At operation 99mTc-MIBI accumulated in 64 nodules of 15 cases of 2-HPT, and all of 60 parathyroid swellings were detected (true-positives 60, sensitivity 100%, accuracy 94%). In the cases of 1-HPT, 99mTc-MIBI revealed 11 hot nodules in 10 cases, and the evaluation was true-positive 10, sensitivity 100%, and accuracy 91%. US and preoperative 99mTc-MIBI scintigraphy in patients with 2-HPT had a sensitivity of 75% and 67% and an accuracy of 70% and 66%, respectively. The usefulness of 99mTc-MIBI-guided surgery for detecting abnormal parathyroid tissue in 2-HPT patients was similar to that in 1-HPT patients but was superior to US and preoperative 99mTc-MIBI scintigraphy. Intraoperative 9mTc-MIBI for patients with 2-HPT is effective and makes the surgery easier, especially when the parathyroid glands are ectopic or when a few glands are markedly enlarged but the other glands are atrophied.

Recent reports have shown that radio-guided surgery with an intraoperative gamma probe (IGP) is useful for identifying parathyroid adenomas. The aim of this study was to evaluate the usefulness of IGP mapping in patients with secondary hyperparathyroidism. Seven patients with secondary hyperparathyroidism underwent technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) scintigraphy immediately before undergoing surgical resection of all parathyroid tissues. We compared the sensitivity of Tc-99m MIBI scintigraphy alone with that of the combination of Tc-99m MIBI scintigraphy and IGP mapping. The sensitivity of the combination of Tc-99m MIBI scintigraphy and IGP mapping was 100% (28 of 28 lesions) and was significantly higher than that of Tc-99m MIBI scintigraphy alone (71.4%, 20 of 28 lesions). The combination of the Tc-99m MIBI scintigraphy and IGP mapping has increased sensitivity for identifying parathyroid lesions during parathyroidectomy in patients with secondary hyperparathyroidism.

Insulin secretion dynamics and response to nateglinide were studied in patients with type 2 diabetes and reduced early-phase insulin secretion. On day 1, 24 patients underwent a 75-g oral glucose tolerance test without taking nateglinide. On day 2, they were given oral nateglinide 90 mg immediately before the oral glucose tolerance test. After glucose loading, insulin levels increased significantly at 30, 60, 90, and 120 minutes after the patients took nateglinide, along with insulinogenic indices, the total area under the insulin curve, the area under the 0- to 90-minute insulin curve, and the area under the 90- to 180-minute insulin curve. Both the plasma glucose level at 60, 90, 120, and 180 minutes and the total area under the glucose curve were significantly reduced following nateglinide administration. Compared with the low responders (n=13), the high responders (n=11) had a significantly shorter duration of disease, significantly higher insulinogenic indices in the absence of nateglinide administration, and a higher homeostasis model assessment-beta cell performance. Nateglinide demonstrated a rapid-onset and rapid-offset insulin secretion-stimulating effect in this study population. A single dose of nateglinide may be indicated for patients with a relatively high homeostasis model assessment-beta cell performance, a short duration of disease, and relatively high insulinogenic indices prior to nateglinide administration.