Effects of sleep restriction on food intake and appetite under free-living conditions: A randomized crossover trial.

To investigate changes in subjective psychological factors and dietary intake during sleep restriction, we carried out a randomized crossover trial with a 3-day sleep restriction condition (SR; 5 h of sleep) and control sleep condition (CS; 8 h of sleep). Days 3 and 4 involved free-living and laboratory (in the morning) conditions, respectively. Subjective psychological factors (hunger, appetite, desire for sweets and fatty foods, sleepiness, and fatigue) were assessed using a 0.0-10.0 cm visual analog scale (VAS) every hour throughout the day on day 3, and at 8:00 a.m. on day 4. Dietary intake on day 3 was assessed on the basis of the food purchased and eaten. Fasting blood samples were collected at 8:00 a.m. on day 4. Dietary intake during the ad libitum breakfast was assessed on day 4. The participants were 13 women and 11 men (mean age, 21.4 ± 1.0 years; mean body mass index, 19.8 ± 1.7 kg/m2). The areas under the curve 0-16 h after waking for hunger, desire for fatty foods, sleepiness, and fatigue were higher in the SR than CS on day 3 (P < 0.05). Energy and carbohydrate intakes from snacks (daytime and nighttime) on day 3 were higher in the SR than CS (P < 0.05) but total dietary intake on day 3 was not different between the conditions (P > 0.05). The 2-arachidonoylglycerol level was different between the conditions (P < 0.05), but was not associated with sweet taste preference, dietary intake, or the active ghrelin level on day 4 (P > 0.05). In conclusion, ratings for subjective psychological factors and energy and carbohydrate intakes from snacks increased in association with sleep restriction under free-living conditions.

Relationship between intra-individual variability in nutrition-related lifestyle behaviors and blood glucose outcomes under free-living conditions in adults without type 2 diabetes.

AIMS: This study determined the relationship between intra-individual variability in day-to-day nutrition-related lifestyle behaviors (meal timing, eating window, food intake, movement behaviors, sleep conditions, and body weight) and glycemic outcomes under free-living conditions in adults without type 2 diabetes. METHODS: We analyzed 104 adults without type 2 diabetes. During the 7-day measurement period, dietary intake, movement behaviors, sleep conditions, and glucose outcomes were assessed. Daily food intake was assessed using a mobile-based health application. Movement behaviors and sleep conditions were assessed using a tri-axial accelerometer. Meal timing was assessed from the participant's daily life record. Blood glucose levels were measured continuously using a glucose monitor. Statistical analyses were conducted using a linear mixed-effects model, with mealtime, food intake, body weight, movement behaviors, and sleep conditions as fixed effects and participants as a random effect. RESULTS: Dinner time and eating window were positively significantly correlated with mean (dinner time, p = 0.003; eating window, p = 0.001), standard deviation (SD; both at p < 0.001), and maximum (both at p < 0.001) blood glucose levels. Breakfast time was negatively associated with glucose outcomes (p < 0.01). Sedentary time was positively significantly associated with blood glucose SD (p = 0.040). Total sleep time was negatively significantly correlated with SD (p = 0.035) and maximum (p = 0.032) blood glucose levels. Total daily energy intake (p = 0.001), carbohydrate intake (p < 0.001), and body weight (p < 0.05) were positively associated with mean blood glucose levels. CONCLUSION: Intra-individual variations in nutrition-related lifestyle behaviors, especially morning and evening body weight, and food intake, were associated with mean blood glucose levels, and a long sedentary time and total sleep time were associated with glucose variability. Earlier dinner times and shorter eating windows per day resulted in better glucose control.

Eating Dinner Early Improves 24-h Blood Glucose Levels and Boosts Lipid Metabolism after Breakfast the Next Day: A Randomized Cross-Over Trial.

Aim: To examine whether mild early time-restricted eating (eating dinner at 18:00 vs. at 21:00) improves 24-h blood glucose levels and postprandial lipid metabolism in healthy adults. Methods: Twelve participants (2 males and 10 females) were included in the study. In this 3-day (until the morning of day 3) randomized crossover study, two different conditions were tested: eating a late dinner (at 21:00) or an early dinner (at 18:00). During the experimental period, blood glucose levels were evaluated by each participant wearing a continuous blood glucose measuring device. Metabolic measurements were performed using the indirect calorimetry method on the morning of day 3. The study was conducted over three days; day 1 was excluded from the analysis to adjust for the effects of the previous day's meal, and only data from the mornings of days 2 and 3 were used for the analysis. Results: Significant differences were observed in mean 24-h blood glucose levels on day 2 between the two groups (p = 0.034). There was a significant decrease in the postprandial respiratory quotient 30 min and 60 min after breakfast on day 3 in the early dinner group compared with the late dinner group (p < 0.05). Conclusion: Despite a difference of only 3 h, eating dinner early (at 18:00) has a positive effect on blood glucose level fluctuation and substrate oxidation compared with eating dinner late (at 21:00).

Acute Sleep Curtailment Increases Sweet Taste Preference, Appetite and Food Intake in Healthy Young Adults: A Randomized Crossover Trial.

This study aimed to examine the effect of acute sleep curtailment on sweet taste preference, appetite and food intake, and the correlation between food intake and sweet taste preference or active ghrelin using a randomized crossover design (5 h sleep curtailment vs. 8 h control). Twenty-four participants (11 men) aged 21.4 ± 1.0 years, with BMI 19.8 ± 1.7 kg/m2, who habitually slept 5 h/night or more experienced interventions lasting three consecutive nights. Participants came into the laboratory for testing on day 4. Fasting blood tests were conducted at 8:00 a.m. to measure active ghrelin and leptin levels. Sweet taste preference was assessed by presenting five different concentration sucrose solutions at 9:00 a.m. Ad libitum intake at breakfast was assessed for 30 min from 9:30 a.m. Sweet taste preference was higher following sleep curtailment than control. Active ghrelin was likewise higher following sleep curtailment than control. Leptin did not differ between conditions. Energy intake was higher following sleep curtailment than control, being derived primarily from carbohydrates. However, sweet taste preference and active ghrelin did not correlate with energy intake. These results suggest that acute consecutive sleep curtailment increases sweet taste preference, active ghrelin, and energy intake in healthy young adults.

Comparison of the efficacy and safety of once-daily insulin degludec/insulin aspart (IDegAsp) and long-acting second-generation basal insulin (insulin degludec and insulin glargine 300 units/mL) in insulin-naïve Japanese adults with type 2 diabetes: a pilot, randomized, controlled study.

To examine the efficacy and safety of once-daily insulin degludec/insulin aspart (IDegAsp) or once-daily second-generation basal insulin analogs (insulin degludec and insulin glargine 300 units/mL) in insulin-naïve Japanese adults with type 2 diabetes in routine clinical practice. A 12-week multicenter, open-label, randomized, pilot study was performed in 52 subjects with type 2 diabetes treated with oral antidiabetic drugs (OADs). Subjects were randomized to once-daily IDegAsp (n = 26) or basal insulin (n = 26). The primary endpoint was percent change in HbA1c from baseline to week 12. Furthermore, it was analyzed post hoc in subgroups stratified by baseline HbA1c. During a follow-up period, percent change in HbA1c was not significantly different between the two groups (p = 0.161). Daily insulin doses and frequency of overall hypoglycemia were also similar in the two groups. In post hoc analyses, once-daily basal insulin was more effective than IDegAsp in subjects with HbA1c more than or equal to 8.5% (p < 0.05); however, in subjects with HbA1c less than 8.5%, once-daily IDegAsp showed a significant improvement in percent change in HbA1c at week 12, compared with basal insulin (p < 0.01). Although there was no apparent difference in the HbA1c-lowering effects between two groups, when compared in subjects with HbA1c less than 8.5%, once-daily IDegAsp showed a significant effect in comparison with once-daily basal insulin. These findings suggest that the baseline HbA1c level might provide the important information for choosing IDegAsp or basal insulin in patients insufficiently controlled with OADs. This trial was registered with UMIN (no. UMIN000035431).

Short-Term Cost-Effectiveness of Switching to Insulin Degludec in Japanese Patients with Type 2 Diabetes Receiving Basal-Bolus Therapy.

INTRODUCTION: With one of the fastest aging populations in the world, demographic changes in Japan are a major public health concern due to the substantial burden that aging-associated diseases, such as type 2 diabetes (T2D), place on public healthcare systems. The aim of this analysis was to evaluate the short-term cost-effectiveness of switching Japanese patients with T2D receiving basal-bolus insulin therapy from their previous basal insulin to insulin degludec (degludec) under conditions of routine clinical practice. METHODS: A previously published, open-source model developed in Microsoft Excel was used to evaluate the cost-effectiveness of switching basal-bolus insulin therapy from patients' previous basal insulin to degludec versus continuing the previous basal insulin therapeutic regimen in terms of costs (2018 Japanese Yen [JPY]) and quality-adjusted life years (QALYs), from a Japanese public healthcare payer perspective. The model captured hypoglycemia rates and insulin dosing over a 1-year time horizon, and was informed by Japanese real-world evidence from the T2D cohort (N = 135) of the Kumamoto Insulin Degludec Observational study. RESULTS: Treatment with degludec was associated with improved effectiveness (+ 0.0354 QALYs), driven by lower daytime non-severe hypoglycemia rates with degludec, at slightly higher annual treatment costs (JPY 9510) versus continuing the previous basal insulin. Switching basal insulin to degludec was found to be a cost-effective intervention with an incremental cost-effectiveness ratio (JPY 268,811 per QALY gained) substantially below the willingness-to-pay threshold of 5 million JPY per QALY used in the Japanese Health Technology Assessment framework. Sensitivity analyses confirmed the robustness of this finding and indicated that the daytime non-severe hypoglycemia benefit with degludec was a key driver of outcomes in the base case. CONCLUSION: Based on Japanese real-world evidence, our analysis suggests that switching Japanese patients with T2D receiving a basal-bolus regimen from their previous basal insulin to degludec would be highly cost-effective. These data may help decision-makers in Japan allocate healthcare resources efficiently. TRIAL REGISTRATION: The KIDUNA study is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR): UMIN000021569. FUNDING: Novo Nordisk Pharma Ltd. Japan.

Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets.

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic ß-cells and improving glucose homeostasis.

Study Design of a Phase II Clinical Trial to Assess the Efficacy and Safety of Eperisone in Japanese Type 2 Diabetes Patients with Risk and Non-risk Alleles of CDKAL1.

Genetic variation in Cdk5 Regulatory Associated Protein 1-Like 1 (CDKAL1) is associated with the development of type 2 diabetes (T2D). Dysfunction of CDKAL1 impairs the translation of proinsulin, which leads to glucose intolerance. Eperisone, an antispasmodic agent, has been shown to ameliorate glucose intolerance in Cdkal1-deficient mice. We have launched a phase II clinical study to investigate the potential anti-diabetic effect of eperisone in T2D patients carrying risk or non-risk alleles of CDKAL1. The primary endpoint is the change of hemoglobin A1c (HbA1c) levels. We also examined whether the efficacy of eperisone in T2D patients is associated with CDKAL1 activity.

Effect of sleep curtailment on dietary behavior and physical activity: A randomized crossover trial.

Our objective was to clarify the effect of sleep curtailment on energy intake (EI) and physical activity under free-living conditions. Participants were 16 healthy women aged 21-22years. A randomized crossover trial design was used to compare a short sleep condition (SS): 4h/night (2:00-6:00) and a control sleep condition (CS): 7h/night (23:00-6:00). Each condition comprised 3 consecutive nights. Sleep duration was assessed using a wristwatch-type accelerometer at home. All living activities except sleeping were free-living. Physical activity was assessed using a tri-axial accelerometer, and was categorized by intensity level (sedentary; sedentary to light; moderate to vigorous). Participants were asked to purchase and consume meals with visible nutrient information. EI was evaluated by adding values from these food labels. Mean sleep duration in the two conditions was significantly different (4.3±0.3 vs. 7.1±0.4h, p<0.01). For the shared wakefulness period in the two conditions (6:00-23:00), step counts and physical activity were not significantly different. Sedentary time (878±61 vs. 727±40min, p<0.01), and sedentary to light-intensity activity time (1122±18 vs. 932±63min, p<0.01) were significantly increased in SS (waking time, 06:00-02:00) compared with CS (waking time, 06:00-23:00). However, these significant effects were clearly attenuated after adjustment for awake time (p>0.05). Total EI was not significantly different between conditions (8.64±0.82 vs. 8.46±1.28MJ, p>0.05), nor were leptin levels (p>0.05), but insulin and cortisol levels after SS were significantly higher than after CS (p<0.05). In this study, physical activity was increased in the SS condition and attributed to differences in awake time between conditions. However, there were no differences in EI. Further studies to investigate the effect of sleep curtailment on weight gain through stress and insulin resistance are necessary.

Impaired balance is related to the progression of diabetic complications in both young and older adults.

AIMS: To investigate the balance ability in younger and older adults with diabetes and evaluate the associations between balance ability and microvascular complications. METHODS: This cross-sectional observational study compared 162 participants and 177 controls with and without type 2 diabetes, respectively. Balance ability was assessed using two static (one-legged stance and postural sway area) and two dynamic (Timed Up and Go [TUG] and Functional Reach) tests. Diabetic microangiopathy was also evaluated. RESULTS: Participants with diabetes, including both younger (<50years) and older (≥50years) participants, showed significantly worse balance ability in all four tests and were more likely to have a history of falls than the controls (all P<0.01). In all age groups, severe impairment of balance ability was associated with progression of diabetic microvascular complications. In all and older diabetic adults, a longer duration of diabetes (P=0.022) and higher TUG test score (P=0.004), and female sex (P=0.01) and higher TUG score (P=0.001), respectively, were related to a history of falls. On the other hand, among younger diabetic adults, only a non-significant association with longer duration of diabetes (P=0.066) was observed. CONCLUSIONS: Impaired balance ability correlates with microvascular diabetic complications. Accurate assessment of balance ability in adults with diabetes could predict the risk of falls, particularly benefitting people with diabetic complications.

Acetate alters expression of genes involved in beige adipogenesis in 3T3-L1 cells and obese KK-Ay mice.

The induction of beige adipogenesis within white adipose tissue, known as "browning", has received attention as a novel potential anti-obesity strategy. The expression of some characteristic genes including PR domain containing 16 is induced during the browning process. Although acetate has been reported to suppress weight gain in both rodents and humans, its potential effects on beige adipogenesis in white adipose tissue have not been fully characterized. We examined the effects of acetate treatment on 3T3-L1 cells and in obese diabetic KK-Ay mice. The mRNA expression levels of genes involved in beige adipocyte differentiation and genes selectively expressed in beige adipocytes were significantly elevated in both 3T3-L1 cells incubated with 1.0 mM acetate and the visceral white adipose tissue from mice treated with 0.6% acetate for 16 weeks. In KK-Ay mice, acetate reduced the food efficiency ratio and increased the whole-body oxygen consumption rate. Additionally, reduction of adipocyte size and uncoupling protein 1-positive adipocytes and interstitial areas with multilocular adipocytes appeared in the visceral white adipose tissue of acetate-treated mice, suggesting that acetate induced initial changes of "browning". In conclusion, acetate alters the expression of genes involved in beige adipogenesis and might represent a potential therapeutic agent to combat obesity.

Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma.

UNLABELLED: Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 µg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended. LEARNING POINTS: There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases.Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear.When total thyroidectomy is performed in patients with RTH, a large amount of thyroxine is needed to maintain their thyroid function.There is no consensus regarding the management of thyroid carcinoma in patient with RTH, but effective treatments such as total thyroidectomy followed by RAI and TSH suppression therapy are recommended.

A 1-year, prospective, observational study of Japanese outpatients with type 1 and type 2 diabetes switching from insulin glargine or detemir to insulin degludec in basal-bolus insulin therapy (Kumamoto Insulin Degludec Observational study).

AIMS/INTRODUCTION: The aim of the present prospective observational study was to assess long-term efficacy and safety of insulin degludec as a part of a basal-bolus therapy for Japanese patients with type 1 or type 2 diabetes in routine clinical practice. MATERIALS AND METHODS: In the present study, 93 type 1 diabetes patients and 135 type 2 diabetes patients treated with insulin glargine or detemir were switched from their basal insulin to insulin degludec. The primary end-points were the changes in glycated hemoglobin (HbA1c) from baseline at 3, 6 and 12 months. The secondary end-points were changes in body mass index, insulin dose, frequency of hypoglycemia and adverse events. RESULTS: HbA1c levels from baseline were significantly reduced at 3, 6, and 12 months by 0.4, 0.4 and 0.3% in type 1 diabetes patients, respectively, and by 0.5, 0.5 and 0.3% in type 2 diabetes patients, respectively. Body mass index in type 1 diabetes patients increased significantly (P < 0.05), whereas that in type 2 diabetes patients did not change. Basal insulin dose decreased significantly at 3 months after switching (P < 0.05), and returned baseline dose at 12 months in type 1 diabetes and type 2 diabetes patients. The frequency of both total and nocturnal hypoglycemia decreased significantly in type 1 diabetes and type 2 diabetes patients (P < 0.05). The result of multiple regression analysis showed that baseline HbA1c was a significant independent variable of the percentage change in HbA1c with switching. CONCLUSION: In both type 1 diabetes and type 2 diabetes patients, switching from insulin glargine or insulin detemir to insulin degludec led to improvement of glycemic control with a significant reduction of hypoglycemia.

Insulin requirement profiles in Japanese hospitalized subjects with type 2 diabetes treated with basal-bolus insulin therapy.

To assess the total daily inulin dose (TDD) and contribution of basal insulin to TDD and to identify the predictive factors for insulin requirement profiles in subjects with type 2 diabetes, we retrospectively examined insulin requirement profiles of 275 hospitalized subjects treated with basal-bolus insulin therapy (BBT) (mean age, 60.1 ± 12.9 years; HbA1c, 10.2 ± 4.5%). Target plasma glucose level was set between 80 and 129 mg/dL before breakfast and between 80 and 179 mg/dL at 2-hour after each meal without causing hypoglycemia. We also analyzed the relationship between the insulin requirement profiles (TDD and basal/total daily insulin ratio [B/TD ratio]) and insulin-associated clinical parameters. The mean TDD was 0.463 ± 0.190 unit/kg/day (range, 0.16-1.13 unit/kg/day). The mean B/TD ratio was 0.300 ± 0.099 (range, 0.091-0.667). A positive correlation of TDD with B/TD ratio was revealed by linear regression analysis (r=0.129, p=0.03). Stepwise multiple regression analysis identified post-breakfast glucose levels before titrating insulin as an independent determinant of the insulin requirement profile [Std ß (standard regression coefficient) = 0.228, p<0.01 for TDD, Std ß = -0.189, p<0.01 for B/TD ratio]. The TDD was <0.6 unit/kg/day and the B/TD ratio was <0.4 in the majority (70.2%) of subjects in the present study. These findings may have relevance in improving glycemic control and decreasing the risk of hypoglycemia and weight gain in subjects with type 2 diabetes treated with BBT.

Comparison of the efficacy of sitagliptin and glimepiride dose-up in Japanese patients with type 2 diabetes poorly controlled by sitagliptin and glimepiride in combination.

AIMS/INTRODUCTION: The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination. MATERIALS AND METHODS: A multicenter, prospective, randomized, open-label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low-dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end-point was the percentage change in glycated hemoglobin (HbA1c). RESULTS: During a follow-up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose-up (P < 0.01 vs baseline), but not by sitagliptin dose-up (P = 0.74). Univariate linear regression analyses showed that the percentage change in HbA1c was significantly associated with the serum level of arachidonic acid (AA) in both groups. CONCLUSIONS: There was no significant difference in the HbA1c-lowering effects between the two groups. However, a significant HbA1c-lowering effect from baseline of glimepiride dose-up was found, and the AA level showed a negative correlation with the decrease in HbA1c in the sitagliptin dose-up group, but a positive correlation in the glimepiride dose-up group. These findings suggest that the AA level is associated with HbA1c reduction in response to dose-up with these drugs in patients with type 2 diabetes in a combination therapy with sitagliptin and glimepiride. This trial was registered with UMIN (no. 000009544).

Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes.

BACKGROUND: An increased leukocyte count is an independent risk factor for cardiovascular events, but the association between leukocyte subtype counts and carotid atherosclerosis in patients with diabetes has not been determined. We therefore investigated the correlation between leukocyte subtype counts and intima-media thickness of the common carotid artery (CCA-IMT) in subjects with type 2 diabetes. METHODS: This cross-sectional study involved 484 in-patients with type 2 diabetes (282 males and 202 females), who were hospitalized for glycemic control and underwent carotid ultrasonography at Kumamoto University Hospital between 2005 and 2011. Mean and maximum CCA-IMT was measured by high-resolution B-mode ultrasonography. RESULTS: Univariate analyses revealed that mean CCA-IMT was positively correlated with age, systolic blood pressure, brachial-ankle pulse wave velocity (PWV), urinary albumin excretion and duration of diabetes, but was negatively correlated with diastolic blood pressure and fasting plasma glucose. Maximum CCA-IMT was positively and negatively correlated with the same factors as mean CCA-IMT except for fasting plasma glucose. Mean CCA-IMT was positively correlated with total leukocyte (r = 0.124, p = 0.007), monocyte (r = 0.373, p < 0.001), neutrophil (r = 0.139, p = 0.002) and eosinophil (r = 0.107, p = 0.019) counts. Maximum CCA-IMT was positively correlated with total leukocyte (r = 0.154, p < 0.001), monocyte (r = 0.398, p < 0.001), neutrophil (r = 0.152, p < 0.001) and basophil counts (r = 0.102, p = 0.027). Multiple regression analyses showed that monocyte count, age and PWV were significant and independent factors associated with mean CCA-IMT (adjusted R2 = 0.239, p < 0.001), and that monocyte count, age and urinary albumin excretion were significant and independent factors associated with maximum CCA-IMT (adjusted R2 = 0.277, p < 0.001). CONCLUSIONS: Monocyte counts were positively correlated with both mean CCA-IMT and maximum CCA-IMT in patients with type 2 diabetes. Monocyte count may be a useful predictor of macrovascular complications in patients with type 2 diabetes. TRIAL REGISTRATION: Trial registry no: UMIN000003526.

Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy.

To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( -0.64±0.60%), and was sustained over 24 weeks ( -0.69±0.85%). 1,5-AG increased significantly from 7.5±4.5 µg/mL at baseline to 9.6±5.5 µg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately controlled with MDI, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157).

Regulation of TNFα converting enzyme activity in visceral adipose tissue of obese mice.

Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine and one of the major mediators of obesity-induced insulin resistance. TNFα is generated through TNFα converting enzyme (TACE)-mediated cleavage of the transmembrane precursor pro-TNFα. Inhibition of TACE resulted in the improvement in glucose and insulin levels in diabetic animals, suggesting a crucial role of TACE activity in glucose metabolism. However, the regulation of TACE activity in insulin-sensitive tissues has not been fully determined. This study aimed to investigate the impact of TACE in insulin-sensitive tissues in the early stage of the development of obesity. C57BL6 mice were fed standard chow (B6-SC) or high-fat/high-sucrose diet (B6-HF/HS). KK-Ay mice were fed SC ad libitum (Ay-AL) or fed reduced amounts of SC (caloric restriction (CR); Ay-CR). As control for Ay-AL, KK mice fed SC ad libitum (KK-AL) were used. TACE activity in visceral adipose tissue (VAT), but not in liver or skeletal muscle, was significantly elevated in B6-HF/HS and Ay-AL compared with B6-SC and KK-AL, respectively. Phosphorylation of JNK and p38MAPK, but not ERK, in VATs from B6-HF/HS and Ay-AL was also significantly elevated. Ay-CR showed significantly lower TACE, JNK and p38MAPK activities in VAT and serum TNFα level compared with those of Ay-AL. In contrast, intraperitoneal injection of TNFα activated TACE, JNK and p38MAPK activities in VAT in KK mice. In conclusion, during the development of obesity, TACE activity is elevated only in VAT, and CR effectively reduced TACE activity and TACE-mediated pro-TNFα shedding in VAT.

Effects of olmesartan, an angiotensin II receptor blocker, on peripheral insulin sensitivity in Japanese subjects with type 2 diabetes and hypertension.

OBJECTIVE: Several studies have assessed the efficacy of angiotensin receptor blockers (ARBs) on peripheral insulin sensitivity using the euglycemic hyperinsulinemic clamp technique in hypertensive subjects. However, these subjects were mostly non-diabetic, and some studies showed that ARB treatment did not improve insulin sensitivity. Thus, it is still uncertain whether ARBs could improve insulin sensitivity in subjects with hypertension and diabetes. Therefore, we evaluated the effect of olmesartan on peripheral insulin sensitivity in subjects with type 2 diabetes and hypertension using M/I value during the euglycemic-hyperinsulinemic clamp technique. METHODS: We enrolled 10 Japanese subjects with type 2 diabetes and hypertension who had never taken antihypertensive agents. Their blood pressure, fasting plasma glucose level, HbA1c and glucose utilization rate during euglycemic-hyperinsulinemic clamp (M/I value) were examined before and after 6 months of treatment with 10-20 mg/day olmesartan (mean: 13.0 mg/day). RESULTS: Blood pressure decreased significantly from 156/88 mmHg before starting olmesartan to 135/76 mmHg after 6 months of olmesartan treatment. The mean M/I value increased significantly from 6.33 ± 3.19 (mg/kg/min/mU/L) × 100 to 8.11 ± 4.20 (mg/kg/min/mU/L) × 100. Peripheral insulin sensitivity improved in eight out of ten subjects. Fasting glucose levels and HbA1c levels also decreased significantly. CONCLUSION: These results indicate that olmesartan improves glucose metabolism by improving the peripheral insulin sensitivity in subjects with type 2 diabetes.

Anti-atherosclerotic potential of dihydropyridine calcium channel blockers.

Dihydropyridine calcium channel blockers (CCBs) are widely used agents for patients with hypertension. Dihydropyridine CCBs lower blood pressure mainly through vasodilation and reduction of peripheral resistance, and several clinical studies have demonstrated that they have clinical benefits in patients with cardiovascular diseases. In addition, some studies have indicated that dihydropyridine CCBs have anti-atherogenic effects beyond their blood pressure-lowering effects. In fact, several studies using atherosclerotic model animals have revealed that dihydropyridine CCBs suppress atherosclerotic lesion formation. It is well known that the production of reactive oxygen species (ROS) is involved in the progression of atherosclerosis by stimulating the production of inflammatory factors such as chemokines, cytokines and adhesion molecules. Dihydropyridine CCBs can suppress ROS generation and subsequent inflammatory actions in vascular cells and arterial walls. Furthermore, several reports have revealed that dihydropyridine CCBs suppress the expression of adhesion molecules, thereby inhibiting monocyte adhesion to endothelial cells, which is thought to be an early step in the pathogenesis of atherosclerosis. In smooth muscle cells, dihydropyridine CCBs suppress cell proliferation and migration in vitro and in vivo. In macrophages, dihydropyridine CCBs decrease cholesterol accumulation and intracellular cholesterol esterification, and increase cholesteryl ester hydrolysis. Moreover, dihydropyridine CCBs suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. Interestingly, recent studies have revealed that the anti-atherosclerotic effects of dihydropyridine CCBs are mediated, at least in part, via the activation of peroxisome proliferator-activated receptor-γ. In this review, we focus on the anti-atherosclerotic effects of dihydropyridine CCBs beyond their blood pressure-lowering effects.