Differences in autonomic nervous system activity between long-acting injectable aripiprazole and oral aripiprazole in schizophrenia.

BACKGROUND: Distinct oral atypical antipsychotics have different effects on autonomic nervous system (ANS) activity. Among them, oral aripiprazole has been linked to dysfunction of the ANS in schizophrenia. Long-acting injectable aripiprazole is a major treatment option for schizophrenia, but the effect of the aripiprazole formulation on ANS activity remains unclear. In this study, we compared ANS activity between oral aripiprazole and aripiprazole once-monthly (AOM) in schizophrenia. METHODS: Of the 122 patients with schizophrenia who participated in this study, 72 received oral aripiprazole and 50 received AOM as monotherapy. We used power spectral analysis of heart rate variability to assess ANS activity. RESULTS: Patients who received oral aripiprazole showed significantly diminished sympathetic nervous activity compared with those who received AOM. Multiple regression analysis revealed that the aripiprazole formulation significantly influenced sympathetic nervous activity. CONCLUSION: Compared with oral aripiprazole, AOM appears to have fewer adverse effects, such as sympathetic nervous dysfunction.

Rapid and dramatic glucose-lowering effect of bromocriptine in an inadequately controlled type 2 diabetes patient with prolactinoma.

Dopamine receptor agonists are typically used to treat Parkinson's disease and certain pituitary tumors, such as prolactinoma or a growth hormone-producing tumor. A 53-year-old woman with a history of prolactinoma was referred to Kumamoto University Hospital (Kumamoto, Japan) with poorly controlled type 2 diabetes. Her glycated hemoglobin and serum prolactin levels were increased (8.8% and 160.3 ng/mL, respectively). Bromocriptine, a dopamine D2 receptor agonist, was administered to reduce her serum prolactin level. Because bromocriptine-QR (quick release) has been approved for the treatment of type 2 diabetes mellitus in the USA, a continuous glucose monitoring system, FreeStyle Libre Pro, was utilized to examine the effect of bromocriptine on glycemic control. After the initial administration of bromocriptine, glucose levels were rapidly and dramatically ameliorated, and the time in range (70-180 mg/dL) improved from <50% to >90% between 1 week before and after the initial administration of bromocriptine.

Impact of tissue macrophage proliferation on peripheral and systemic insulin resistance in obese mice with diabetes.

INTRODUCTION: Obesity-related insulin resistance is a widely accepted pathophysiological feature in type 2 diabetes. Systemic metabolism and immunity are closely related, and obesity represents impaired immune function that predisposes individuals to systemic chronic inflammation. Increased macrophage infiltration and activation in peripheral insulin target tissues in obese subjects are strongly related to insulin resistance. Using a macrophage-specific proliferation inhibition mouse model (mac-p27Tg), we previously reported that suppressed plaque inflammation reduced atherosclerosis and improved plaque stabilization. However, the direct evidence that proliferating macrophages are responsible for inducing insulin resistance was not provided. RESEARCH DESIGN AND METHODS: The mac-p27Tg mice were fed a high-fat diet, and glucose metabolism, histological changes, macrophage polarization, and tissue functions were investigated to reveal the significance of tissue macrophage proliferation in insulin resistance and obesity. RESULTS: The mac-p27Tg mice showed improved glucose tolerance and insulin sensitivity, along with a decrease in the number and ratio of inflammatory macrophages. Obesity-induced inflammation and oxidative stress was attenuated in white adipose tissue, liver, and gastrocnemius. Histological changes related to insulin resistance, such as liver steatosis/fibrosis, adipocyte enlargement, and skeletal muscle fiber transformation to fast type, were ameliorated in mac-p27Tg mice. Serum tumor necrosis factor alpha and free fatty acid were decreased, which might partially impact improved insulin sensitivity and histological changes. CONCLUSIONS: Macrophage proliferation in adipose tissue, liver, and skeletal muscle was involved in promoting the development of systemic insulin resistance. Controlling the number of tissue macrophages by inhibiting macrophage proliferation could be a therapeutic target for insulin resistance and type 2 diabetes.

The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.

BACKGROUND: Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction. METHODS: A total of 91 schizophrenia patients treated with olanzapine monotherapy participated in this study. A power spectral analysis of heart rate variability was used to assess ANS activity. The TaqMan system was used to genotype seven single nucleotide polymorphisms (SNPs) in CYP1A2 (rs2069514 and rs762551), UGT1A4 (rs2011425), and ABCB1 (rs1045642, rs1128503, rs2032582, rs2235048). RESULTS: Sympathetic nervous activity was significantly higher in individuals with the UGT1A4 rs2011425 G allele than in those with the UGT1A4 rs2011425 non-G allele (sympathetic activity, p = .001). Furthermore, sympathetic nervous activity was also significantly associated with UGT1A4 rs2011425 genotype as revealed by multiple regression analysis (sympathetic activity, p = .008). CONCLUSIONS: We suggest that the UGT1A4 rs2011425 polymorphism affects olanzapine tolerability because it is associated with the observed side effects of olanzapine in schizophrenia patients, namely sympathetic dysfunction.

Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions.

BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS: Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control. RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS: Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.

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).

Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ.

BACKGROUND AND AIMS: Local macrophage proliferation is linked to enhanced atherosclerosis progression. Our previous study found that troglitazone, a thiazolidinedione (TZD), suppressed oxidized low-density lipoprotein (Ox-LDL)-induced macrophage proliferation. However, its effects and mechanisms are unclear. Therefore, we investigated the effects of pioglitazone, another TZD, on macrophage proliferation. METHODS: Normal chow (NC)- or high-fat diet (HFD)-fed apolipoprotein E-deficient (Apoe-/-) mice were treated orally with pioglitazone (10 mg/kg/day) or vehicle (water) as a control. Mouse peritoneal macrophages were used in in vitro assays. RESULTS: Atherosclerosis progression was suppressed in aortic sinuses of pioglitazone-treated Apoe-/- mice, which showed fewer proliferating macrophages in plaques. Pioglitazone suppressed Ox-LDL-induced macrophage proliferation in a dose-dependent manner. However, treatment with peroxisome proliferator-activated receptor-γ (PPARγ) siRNA ameliorated pioglitazone-induced suppression of macrophage proliferation. Low concentrations (less than 100 µmol/L) of pioglitazone, which can suppress macrophage proliferation, activated PPARγ in macrophages, but did not induce macrophage apoptosis. Pioglitazone treatment did not induce TUNEL-positive cells in atherosclerotic plaques of aortic sinuses in Apoe-/- mice. CONCLUSIONS: Pioglitazone suppressed macrophage proliferation through PPARγ without inducing macrophage apoptosis. These findings imply that pioglitazone could prevent macrovascular complications in diabetic individuals.

Impacts of the 2016 Kumamoto Earthquake on glycemic control in patients with diabetes.

AIMS/INTRODUCTION: On April 14 and 16 2016, the Kumamoto area was severely damaged by several massive magnitude 7 class earthquakes. MATERIALS AND METHODS: To examine the effects of these earthquakes on glycemic control and stress factors, glycated hemoglobin, glycated albumin, other biochemical parameters, a self-administered lifestyle-associated questionnaire and disaster-associated stress scores were analyzed. A total of 557 patients with diabetes were enrolled, and data were collected at 13 months before to 13 months after the earthquakes. RESULTS: In patients with type 1 diabetes and specific types of diabetes due to other causes, glycemic control was not altered during the observational period. This glycemic stability in type 1 diabetes might result from self-management of insulin doses. In patients with type 2 diabetes, glycated hemoglobin decreased by 0.11% (from 7.33 to 7.22%) at 1-2 months after the earthquakes, and increased thereafter. The reduction of glycated hemoglobin after 1-2 months in type 2 diabetes was associated with 'early restoration of lifelines' and 'sufficient sleep.' The glycemic deterioration at a later stage was related to 'shortage of antidiabetic agents,' 'insufficient amount of food,' 'largely destroyed houses' and 'changes in working environments.' Disaster-associated stress levels were positively correlated with 'age,' 'delayed restoration of lifelines,' 'self-management of antidiabetic agents' and 'increased amount of physical activity/exercise,' and negatively associated with 'early restoration of lifelines' and 'sufficient sleep.' CONCLUSIONS: Glycemic control, associated factors and stress levels are altered in chronological order. Post-disaster diabetic medical care must consider these corresponding points in accordance with the time-period.

Effects of long-acting injectable antipsychotics versus oral antipsychotics on autonomic nervous system activity in schizophrenic patients.

OBJECTIVE: Long-acting injections (LAIs) of antipsychotics show distinct pharmacokinetic profiles from oral antipsychotics (OAPs). Although there may be differences in adverse event frequency, any differences in their effects on autonomic nervous system (ANS) remain unclear. PATIENTS AND METHODS: In total, 270 schizophrenic patients were recruited in this study: 241 received OAPs (risperidone, olanzapine, quetiapine, or aripiprazole) and 29 received LAIs (risperidone LAI, aripiprazole LAI, or paliperidone palmitate) as monotherapy. Heart rate variability was measured as an index of ANS activity, and the low-frequency (0.03-0.15 Hz) component, high-frequency (0.15-0.40 Hz) component, and total power (0.03-0.40 Hz) were calculated. Components were compared between the groups using t-tests. RESULTS: A significant difference was detected in the low-frequency component between the OAP and LAI groups (P=0.046). No significant difference was found in total power or the high-frequency component between the two groups. CONCLUSION: Compared with OAPs, LAIs have fewer adverse effects on ANS activity, particularly the low-frequency component, as determined using a spectral analysis of heart rate variability.

Association between dysfunction of autonomic nervous system activity and mortality in schizophrenia.

BACKGROUND: Patients with schizophrenia have a higher mortality risk than the general population. Additionally, the autonomic nervous system (ANS) activity of patients with schizophrenia is lower and more dysfunctional than that of the general population. Nonetheless, the association between ANS dysfunction and mortality in schizophrenia is unclear. The aim of this study was to investigate the association between ANS activity and mortality in schizophrenia and to evaluate the predictive values of heart rate variability for long-term survival. METHODS: This study involves the 10-year follow-up of a sample population consisting of 59 Japanese inpatients with schizophrenia between 60 and 70 years of age from 2007 to 2016. The ANS activity of all patients was evaluated using heart rate variability in 2007. RESULTS: Fifty-three participants could be followed up because they stayed in the hospital during the follow-up period. Of these patients, 11 died during follow-up. Their mean age at death was 70.55 ±â€¯3.45 years. The parasympathetic activity of nonsurvivors was significantly lower than that of survivors, and multiple logistic regression analysis showed a significant association between death and parasympathetic activity. CONCLUSION: We suggest that decreased parasympathetic activity could be associated with 10-year all-cause mortality in older schizophrenic patients.

A Rare Case of Thyrotropin-Secreting Pituitary Adenoma Coexisting with Papillary Thyroid Carcinoma Presenting with Visual Disturbance without Hyperthyroidism.

BACKGROUND: Thyroid-stimulating hormone-secreting pituitary adenomas (TSHomas) are uncommon, and majority of the patients present with symptoms of hyperthyroidism. Herein, we report the first case of TSHoma with differentiated thyroid carcinoma (DTC) that presented with visual disturbance without any clinical feature of hyperthyroidism. CASE DESCRIPTION: A 57-year-old man presented with left temporal hemianopsia of his left eye without any sign of hyperthyroidism. A mass lesion in the sellar and suprasellar region compressing the optic nerves was identified via magnetic resonance imaging. Free thyroxine and free triiodothyronine levels were slightly elevated, whereas the serum level of thyroid-stimulating hormone remained within normal range. Further endocrinologic examination led to the preoperative diagnosis of TSHoma. Ultrasonography and 111In-octreotide scan showed a mass lesion in left lobe of the thyroid gland, and subsequent thyroid aspiration biopsy confirmed the diagnosis of papillary thyroid carcinoma. After administration of short-acting octreotide to prevent thyrotoxic crisis in the perioperative period, the tumor was removed via endoscopic transnasal-transsphenoidal surgery, and the pathologic diagnosis of TSHoma was made. His visual acuity improved, and free triiodothyronine and free thyroxine levels normalized. He underwent thyroidectomy 3 months later after endoscopic transnasal-transsphenoidal surgery. CONCLUSIONS: Herein, we report the first case of TSHoma with DTC that presented with visual disturbance without any clinical feature of hyperthyroidism and reviewed the 13 reported cases of TSHoma coexisting with DTC. The optimal treatment strategy in patients with TSHoma and coexistent DTC has not been established, and individualized therapeutic strategies are needed.

Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia.

BACKGROUND: There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. METHODS: In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. RESULTS: For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier-rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier-rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642-rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). CONCLUSION: We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

Inhibition of Local Macrophage Growth Ameliorates Focal Inflammation and Suppresses Atherosclerosis.

OBJECTIVE: Macrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed. APPROACH AND RESULTS: Inhibition of macrophage proliferation was achieved by inducing the expression of cyclin-dependent kinase inhibitor 1B, also known as p27kip, under the regulation of a scavenger receptor promoter/enhancer. The macrophage-specific human p27kip Tg mice were subsequently crossed with apolipoprotein E-deficient mice for the atherosclerotic plaque study. Results showed that a reduced number of local macrophages resulted in marked suppression of atherosclerotic plaque formation and inflammatory response in the plaque. Moreover, fewer local macrophages in macrophage-specific human p27kip Tg mice helped stabilize the plaque, as evidenced by a reduced necrotic core area, increased collagenous extracellular matrix, and thickened fibrous cap. CONCLUSIONS: These results provide direct evidence of the involvement of local macrophage proliferation in formation and progression of atherosclerotic plaques and plaque stability. Thus, control of macrophage proliferation might represent a therapeutic target for treating atherosclerotic diseases.

Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia.

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined-risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity.

Long term effects of smoking cessation in hospitalized schizophrenia patients.

BACKGROUND: The prevalence of smoking in patients with schizophrenia is higher than that in the general population and is an important medical issue. Short-term smoking cessation tends to worsen psychiatric symptoms in patients with schizophrenia but decreases sympathetic nervous system activity and improves plasma cholesterol levels in healthy people. Few studies have assessed the long-term effects of smoking cessation in patients with schizophrenia. METHODS: Subjects were 70 Japanese patients with schizophrenia (38 smokers, 32 non-smokers). We compared the following clinical parameters between the two groups at baseline (before smoking cessation) and in each group separately between baseline and at three years after smoking cessation: autonomic nervous system activity, plasma cholesterol levels, body weight, drug therapy, and Global Assessment of Functioning scores. We also compared the mean changes in clinical parameters throughout this study between the groups at both time points. Autonomic nervous system activity was assessed by power spectral analysis of heart rate variability. RESULTS: Parasympathetic nervous system activity and the doses of antiparkinsonian drugs in smokers were significantly higher than those in non-smokers at baseline. Smoking cessation was associated with significantly decreased sympathetic nervous system activity and decreased doses of antipsychotics and antiparkinsonian drugs at three years after smoking cessation. However, there was no significant difference in the mean change in clinical factors scores, except for Global Assessment of Functioning scores, between smokers and non-smokers at three years after smoking cessation. CONCLUSIONS: Our results suggest that smoking reduces both autonomic nervous system activity and the effectiveness of drug therapy with antipsychotics and antiparkinsonian drugs in patients with schizophrenia, but that both factors could be ameliorated over the long term by smoking cessation. Taken together with the findings of previous studies, smoking cessation in patients with schizophrenia has many long-term positive physiological effects.

Association of the Cholinergic Muscarinic M2 Receptor with Autonomic Nervous System Activity in Patients with Schizophrenia on High-Dose Antipsychotics.

BACKGROUND: Patients with schizophrenia have abnormal autonomic nervous system (ANS) activity compared with the general population. One reason for this difference is the muscarinic affinity for antipsychotic drugs; therefore, single nucleotide polymorphisms (SNPs) of the muscarinic receptor gene influence this ANS dysfunction. This study sought to determine the effect of SNPs of the cholinergic muscarinic receptor (CHRM) gene on ANS activity in patients with schizophrenia receiving antipsychotic drugs. METHODS: A total of 173 Japanese patients with schizophrenia were included in this study. Heart rate variability (HRV) was measured as an index of ANS activity. SNPs in CHRM1 (rs542269 and rs2075748), CHRM2 (rs324640, rs8191992, rs1824024, and rs7810473), and CHRM3 (rs3738435, rs4620530, and rs6429157) were genotyped using the TaqMan® method. Patients were grouped according to standard equivalent conversions of chlorpromazine (CP) into a high-CP group (HG; ≥1,000 mg) and a low-CP group (LG; <1,000 mg). ANS activity was compared between the groups. In addition, we compared the total, low-frequency (LF), high-frequency (HF), and LF/HF components of the patients' HRV, and the genotype of the SNPs in both the HG and LG groups. Bonferroni correction was applied for multiple comparisons, and the Bonferroni-corrected critical p value was <0.005. RESULTS: The A allele of the CHRM2 rs8191992 polymorphism in HG was associated with decreased ANS activity. CONCLUSION: Our results show reduced ANS activity in association with the CHRM2 rs8191992 polymorphism in patients with schizophrenia on high-dose antipsychotics. CHRM2 polymorphisms may play an important role in ANS activity in patients with schizophrenia.

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.

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.