Updates of incretin-related drugs for the treatment of type 2 diabetes.

Mechanisms of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor dual-agonist in glycemic control and/or weight loss.

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.

Impacts of tight multifactorial intervention in patients with type 2 diabetes: Implications from the Japan Diabetes Outcome Intervention Trial 3.

Effects of intensive versus conventional therapy on the primary and secondary outcomes.

Are saving appearance responses typical communication patterns in Alzheimer's disease?

INTRODUCTION: To keep up appearances, people with dementia sometimes pretend to know the correct answer, as seen during administration of neuropsychological tests such as the Mini-Mental State Examination (MMSE). These saving appearance responses (SARs) of people with dementia often lead to caregivers and/or medical staff underestimating the severity of dementia and impede proper early initiation of treatment. However, most descriptions of SARs are based on empirical knowledge of clinicians. In this study, we investigated whether SARs are typical communication patterns in people with Alzheimer's disease (AD), compared with mild cognitive impairment (MCI) or dementia with Lewy bodies (DLB). METHODS: The participants were 107 outpatients with AD, 16 with mixed AD with cerebrovascular dementia, 55 with MCI, and 30 with DLB. We assessed the occurrence of SARs during the MMSE. The relationships between the SARs and AD were examined by the χ2 test and logistic regression analysis. RESULTS: People with AD who showed SARs were 57.9%, whereas those with MCI were 18.2% and DLB were 20.0% (P with Bonferroni correction < 0.05). Although there were significant differences in some variables in each group of diagnosis, logistic regression analysis showed that people with AD were more likely to show SARs than those with MCI (Odds ratio = 3.48, 95% Confidential Interval = 1.18-10.28) and DLB (Odds ratio = 4.24, 95% Confidential Interval = 1.50-12.01), even after controlling for sex, estimated disease duration, MMSE, and frontal assessment battery scores. CONCLUSION: The occurrence of SARs could be found most frequently in people with AD. Clinicians should develop a respectful attitude toward dementia patients with SARs because SARs imply conflicted feelings about questions that patients cannot answer correctly.

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.

Identification of microRNA that represses IRS-1 expression in liver.

MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally regulate gene expression and have been shown to participate in almost every cellular process. Several miRNAs have recently been implicated in glucose metabolism, but the roles of miRNAs in insulin-resistant conditions, such as obesity or type 2 diabetes, are largely unknown. Herein, we focused on miR-222, the expression of which was increased in the livers of high fat/high sucrose diet-fed mice injected with gold thioglucose (G+HFHSD). Overexpression of miR-222 in primary mouse hepatocytes attenuated Akt phosphorylation induced by insulin, indicating that miR-222 negatively regulates insulin signaling. As per in silico analysis, miR-222 potentially binds to the 3' untranslated region (3' UTR) of the IRS-1 gene, a key insulin signaling molecule. In fact, IRS-1 protein expression was decreased in the livers of G+HFHSD-fed mice. We further confirmed a direct interaction between miR-222 and the 3' UTR of IRS-1 via luciferase assays. Our findings suggest that up-regulation of miR-222 followed by reduction in IRS-1 expression may be a viable mechanism of insulin resistance in the liver.

Why do people with dementia pretend to know the correct answer? A qualitative study on the behaviour of toritsukuroi to keep up appearances.

BACKGROUND: Toritsukuroi is a particular type of behaviour intended to save face or preserve appearances. Clinicians often observe toritsukuroi in people with dementia, but current knowledge about this behaviour is based on clinicians' empirical knowledge rather than on observational studies. This study was designed to clarify which behaviours are related to toritsukuroi based on neuropsychological examinations. METHODS: The subjects were 91 outpatients with dementia. Verbal responses, with the exceptions of 'I don't know' and erroneous answers, were recorded by certificated clinical psychologists and analyzed by qualitative study procedures. A qualitative study was separately conducted by two researchers to identify themes and types of reactions. The themes found through content analysis were organized and labelled by a senior psychiatrist. RESULTS: Among the patients, 41.8% verbally responded in way to 'keep up appearances'. Six distinct thematic categories were identified through conventional content analysis: (i) refuting sudden questions; (ii) disclosing trait; (iii) disclosing experience; (iv) demonstrating slight hesitation; (v) appealing to indifference; and (vi) other. CONCLUSIONS: All the responses that we defined as being toritsukuroi reflect a denial of acquired cognitive impairment. Further study is needed to clarify the association between toritsukuroi and either cognitive function or disease specificity.

Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells.

AIMS/INTRODUCTION: Overproduction of reactive oxygen species (ROS) in endothelial cells (ECs) plays a pivotal role in endothelial dysfunction. Mitochondrial ROS (mtROS) is one of the key players in the pathogenesis of diabetic vascular complications. Hypoglycemia is linked to increased ROS production and vascular events; however, the underlying mechanisms remain unclear. In the present study, we aimed to determine whether and how low glucose (LG) mediates mtROS generation in ECs, and to examine the impact of LG-induced mtROS on endothelial dysfunction. MATERIALS AND METHODS: Metabolomic profiling, cellular oxygen consumption rate, mtROS, endothelial nitric oxide synthase phosphorylation, and the expression of vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 were evaluated in bovine aortic ECs. RESULTS: We found that LG increased mtROS generation in ECs; which was suppressed by overexpression of manganese superoxide dismutase. Comprehensive metabolic analysis using capillary electrophoresis-mass spectrometry and oxygen consumption rate assessment showed that the pathway from fatty acid to acetyl-CoA through fatty acid oxidation was upregulated in ECs under LG conditions. In addition, etomoxir, a specific inhibitor of the free fatty acid transporter, decreased LG-induced mtROS production. These results suggested that LG increased mtROS generation through activation of fatty acid oxidation. We further revealed that LG inhibited endothelial nitric oxide synthase phosphorylation, and increased the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. These effects were suppressed either by overexpression of manganese superoxide dismutase or by treatment with etomoxir. CONCLUSIONS: The activation of fatty acid oxidation followed by mtROS production could be one of the causes for endothelial dysfunction during hypoglycemia.

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.

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).

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).

[Type 2 diabetes and impaired glucose tolerance].

Due to the changes of lifestyle in Japan, the number of subjects with type 2 diabetes due to obesity has been increasing. Obesity usually accompanies with an increase of the size of fat cells, which causes the changes of adipokines, such as the decrease of adiponectin and the increase of TNFalpha and free fatty acids, and leads to insulin resistance. As it has been suggested that the capacity of insulin secretion in pancreatic beta cells of Japanese is lower than that of Caucasian, the Japanese likely to develop diabetes with mild obesity. In the treatment of type 2 diabetes accompanied with obesity, more strict diet therapy and exercise are required. In drug therapy of such patients, the drugs to improve insulin resistance, such as biguanides, thiazolidine derivatives, DPP-4 inhibitors and GLP-1 analogues should be selected.

Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.

Rapid amelioration of hyperglycemia facilitated by dasatinib in a chronic myeloid leukemia patient with type 2 diabetes mellitus.

Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with chronic myeloid leukemia (CML); however, their precise mechanism of action remains unknown. We herein report the case of a 57-year-old diabetic CML patient who was resistant to imatinib and initially required 20 units of insulin daily to control his blood glucose levels. After the initiation of dasatinib, the patient's insulin requirements declined rapidly and insulin treatment was discontinued within two weeks. Meanwhile, the fasting C-peptide immunoreactivity increased two-fold, suggesting that dasatinib facilitated the recovery of insulin production. Dasatinib may therefore be beneficial for diabetic CML patients, especially those who require insulin treatment.

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.

The impact of Ca²âº/calmodulin-dependent protein kinase II on insulin gene expression in MIN6 cells.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is expressed in insulin-secreting ß cells. However, the effects of CaMKII on insulin synthesis are unknown. Although Ser133 phosphorylation of cyclic AMP-responsive element-binding protein (CREB) typically increases CREB transcriptional activity, CaMKII phosphorylates CREB at Ser142 and at Ser133 to exert a dominant inhibitory effect. Our objective was to characterize the role of CaMKII in insulin gene expression. In MIN6 cells, insulin gene promoter activity was significantly down-regulated by wild-type (WT) CaMKIIδ2, but was significantly upregulated after small interfering RNA (siRNA) knockdown of CaMKIIδ expression. These results were independent of glucose concentrations and membrane depolarization. Insulin mRNA levels were also decreased by WT CaMKIIδ2 and increased by CaMKIIδ siRNA. Downregulation of insulin gene promoter activity by WT CaMKIIδ2 was partly mediated via cyclic AMP-responsive element 2 (CRE2). WT CaMKIIδ2 significantly increased CREB phosphorylation at Ser142 and significantly decreased binding to CREB binding protein (CBP), whereas kinase dead CaMKIIδ2 did not. Our results indicate that CaMKIIδ2 downregulates insulin gene expression by Ser142 phosphorylation of CREB and reducing binding of CREB to CBP.

Hyperthermia with mild electrical stimulation protects pancreatic ß-cells from cell stresses and apoptosis.

Induction of heat shock protein (HSP) 72 improves metabolic profiles in diabetic model mice. However, its effect on pancreatic ß-cells is not known. The current study investigated whether HSP72 induction can reduce ß-cell stress signaling and apoptosis and preserve ß-cell mass. MIN6 cells and db/db mice were sham-treated or treated with heat shock (HS) and mild electrical stimulation (MES) (HS+MES) to induce HSP72. Several cellular markers, metabolic parameters, and ß-cell mass were evaluated. HS+MES treatment or HSP72 overexpression increased HSP72 protein levels and decreased tumor necrosis factor (TNF)-α-induced Jun NH(2)-terminal kinase (JNK) phosphorylation, endoplasmic reticulum (ER) stress, and proapoptotic signal in MIN6 cells. In db/db mice, HS+MES treatment for 12 weeks significantly improved insulin sensitivity and glucose homeostasis. Upon glucose challenge, a significant increase in insulin secretion was observed in vivo. Compared with sham treatment, levels of HSP72, insulin, pancreatic duodenal homeobox-1, GLUT2, and insulin receptor substrate-2 were upregulated in the pancreatic islets of HS+MES-treated mice, whereas JNK phosphorylation, nuclear translocation of forkhead box class O-1, and nuclear factor-κB p65 were reduced. Apoptotic signals, ER stress, and oxidative stress markers were attenuated. Thus, HSP72 induction by HS+MES treatment protects ß-cells from apoptosis by attenuating JNK activation and cell stresses. HS+MES combination therapy may preserve pancreatic ß-cell volume to ameliorate glucose homeostasis in diabetes.

Ezetimibe improves glucose metabolism by ameliorating hepatic function in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: Several experimental studies have shown that ezetimibe improves steatosis and insulin resistance in the liver. This suggests that ezetimibe may improve glucose metabolism, as well as lipid metabolism, by inhibiting hepatic lipid accumulation. Therefore, we compared HbA1c levels after 3 months ezetimibe treatment with baseline levels in patients with type 2 diabetes and examined the factors associated with reductions in HbA1c following ezetimibe administration. MATERIALS AND METHODS: Lipid profiles, hepatic function, and HbA1c were assessed before and after 3 months treatment with 10 mg/day ezetimibe in 96 patients with type 2 diabetes and hypercholesterolemia. Regression analysis was used to investigate associations between metabolite levels and the percentage change in HbA1c. RESULTS: Low-density lipoprotein-cholesterol was significantly lower after 3 months treatment compared with baseline, and HbA1c decreased in approximately 50% of patients. Univariate linear regression analyses showed that changes in HbA1c were significantly associated with serum alanine aminotransferase (ALT), the aspartate aminotransferase (AST)/ALT ratio, and age. Two-tailed chi-square tests revealed that serum ALT ≥35 IU/L and an AST/ALT ratio <1.0 were significantly associated with decreases in HbA1c following ezetimibe administration. CONCLUSIONS: The results of the present study indicate that ezetimibe may improve glucose metabolism. Serum ALT levels and the AST/ALT ratio were useful predictors of a glucose metabolism response to ezetimibe. This trial was registered with UMIN (no. UMIN000005307). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00147.x, 2011).