Switching From Daily DPP-4 Inhibitor to Once-Weekly GLP-1 Receptor Activator Dulaglutide Significantly Ameliorates Glycemic Control in Subjects With Poorly Controlled Type 2 Diabetes Mellitus: A Retrospective Observational Study.

Aim: At present, daily DPP-4 inhibitors are quite frequently prescribed in subjects with type 2 diabetes mellitus (T2DM). Recently, it has been drawing much attention that once-weekly incretin-based injection dulaglutide was developed. In this study, we aimed to examine the possible effects of once-weekly GLP-1 receptor activator (GLP-1RA) dulaglutide on glycemic control as well as various metabolic parameters. Methods: We made a direct comparison between the effect of daily DPP-4 inhibitor and once-weekly dulaglutide on glycemic control in "study 1 (pre-post comparison)" and set the control group using the propensity score matching method in "study 2". Results: In study 1, switching from daily DPP-4 inhibitor to dulaglutide significantly ameliorated glycemic control in subjects with T2DM. Such effects were more obvious in poorly controlled subjects. After 1:1 propensity score matching, the switching group improved glycemic control compared with the non-switching group in study 2. Conclusion: We should bear in mind that switching from daily DPP-4 inhibitor to once-weekly GLP-1RA dulaglutide exerts more favorable effects on glycemic control regardless of age, body weight, and duration of diabetes in subjects with T2DM, especially when we fail to obtain good glycemic control with daily DPP-4 inhibitor.

Association Between Severity of Diabetic Neuropathy and Success in Weight Loss During Hospitalization Among Japanese Patients with Type 2 Diabetes: A Retrospective Observational Study.

INTRODUCTION: This study aimed to examine the association between severity of diabetic neuropathy and weight loss during hospitalization in overweight participants with type 2 diabetes. PATIENTS AND METHODS: Participants of this study comprised 193 patients who were hospitalized for type 2 diabetes treatment. The participants were divided into two groups in the study, based on whether or not reduction of bodyweight was at least 3% during hospitalization. Using Cox models, the association between severity of neuropathy and effectiveness of weight loss under a controlled diet was analyzed. Autonomic neuropathy was assessed on patient admission by R-R interval, as measured in an electrocardiogram (CVRR), and sensory neuropathy was assessed using both 128-Hz tuning-fork vibration and Achilles tendon reflex (ATR). RESULTS: The adjusted hazard ratio for weight loss of at least 3% for CVRR was 1.17 (95% confidence interval 1.07-1.28, P=0.0006) and for vibration time 1.93 (1.01-3.68, P=0.045). After dividing CVRR and vibration time into tertiles based on participant number, the adjusted hazard ratio for the high tertile of CVRR was 2.17 (1.29-3.62, P=0.003), and for the long tertile of vibration time 1.84 (1.10-3.08, P=0.02), compared with the low and short tertiles, respectively. No association was detected between ATR category and weight loss. CONCLUSION: Severity of diabetic neuropathy was found to be a determinant in weight loss under a caloric restriction regimen for patients with type 2 diabetes. The results of the study suggest that the peripheral nervous system is involved in responses to medical intervention for treatment for type 2 diabetes including bodyweight management.

Effect of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy in Japanese Subjects with Type 2 Diabetes Mellitus: A Retrospective Study.

Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been very often used in subjects with type 2 diabetes mellitus (T2DM). In addition, combination drugs of both inhibitors have attracted much attention in aspects of its cost-effectiveness and improvement of patients' adherence. However, it is still poorly understood which factors are related to the efficacy of SGLT2 inhibitors as add-on therapy to DPP-4 inhibitors. Therefore, we aimed to elucidate in which type of individuals and/or under which conditions canagliflozin as add-on therapy to teneligliptin could exert more beneficial effects on glycemic control and/or renal protection. We retrospectively analyzed 56 Japanese subjects with T2DM in the real-world clinical practice. Three months after starting the combination therapy, the change of HbA1c (ΔHbA1c) was strongly related to HbA1c levels at baseline. As expected, serum glucagon level was increased after starting the combination therapy. Interestingly, however, the change of glucagon levels (Δglucagon) was not related to HbA1c levels at baseline, ΔHbA1c, and other parameters, which indicated that the increase of glucagon did not clinically affect the effectiveness of combination therapy. In addition, the change of urinary albumin excretion (ΔUAE) was negatively correlated with systolic blood pressure and HbA1c levels at baseline and positively correlated with the change of systolic blood pressure (ΔsBP) in univariate analysis. Furthermore, in multivariate analysis, only ΔsBP was the independent factor associated with ΔUAE. Taken together, canagliflozin as add-on therapy to teneligliptin improves glycemic control in a Δglucagon-independent manner and reduces UAE in a ΔsBP-dependent manner in Japanese subjects with T2DM.

Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography. RESULTS: There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable. CONCLUSIONS: The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

Impact of physical activity and sedentary time on glycated hemoglobin levels and body composition: Cross-sectional study using outpatient clinical data of Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: This study examined the association among sedentary time (ST), physical activity (PA), glycated hemoglobin and body composition in Japanese type 2 diabetes patients. MATERIALS AND METHODS: Patients with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital, Okayama, Japan, comprised the study's participants. Self-administered International Physical Activity Questionnaire short forms were obtained and analyzed for 1,053 patients, including 158 patients for whom waist circumference and visceral fat accumulation were measured. From the questionnaire, three categorical data (low, moderate, high) and continuous data (METs/h/week) regarding PA and ST (min/day), respectively, were obtained. RESULTS: The patients categorized as having low PA had significantly higher body mass index than those categorized as having high levels, after adjustment was made for confounders. Continuous data of PA were negatively associated with waist circumference and visceral fat accumulation. ST was positively associated with body mass index. After dividing the participants into four groups according to medians of ST and PA, the following categories were established: long ST and low PA, long ST but high PA, short ST but low PA and short ST and high PA. In terms of body mass index, short ST and high PA measured significantly lower than long ST and low PA. For waist circumference and visceral fat accumulation, short ST but low PA and short ST and high PA measured significantly lower than long ST and low PA and long ST but high. CONCLUSIONS: These results imply that the combination of avoiding sedentary behavior and increasing PA might be important in the prevention bodyweight gain and in the avoidance of central obesity, respectively, in Japanese type 2 diabetes patients.

Correction to: Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice.

It has been brought to our attention that Fig. 5a showing the vasculature in islets of control flox mice is not in fact an endocrine cell but rather exocrine tissue.

Comparison of HbA1c levels and body mass index for prevention of diabetic kidney disease: A retrospective longitudinal study using outpatient clinical data in Japanese patients with type 2 diabetes mellitus.

AIM: This study examined the association among the onset of diabetic kidney disease (DKD), blood glucose levels (HbA1C), and body mass index (BMI) in Japanese patients with type 2 diabetes mellitus. METHODS: Patients eligible for this study included those with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2018 and were followed up for more than two years. The Cox proportional hazards model was used in four categories of subjects: at the beginning of the follow-up period, "controlled" or "uncontrolled" glycemic control based on HbA1c and "overweight" or "non-overweight" based on BMI. RESULTS: After dividing the participants into four categories according to HbA1c (lower than 7.0% (C) or higher (U)), and BMI (25 kg/m2 or higher (O) or lower (N)), hazard ratios for groups CO, UN, and UO were 1.40 (95% CI 1.03-1.90, P = 0.030), 1.40 (1.04-1.88, P = 0.027), and 1.54 (1.12-2.11, P = 0.008), respectively, compared with the CN reference group, after adjustment was made for age, sex, duration of diabetes, and medication for hypertension or dyslipidemia. CONCLUSION: Maintenance of both an HbA1c level lower than 7.0% and a BMI lower than 25 kg/m2 was important for the prevention of DKD in Japanese patients with type 2 diabetes mellitus. Both factors had a similar effect on DKD in this study.

Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice.

AIMS/HYPOTHESIS: The aim of this study was to elucidate the impact of 3'-phosphoinositide-dependent protein kinase-1 (PDPK1) in vascular endothelial cells on the maintenance of pancreatic beta cell mass and function. METHODS: Male vascular endothelial cell-specific Pdpk1-knockout mice (Tie2+/-/Pdpk1flox/flox mice) and their wild-type littermates (Tie2-/-/Pdpk1flox/flox mice; control) were used for this study. At 12 weeks of age, an IPGTT and OGTT were conducted. Pancreatic blood flow was measured under anaesthesia. Thereafter, islet blood flow was measured by the microsphere method. Mice were killed for islet isolation and further functional study and mRNA was extracted from islets. Pancreases were sampled for immunohistochemical analyses. RESULTS: During the IPGTT, the blood glucose level was comparable between knockout mice and control flox mice, although serum insulin level was significantly lower in knockout mice. During the OGTT, glucose tolerance deteriorated slightly in knockout mice, accompanied by a decreased serum insulin level. During an IPGTT after pre-treatment with exendin-4 (Ex-4), glucose tolerance was significantly impaired in knockout mice. In fact, glucose-stimulated insulin secretion of isolated islets from knockout mice was significantly reduced compared with control flox mice, and addition of Ex-4 revealed impaired sensitivity to incretin hormones in islets of knockout mice. In immunohistochemical analyses, both alpha and beta cell masses were significantly reduced in knockout mice. In addition, the CD31-positive area was significantly decreased in islets of knockout mice. The proportion of pimonidazole-positive islets was significantly increased in knockout mice. mRNA expression levels related to insulin biosynthesis (Ins1, Ins2, Mafa, Pdx1 and Neurod [also known as Neurod1]) and beta cell function (such as Gck and Slc2a2) were significantly decreased in islets of knockout mice. Microsphere experiments revealed remarkably reduced islet blood flow. In addition, mRNA expression levels of Hif1α (also known as Hif1a) and its downstream factors such as Adm, Eno1, Tpi1 (also known as Ets1), Hmox1 and Vegfa, were significantly increased in islets of knockout mice, indicating that islets of knockout mice were in a more hypoxic state than those of control flox mice. As a result, mRNA expression levels related to adaptive unfolded protein response and endoplasmic reticulum stress-related apoptotic genes were significantly elevated in islets of knockout mice. In addition, inflammatory cytokine levels were increased in islets of knockout mice. Electron microscopy revealed reduced endothelial fenestration and thickening of basal membrane of vascular endothelium in islets of knockout mice. CONCLUSIONS/INTERPRETATION: Vascular endothelial PDPK1 plays an important role in the maintenance of pancreatic beta cell mass and function by maintaining vascularity of pancreas and islets and protecting them from hypoxia, hypoxia-related endoplasmic reticulum stress, inflammation and distortion of capillary structure.

Eicosapentaenoic acid/arachidonic acid ratio and weight loss during hospitalization for glycemic control among overweight Japanese patients with type 2 diabetes: a retrospective observational study.

BACKGROUND: The study aimed to examine the relationship between levels of serum eicosapentaenoic acid (EPA), arachidonic acid (AA), as well as EPA/AA ratio and weight loss during hospitalization in participants considered to be overweight, with type 2 diabetes. METHODS: The study participants included 142 patients who were hospitalized for treatment of type 2 diabetes. We divided the participants into two groups depending on the achievenemt in reduction of bodyweight 3% or more during hospitalization and examined the relationship between serum levels of EPA and AA, as well as ratio of EPA/AA on admission and effectiveness of weight loss under strict dietary therapy during hospitalization, using Cox proportional hazard models. RESULTS: After adjustment was made for several confounders, the hazard ratio of effective weight loss for logarithmical serum EPA was 1.59 (95% CI 1.02-2.49, P = 0.04) and for logarithmical EPA/AA ratio 1.64 (1.03-2.61, P = 0.04), whereas the hazard ratio for effective weight loss for logarithmical serum AA was 1.11 (0.45-2.78, P = 0.82). In addition, after dividing EPA/AA ratio and serum EPA into quartiles based on participant number, the hazard ratio for the highest quartile of EPA/AA ratio was 2.33 (1.14-4.77, P = 0.02), and for the highest quartile of serum EPA 1.60 (0.80-3.19, P = 0.18) compared with the lowest quartile. CONCLUSION: These results suggest the possibility that EPA is involved in bodyweight change under a caloric-restriction regimen. In addition, EPA/AA ratio was found to be a better predictor of medical intervention for weight loss among overweight patients with type 2 diabetes, compared with serum EPA level.

Association of the Glycemic Fluctuation as well as Glycemic Control with the Pancreatic ß-cell Function in Japanese Subjects with Type 2 Diabetes Mellitus.

Objective It is important to preserve the pancreatic ß-cell function in order to maintain good glycemic control for a long period. The aim of this study was to examine which factors are associated with the ß-cell function in subjects with type 2 diabetes mellitus. Methods A total of 372 subjects with type 2 diabetes who had been hospitalized for the amelioration of their glycemic control and/or education about diabetes in Kawasaki Medical School Hospital were included in this study. We evaluated the remnant ß-cell function as the HOMA-%ß using the computer software program HOMA2 and estimated the glycemic fluctuation with the glycoalbumin (GA)/hemoglobin A1c (HbA1c) ratio. In addition, we divided the subjects into a relatively young group (<65 years old) (n=210) and an elderly group (≥65 years old) (n=162) and performed several analyses in each group. Results The GA/HbA1c ratio, GA and HbA1c were independent determinant factors for the HOMA-%ß regardless of age. We obtained almost the same results even after excluding those subjects using insulin secretagogues. These data suggest that the glycemic fluctuation and glycemic control are associated with the remnant ß-cell function in Japanese subjects with type 2 diabetes. Conclusion It is very important to reduce glycemic fluctuation as well as to maintain good glycemic control in order to preserve ß-cell function in subjects with type 2 diabetes.

Effect of mild exercise on glycemic and bodyweight control in Japanese type 2 diabetes patients: A retrospective analysis.

We retrospectively evaluated the effects of mild physical exercise (P) in a routine clinical setting on glycemic and bodyweight control in Japanese type 2 diabetes patients with and without individualized nutritional therapy (D). We analyzed 49 patients who participated in P that measured 2.5 metabolic equivalents and was held once every 2 weeks, compared with 83 non-participant controls, followed over a period of approximately 1.6 years. With a Cox model, the adjusted hazard ratio for improved glycated hemoglobin by numerical count of P was 1.03 (95% confidence interval [CI] 1.00-1.07; P = 0.025). Among four categories - with neither P nor D, only P, only D, and both P and D - the hazard ratios for reduced body mass index were 1.0, 0.87 (95% CI 0.46-1.67), 0.58 (95% CI 0.25-1.30) and 2.17 (95% CI 1.03-4.59), respectively. Even mild physical exercise contributed to glycemic control. The combination of P and D exerted beneficial effects on bodyweight control.

Suppression of free fatty acid receptor 1 expression in pancreatic ß-cells in obese type 2 diabetic db/db mice: a potential role of pancreatic and duodenal homeobox factor 1.

It is known that long-chain fatty acids bind to free fatty acid receptor 1 (Ffar1), also known as G protein-coupled receptor 40 (GPR40), and amplify glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells and that Ffar1 agonists facilitates insulin secretion and ameliorates glycemic control. On the other hands, pancreatic and duodenal homeobox factor 1 (Pdx1) is an important transcription factor for various ß-cell-related genes including insulin gene and thereby contributes to the maintenance of mature ß-cell function. The aim of this study was to evaluate how Ffar1 expression in ß-cells is altered under diabetic conditions. In this study, we used male obese type 2 diabetic mice and control mice. We evaluated Ffar1 and Pdx1 mRNA and protein expression levels in both mice. In addition, we examined whether Pdx1 is a possible regulator of Ffar1 expression using small interfering RNA for Pdx1 (siPdx1) in ß-cell-derived cell line. As the results, Ffar1 mRNA and protein expression in ß-cells were significantly lower in obese type 2 diabetic db/db mice compared to control mice which was accompanied by the decreased expression of Pdx1. In addition, down-regulation of Pdx1 expression using siPdx1 suppressed Ffar1 expression. Furthermore, adenoviral Pdx1 overexpression significantly increased Ffar1 expression. In conclusion, Ffar1 expression is markedly down-regulated under diabetic conditions which is accompanied by decreased expression of Pdx1. Furthermore, it is likely that Pdx1 is a regulator of Ffar1 expression in ß-cells.

Verification of Kumamoto Declaration 2013 and Glycemic Targets for Elderly Patients with Diabetes in Japan for prevention of diabetic complications: A retrospective longitudinal study using outpatient clinical data.

AIMS/INTRODUCTION: The present study examined the association between the onset of micro- and macroangiopathy in type 2 diabetes mellitus patients and levels of glycated hemoglobin (HbA1c) described in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 or those indicated in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2016 and received follow up for >2 years were eligible for the present study. Two datasets, comprising 2,424 or 3,316 patients without micro- or macroangiopathy at the start of follow up, were used, respectively. The Cox model was used in two categories of patients, younger and elderly, with the dividing line set at the age of 65 years. RESULTS: For the prevention of microangiopathy, in all patients, there was found to be no advantage in controlling HbA1c at a level of <6.0% based on the categories in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013, and there was found to be a disadvantage in maintaining HbA1c ≥8.5% based on the categories in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes guideline. For the prevention of macroangiopathy in younger patients, there seemed to be an advantage in maintaining HbA1c within the range of 6.0-6.9% and <7.0% based on the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 and the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes, respectively. CONCLUSIONS: In all type 2 diabetes mellitus patients, average HbA1c should be maintained <7.0% to prevent microangiopathy. However, in elderly patients, no optimal target for preventing macroangiopathy was found, in contrast to the younger patients in the present study.

Administration of RAS Inhibitor before the Onset of Diabetic Nephropathy Counteracts the Adverse Effect of Chronic Hyperglycemia and Reduces the Augmentation of Urinary Albumin Excretion: A Retrospective Clinical Study.

It is very important to explore how we can reduce urinary albumin excretion which is an independent risk factor for ischemic heart disease. In this study, we retrospectively evaluated the effects of RAS inhibitor therapy on diabetic nephropathy in Japanese subjects whose urinary albumin levels were within normal range. We enrolled 100 subjects with type 2 diabetes who did not take any renin-angiotensin system (RAS) inhibitor. We defined the subjects taking RAS inhibitor for more than 3 years as RAS inhibitor group. RAS inhibitor exerted protective effect on the progression of urinary albumin excretion in subjects with type 2 diabetes without diabetic nephropathy. In addition, RAS inhibitor exerted more protective effects on renal function especially in subjects with poor glycemic control. In conclusion, RAS inhibitor could protect renal function against the deleterious effect of chronic hyperglycemia in Japanese subjects with type 2 diabetes even before the onset of diabetic nephropathy.

Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity.

It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression.

There is a Close Association Between the Recovery of Liver Injury and Glycemic Control after SGLT2 Inhibitor Treatment in Japanese Subjects with Type 2 Diabetes: A Retrospective Clinical Study.

INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT2) inhibitors function not only to reduce hyperglycemia but also to ameliorate liver injury and reduce body weight. The aim of this study was to examine in which subjects SGLT2 inhibitors are more effective for glycemic control, liver injury, and obesity in Japanese subjects with type 2 diabetes mellitus. METHODS: We enrolled a total of 156 subjects with type 2 diabetes who initiated SGLT2 inhibitor treatment after September 1, 2014 in Kawasaki Medical School (Protocol No. 2375). We evaluated the alteration of glycemic control, liver injury, body mass composition, and various clinical parameters. RESULTS: SGLT2 inhibitors significantly ameliorated glycemic control and improved liver injury in Japanese subjects with type 2 diabetes. SGLT2 inhibitors were more effective for liver injury when glycemic control was improved with SGLT2 inhibitors. In multivariate analyses, the amelioration of glycemic control was an independent determinant factor for the improvement of liver damage in Japanese subjects with type 2 diabetes. The reverse was also correct; the improvement of liver damage was an independent determinant factor for the amelioration of glycemic control. CONCLUSION: Recovery of liver injury with SGLT2 inhibitor treatment was closely associated with their effects on glycemic control in Japanese subjects with type 2 diabetes.

Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic ß-cells in db/db mice: The earlier and longer, the better.

AIMS: We compared the protective effects of sodium glucose co-transporter (SGLT) 2 inhibitor luseogliflozin on pancreatic ß-cells between early and advanced stages of diabetes and between short- and long-term use. MATERIALS AND METHODS: Diabetic db/db mice were treated with luseogliflozin for 2 weeks in an early stage of diabetes (7-9 weeks of age) and an advanced stage of diabetes (16-18 weeks) for a longer period of time (7-18 weeks). We performed various morphological analyses of pancreatic islets and examined gene expression profiles in islets after such treatment. RESULTS: In diabetic db/db mice, insulin biosynthesis and secretion were markedly increased by luseogliflozin in an early stage of diabetes but not in an advanced stage. In addition, ß-cell mass was preserved by luseogliflozin only in an early stage. Furthermore, when db/db mice were treated with luseogliflozin for a longer period of time, starting from an early stage, ß-cell function and mass were markedly preserved even after a longer period of time compared to untreated db/db mice. CONCLUSION: Luseogliflozin exerts more protective effects in an early stage of diabetes compared to an advanced stage, and longer-term use of luseogliflozin exerts more beneficial effects on pancreatic ß-cells compared to short-term use.

Efficacy and Safety of Switching from Insulin Glargine 100 U/mL to the Same Dose of Glargine 300 U/mL in Japanese Type 1 and 2 Diabetes Patients: A Retrospective Analysis.

Objective Insulin glargine [300 U/mL (Gla-300)] achieved better glycemic control and reduced the risk of hypoglycemia in comparison to glargine [100 U/mL; (Gla-100)] in phase 3 trials. This is the first study to retrospectively evaluate the efficacy and safety of Gla-300 in Japanese type 1 and 2 diabetes patients in a routine clinical setting. Methods We analyzed 20 type 1 diabetes patients and 62 type 2 diabetes patients who switched from Gla-100 to the same dose of Gla-300. Sixty type 2 diabetes patients who continued the use of Gla-100 during the study were included as controls. Results At three months after switching, the HbA1c levels were decreased in the patients with type 1 diabetes, but not to a significant extent. In the type 2 diabetes patients, the HbA1c levels were significantly decreased after switching (p<0.01). In contrast, there was no change in the HbA1c levels of the type 2 diabetes patients who continued the use of Gla-100 over the same period. The BMI values of the type 1 diabetes patients tended to decrease (p=0.06) and there was a significant decrease in the BMI values of the type 2 diabetes patients (p<0.05). There was no change in the BMI values of the type 2 diabetes patients who continued the use of Gla-100. The rates of hypoglycemia and adverse events did not change during the follow-up period. Conclusion In the clinical setting, switching from Gla-100 to the same dose of Gla-300 had a favorable effect on glycemic control and body weight control in Japanese type 1 and type 2 diabetes patients, without any increase in adverse events; however, a prospective study should be performed to confirm these findings.