Search

Abstract Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic β-cells. First, single-dose administration of imeglimin enhanced insulin secretion from β-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in β-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic β-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in β-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from β-cells, increases the number of insulin granules, exerts favorable effects on morphology in β-cell mitochondria, and reduces apoptotic β-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as β-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic β-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of β-cell glucose toxicity in the future.

Abstract This study examined the association between Grit Scales and adherence to a schedule of regular hospital visits among Japanese type 2 diabetes patients. Patients with type 2 diabetes who visited the outpatient clinic as new patients comprised the study’s participants. Self‐administered Short Grit Scale data were obtained from 122 patients at the first consultation and were then observed for 1 year. As the results, 21 participants failed to attend the hospital. In a logistic regression analysis, the Grit Scale as a continuous variable was positively associated with adherence to regular clinical visits. Its odds ratio and 95% confidential interval was 9.68 and 2.87–32.65 (P = 0.0003). In conclusion, it is likely that the Grit Scale is closely associated with adherence to regular hospital visits among Japanese type 2 diabetes patients.

Abstract Aims/Introduction This study examined the effect of daily walking steps on glycated hemoglobin, body mass index (BMI) and body composition while taking into consideration sedentary time (ST) in Japanese type 2 diabetes patients over a period of 12 months. Materials and Methods Self‐administered ST values and information regarding daily walking steps were obtained and analyzed for 236 patients with type 2 diabetes who regularly visited the outpatient clinic. The patients – divided into three categories of daily walking steps: non‐step counter user,

Abstract Background Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas. Case presentation A 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon. Conclusions We should bear in m ind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

Abstract Effects of combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor on β-cells are still unclear, although combination agent of these two drugs has become common in clinical practice. Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old db/db mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2 weeks with oral administration of linagliptin, empagliflozin, linagliptin + empagliflozin (L + E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L + E group were significantly lower than Cont group after treatment. In addition, β-cell mass in L + E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive β-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L + E group in an early phase. Furthermore, mRNA expression levels related to β-cell differentiation and proliferation were significantly increased only in L + E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on β-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.

Abstract Background Tamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it. Case presentation 47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically. Conclusions From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.

Abstract There has been no report about the mechanism for anti-atherosclerotic effects of dulaglutide (Dula) and/or about the difference of its effectiveness between in an early and a late phase of diabetes. To address such questions, streptozotocin (STZ) was intraperitoneally injected to ApoE knockout mice at 8 weeks of age. Either Dula or vehicle was administered to STZ-induced diabetic ApoE knockout mice from 10 to 18 weeks of age as an early intervention group and from 18 to 26 weeks as a late intervention group. Next, non-diabetic ApoE knockout mice without STZ injection were subcutaneously injected with either Dula or vehicle. In an early intervention group, atherosclerotic lesion in aortic arch and Mac-2 and CD68-positive areas in aortic root were significantly smaller in Dula group. In abdominal aorta, expression levels of some villain factors were lower in Dula group. In a late intervention group, there were no immunohistological differences in aortic root and expression levels of various factors between two groups. Furthermore, even in non-diabetic ApoE knockout mice, expression levels of inflammatory and macrophage markers were reduced by treatment with Dula. Taken together, Dula exerts more beneficial anti-atherosclerotic effects in an early phase of diabetes rather than in a late phase.

Background & Aims Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities. Methods We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions. Results Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since xeroderma pigmentosum complementation group G (XPG) could not accumulate without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo settings. A higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC was observed. Conclusions We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations. Lay summary Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract 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.

Background: Extraocular myositis is characterized by acute onset of orbital pain, extraocular muscle swelling, absence of thyroid disease, and effectiveness of steroid therapy. While oculomotor nerve paralysis is often observed in subjects with diabetes mellitus, extraocular muscle paralysis is very rare among various diabetic mononeuropathies. In addition, while most diabetic mononeuropathies are observed as sporadic and/or unilateral neuropathy, bilateral mononeuropathy is also very rare.Case presentation: A 58-year-old male visited our institution due to diplopia. He was diagnosed as type 2 diabetes mellitus about 10 years before and treated with oral diabetes agents. To examine the cause of his symptom, he was hospitalized in our institution. Slight ptosis was observed, and failure of adduction was observed in the right eye. Glycemic control was poor; HbA1c was 9.3%. Liver, renal, and thyroid function were within normal range. Immunoglobulin (Ig) G was slightly high, but IgA, IgM, and IgG4 were within normal range. Various antibodies were all negative. Angiotensin-converting enzyme level was within normal range. There were no abnormalities in brain magnetic resonance imaging (MRI). After admission, to alleviate glucose toxicity, we started insulin therapy. On day 17, adduction failure of the left eye was observed in addition to the right eye. Vertical movement was also impaired in both eyes. Slight ptosis was observed in both eyes, and the right eye was completely close. In orbital MRI, some high signal was detected in both extraocular muscles. We performed steroid pulse therapy twice. About 4 months later, ptosis and vertical and horizontal movements in both eyes were almost completely recovered. Finally, we diagnosed him as idiopathic bilateral extraocular myositis.Conclusions: We should bear in mind the possibility of idiopathic bilateral extraocular myositis especially in subjects with poor glycemic control, although its incident rate is extremely rare.

AimAt 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.MethodsWe 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”.ResultsIn 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.ConclusionWe 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.

Abstract 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

Abstract 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.

Abstract 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.

Although the importance of adjuvant chemotherapy (AC) has been recognized in pancreatic cancer (PC) patients, there are few studies to address the underlying mechanisms of failure to complete AC. This study aims to investigate the relationship between nutritional state represented by sarcopenia and failure to complete AC in patients after curative-intent surgery for PC. This study included 110 patients who underwent pancreaticoduodenectomy for potentially resectable pancreatic cancers with intention of adjuvant S-1. Sarcopenia was defined using the psoas muscle mass index with cutoff values of 6.36 cm² /m² for men and 3.92 cm² /m2 for women, which were calculated with a 3-D volumetric software. The relation between sarcopenia and successful AC and long-term survival were investigated. Twenty-nine (26%) patients were diagnosed as having sarcopenia (Sarcopenia group). Sarcopenia group comprised significantly older patients than Non-sarcopenia group (72 vs. 67 years old, p = 0.0087). AC was successfully completed in 14 patients (48%) in Sarcopenia group compared to 72 patients (89%) in Non-sarcopenia group (p < 0.0001). Multivariate analysis identified age ≥ 70 years and sarcopenia as significant risk factors for failure of AC. Among patients ≥ 70 years old, rate of successful AC was significantly higher in sarcopenia groups than non-sarcopenia group (17% vs. 78%, p < 0.001). In conclusions, age and sarcopenia were critical risk factors for the failure of 6 months of adjuvant chemotherapy. Among elderly patients, sarcopenia can predict the poor success rate of AC. [ABSTRACT FROM AUTHOR]

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.

Various important transcription factors in the pancreas are involved in the process of pancreas development, the differentiation of endocrine progenitor cells into mature insulin-producing pancreatic β-cells and the preservation of mature β-cell function. However, when β-cells are continuously exposed to a high glucose concentration for a long period of time, the expression levels of several insulin gene transcription factors are substantially suppressed, which finally leads to pancreatic β-cell failure found in type 2 diabetes mellitus. Here we show the possible underlying pathway for β-cell failure. It is likely that reduced expression levels of MafA and PDX-1 and/or incretin receptor in β-cells are closely associated with β-cell failure in type 2 diabetes mellitus. Additionally, since incretin receptor expression is reduced in the advanced stage of diabetes mellitus, incretin-based medicines show more favorable effects against β-cell failure, especially in the early stage of diabetes mellitus compared to the advanced stage. On the other hand, many subjects have recently suffered from life-threatening coronavirus infection, and coronavirus infection has brought about a new and persistent pandemic. Additionally, the spread of coronavirus infection has led to various limitations on the activities of daily life and has restricted economic development worldwide. It has been reported recently that SARS-CoV-2 directly infects β-cells through neuropilin-1, leading to apoptotic β-cell death and a reduction in insulin secretion. In this review article, we feature a possible molecular mechanism for pancreatic β-cell failure, which is often observed in type 2 diabetes mellitus. Finally, we are hopeful that coronavirus infection will decline and normal daily life will soon resume all over the world.

Abstract Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/β-catenin signaling is activated in HCC, we focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.

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.

Sodium-glucose cotransporter 2 inhibitor tofogliflozin is a new type of antidiabetic drug for individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to examine in which type of individuals and/or under which conditions tofogliflozin could exert more beneficial effects on body composition and/or glycemic control in Japanese individuals with T2DM. We retrospectively evaluated the effects of tofogliflozin on body composition and/or glycemic control in individuals with T2DM who newly started taking tofogliflozin. After tofogliflozin treatment, body weight was significantly reduced and HbA1c levels were significantly decreased. Body fat mass, skeletal muscle mass, and skeletal muscle index, a marker for sarcopenia, were also reduced after the treatment. In univariate analyses, there was a statistically significant association between the decrease of HbA1c level after tofogliflozin treatment (Δ HbA1c) and the following parameters such as HbA1c levels at baseline, visceral fat area (VFA) at baseline, and reduction of VFA after the treatment (Δ VFA). Furthermore, in multivariate analyses, HbA1c levels at baseline and duration of diabetes were independently associated with Δ HbA1c. These results suggest that tofogliflozin would be more suitable for relatively obese individuals whose duration of diabetes is relatively short.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are often used all over the world and exert various beneficial effects including glucose-lowering effect in many subjects with type 2 diabetes. It is poorly understood, however, which factors are closely related with the durability of glucose-lowering effect by DPP-4 inhibitor. In this study, we examined retrospectively which factors could mainly influence the durability of DPP-4 inhibitor. We enrolled 212 participants with type 2 diabetes to whom DPP-4 inhibitor was administered for over 1 year without an addition or increase of other hypoglycemic agents. Age and baseline HbA1c level were significantly higher in the effective group than those in the ineffective group. The effective group had a tendency of smaller amounts of weight change, average total cholesterol, and average triglyceride compared with the ineffective group. Multiple logistic regression analysis showed that average triglyceride and baseline HbA1c were independent predictors associated with the durability of DPP-4 inhibitor. Moreover, an average triglyceride level contributed to the durability of DPP-4 inhibitor in the obese group (BMI ≥ 25 kg/m2) but not in the nonobese group (BMI