Periodic paralysis due to cumulative effects of rare variants in SCN4A with small functional alterations.

INTRODUCTION/AIMS: Mutations in the SCN4A gene encoding a voltage-gated sodium channel (Nav1.4) cause hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). Typically, both HyperPP and HypoPP are considered as monogenic disorders caused by a missense mutation with a large functional effect. However, a few cases with atypical periodic paralysis phenotype have been caused by multiple mutations in ion-channel genes expressed in skeletal muscles. In this study we investigated the underlying pathogenic mechanisms in such cases. METHODS: We clinically assessed two families: proband 1 with HyperPP and proband 2 with atypical periodic paralysis with hypokalemia. Genetic analyses were performed by next-generation sequencing and conventional Sanger sequencing, followed by electrophysiological analyses of the mutant Nav1.4 channels expressed in human embryonic kidney 293T (HEK293T) cells using the whole-cell patch-clamp technique. RESULTS: In proband 1, K880del was identified in the SCN4A gene. In proband 2, K880del and a novel mutation, R1639H, were identified in the same allele of the SCN4A gene. Functional analyses revealed that the K880del in SCN4A has a weak functional effect on hNav1.4, increasing the excitability of the sarcolemma, which could represent a potential pathogenic factor. Although R1639H alone did not reveal functional changes strong enough to be pathogenic, Nav1.4 with both K880del and R1639H showed enhanced activation compared with K880del alone, indicating that R1639H may modify the hNav1.4 channel function. DISCUSSION: A cumulative effect of variants with small functional alterations may be considered as the underpinning oligogenic pathogenic mechanisms for the unusual phenotype of periodic paralysis.

The impact of culture dimensionality on behavioral epigenetic memory contributing to pluripotent state of iPS cells.

Three-dimensional (3D) culture platforms have been explored to establish physiologically relevant cell culture environment and permit expansion scalability; however, little is known about the mechanisms underlying the regulation of pluripotency of human induced pluripotent stem cells (hiPSCs). This study elucidated epigenetic modifications contributing to pluripotency of hiPSCs in response to 3D culture. Unlike two-dimensional (2D) monolayer cultures, 3D cultured cells aggregated with each other to form ball-like aggregates. 2D cultured cells expressed elevated levels of Rac1 and RhoA; however, Rac1 level was significantly lower while RhoA level was persisted in 3D aggregates. Compared with 2D monolayers, the 3D aggregates also exhibited significantly lower myosin phosphorylation. Histone methylation analysis revealed remarkable H3K4me3 upregulation and H3K27me3 maintenance throughout the duration of 3D culture; in addition, we observed the existence of naïve pluripotency signatures in cells grown in 3D culture. These results demonstrated that hiPSCs adapted to 3D culture through alteration of the Rho-Rho kinase-phospho-myosin pathway, influencing the epigenetic modifications and transcriptional expression of pluripotency-associated factors. These results may help design culture environments for stable and high-quality hiPSCs.

The rBC2LCN-positive subpopulation of PC-3 cells exhibits cancer stem-like properties.

The recombinant lectin rBC2LCN is a useful marker for discriminating the undifferentiated status of human induced or embryonic stem cells. Recently, rBC2LCN has also been used for detecting some cancers and niche cells. However, the generality of which types of cells are detected by rBC2LCN is unclear. In this study, we demonstrated the potential of rBC2LCN as a probe for detecting and isolating cancer stem-like cells. Interestingly, flow cytometric analysis of various human cell lines indicated that the human prostate cancer cell line PC-3 consisted of rBC2LCN-positive and -negative subpopulations. Compared with the rBC2LCN-negative subpopulation, the rBC2LCN-positive subpopulation possessed representative features of cancer stem cells and malignancy, such as slow proliferation, increased cell motility, anchorage-independent growth, and drug resistance. The comprehensive expression profiles revealed that the rBC2LCN-positive subpopulation expressed higher levels of cancer stem cell markers. These findings indicate that rBC2LCN is useful for detecting not only pluripotent stem cells but also the cancer stem-like subpopulation of PC-3 cells. Pluripotent and cancer cells with rBC2LCN positivity would be important for future stem cell research.

Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study).

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.

Identification and comparative analyses of Siamois cluster genes in Xenopus laevis and tropicalis.

Two siamois-related homeobox genes siamois (sia1) and twin (sia2), have been reported in Xenopus laevis. These genes are expressed in the blastula chordin- and noggin-expressing (BCNE) center and the Nieuwkoop center, and have complete secondary axis-inducing activity when over-expressed on the ventral side of the embryo. Using whole genome sequences of X. tropicalis and X. laevis, we identified two additional siamois-related genes, which are tandemly duplicated near sia1 and sia2 to form the siamois gene cluster. Four siamois genes in X. tropicalis are transcribed at blastula to gastrula stages. In X. laevis, the siamois gene cluster is present on both homeologous chromosomes, XLA3L and XLA3S. Transcripts from seven siamois genes (three on XLA3L and four on XLA3S) in X. laevis were detected at blastula to gastrula stages. A transcribed gene, sia1p. S, encodes an inactive protein without a homeodomain. When over-expressed ventrally, all siamois-related genes tested in this study except for sia1p. S induced a complete secondary axis, indicating that X. tropicalis and X. laevis have four and six active siamois-related genes, respectively. Of note, each gene required different amounts of mRNA for full activity. These results suggest the possibility that siamois cluster genes have functional redundancy to endow robustness and quickness to organizer formation in Xenopus species.

Roles of Xenopus chemokine ligand CXCLh (XCXCLh) in early embryogenesis.

Several chemokine molecules control cell movements during early morphogenesis. However, it is unclear whether chemokine molecules affect cell fate. Here, we identified and characterized the CXC-type chemokine ligand in Xenopus laevis, Xenopus CXCLh (XCXCLh), during early embryogenesis. XCXCLh is expressed in the dorsal vegetal region at the gastrula stage. Both overexpression and knockdown of XCXCLh in the dorsal region inhibited gastrulation. XCXCLh contributed to the attraction of mesendodermal cells and accelerated the reassembly of scratched culture cells. Also, XCXCLh contributed to early endodermal induction. Overexpression of VegTmRNA or high concentrations of calcium ions induced XCXCLh expression. XCXCLh may play roles in both cell movements and differentiation during early Xenopus embryogenesis.

[Three Long-Surviving Cases of Recurrent Rectal Carcinomas Treated Non-Surgically and Cured].

Few cases of recurrent colorectal carcinomas were treated non-surgically and cured. Here, we report 3 such cases. Case No. 1 was of a 66-year-old woman, who underwent ISR for very low rectal cancer. Her disease Stage was tub2, T2N0M0. Two years and 6 months later, she developed intrapelvic recurrence involving sacral bones(S1-S3). Radiotherapy of 50 Gy followed by mFOLFOX6 with bevacizumab was administered for a year. She has been cancer-free for 6 years. Case No. 2 was of a 47-year-old man who underwent preoperative CRT of 40 Gy with 5-FU plus Leucovorin, and LAR was performed for very low rectal cancer. The disease Stage was tub2, T3N2M0. One year later, he was diagnosed with recurrent aortic lymph node metastasis. After 7 months of mFOLFOX6 with bevacizumab, he developed an anastomotic fistula. His chemotherapy was discontinued; he was cancer-free for 6 years. Case No. 3 was of a 56-year-old man who underwent TPE for low rectal cancer. The disease Stage was muc, T4b(urinary bladder)N0M1a(perianal skin). One year and 6 months later, he developed ileus and was diagnosed with intrapelvic recurrence. He underwent intestinal bypass operation, and CRT of 46 Gy with capecitabine was administered. He attained CR quickly, and was cancer-free for 5 years. Collecting similar cases to analyze the key to successful treatment is important.

α2-6 sialylation is a marker of the differentiation potential of human mesenchymal stem cells.

Human somatic stem cells such as human mesenchymal stem cells (hMSCs) are considered attractive cell sources for stem cell-based therapy. However, quality control issues have been raised concerning their safety and efficacy. Here we used lectin microarray technology to identify cell surface glycans as markers of the differentiation potential of stem cells. We found that α2-6Sia-specific lectins show stronger binding to early passage adipose-derived hMSCs (with differentiation ability) than late passage cells (without the ability to differentiate). Flow cytometry analysis using α2-6Sia-specific lectins supported the results obtained by lectin microarray. Similar results were obtained for bone marrow-derived hMSCs and cartilage tissue-derived chondrocytes. Little or no binding of α2-6Sia-specific lectins was observed for human dermal fibroblasts, which are unable to differentiate, suggesting that the binding of α2-6Sia-specific lectins is associated with the differentiation ability of cells, but not to their capacity to proliferate. Quantitative analysis of the linkage mode of Sia using anion-exchange chromatography showed that the percentage of α2-6Sia linkage type was higher in early passage adipose-derived hMSCs than late passage cells. Integrinα5 was found to be a carrier protein of α2-6Sia. Sialidase treatment significantly reduced the differentiation efficiency of bone marrow-derived hMSCs. Based on these findings, we propose that α2-6sialylation is a marker of differentiation potential in stem cells such as adipose-derived hMSCs, bone marrow-derived hMSCs, and cartilage tissue-derived chondrocytes.

Indicators of the need for insulin treatment and the effect of treatment for gestational diabetes on pregnancy outcomes in Japan.

This study assessed indicators of the need for insulin therapy and the effect of treatment on pregnancy outcomes in Japanese patients with gestational diabetes mellitus (GDM). All patients diagnosed with GDM were hospitalized for three days. Plasma glucose profiles in patients under strict dietary management and the characteristics of GDM patients with high daily glucose levels were investigated. Patients who failed to achieve glycemic targets were treated with insulin. Indicators of the need for insulin treatment were investigated. Pregnancy outcomes in patients prescribed dietary management and patients prescribed insulin treatment were compared. The study included 112 patients with GDM. GDM patients with high daily glucose levels in the hospital exhibited significantly higher 1-h and 2-h plasma glucose levels in oral glucose tolerance tests (OGTTs) at diagnosis. In our hospital, 102 GDM patients with singleton pregnancies were followed until delivery; 32 (31.3%) were treated with insulin. Univariate analysis identified significant associations of insulin requirement with family history of diabetes and with 1-h and 2-h OGTT values at diagnosis. Multivariate analysis showed that the 1-h OGTT plasma glucose level at diagnosis was an independent predictor of the need for insulin. In perinatal outcomes, insulin treatment was associated with low birth weight.

Aminolevulinate synthase 2 mediates erythrocyte differentiation by regulating larval globin expression during Xenopus primary hematopoiesis.

Hemoglobin synthesis by erythrocytes continues throughout a vertebrate's lifetime. The mechanism of mammalian heme synthesis has been studied for many years; aminolevulinate synthase 2 (ALAS2), a heme synthetase, is associated with X-linked dominant protoporphyria in humans. Amphibian and mammalian blood cells differ, but little is known about amphibian embryonic hemoglobin synthesis. We investigated the function of the Xenopus alas2 gene (Xalas2) in primitive amphibian erythrocytes and found that it is first expressed in primitive erythroid cells before hemoglobin alpha 3 subunit (hba3) during primary hematopoiesis and in the posterior ventral blood islands at the tailbud stage. Xalas2 is not expressed during secondary hematopoiesis in the dorsal lateral plate. Hemoglobin was barely detectable by o-dianisidine staining and hba3 transcript levels decreased in Xalas2-knockdown embryos. These results suggest that Xalas2 might be able to synthesize hemoglobin during hematopoiesis and mediate erythrocyte differentiation by regulating hba3 expression in Xenopus laevis.

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.

Structural and quantitative evidence for dynamic glycome shift on production of induced pluripotent stem cells.

We recently reported that induced pluripotent stem cells (iPSCs) prepared from different human origins acquired similar glycan profiles to one another as well as to human embryonic stem cells. Although the results strongly suggested attainment of specific glycan expressions associated with the acquisition of pluripotency, the detailed glycan structures remained to be elucidated. Here, we perform a quantitative glycome analysis targeting both N- and O-linked glycans derived from 201B7 human iPSCs and human dermal fibroblasts as undifferentiated and differentiated cells, respectively. Overall, the fractions of high mannose-type N-linked glycans were significantly increased upon induction of pluripotency. Moreover, it became evident that the type of linkage of Sia on N-linked glycans was dramatically changed from α-2-3 to α-2-6, and the expression of α-1-2 fucose and type 1 LacNAc structures became clearly apparent, while no such glycan epitopes were detected in fibroblasts. The expression profiles of relevant glycosyltransferase genes were fully consistent with these results. These observations indicate unambiguously the manifestation of a "glycome shift" upon conversion to iPSCs, which may not merely be the result of the initialization of gene expression, but could be involved in a more aggressive manner either in the acquisition or maintenance of the undifferentiated state of iPSCs.

Effect of conditioned media on the angiogenic activity of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are promising candidates for use in novel cell therapies, although such live cell products are highly complex compared with traditional drugs. For example, difficulties such as the control of manufacturing conditions hinder the manufacture of stable cell populations that maintain their therapeutic potency. Here, assuming that medium selection significantly affects cell potency, we focused on the culture media as a critical manufacturing factor influencing the therapeutic efficacy of MSCs. We therefore performed a tube formation assay to quantify the angiogenic activities of conditioned media used to culture human umbilical vein endothelial cells compared with unconditioned media. Comprehensive molecular genetic analysis using microarrays was applied to determine the effects of these media on signal transduction pathways. We found that activation of the vascular endothelial growth factor (VEGF) signaling pathway differed, and that VEGF concentration was dependent on the composition of the conditioned media. These results indicate that the activation level of cell signaling pathways which contribute to therapeutic efficacy may vary depending on the media components affecting MSCs during their cultivation. Moreover, they indicate that therapeutic efficacy will likely depend on how cells are handled during manufacture. These findings will enhance our understanding of the quality control measures required to ensure the efficacy and safety of cell therapy products.

Impact of Straight Stomach Reconstruction on Delayed Gastric Emptying and Nutritional Recovery After Pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to evaluate the effectiveness of a modified reconstruction technique-anchored straight stomach reconstruction-in reducing the incidence of delayed gastric emptying (DGE) after pancreaticoduodenectomy (PD) and its impact on postoperative nutritional recovery. METHODS: A case series analysis of 125 consecutive PD patients was conducted: 104 of them had undergone anchored straight stomach reconstruction (SSR group) and the remaining 21 without (Non-SSR group). The incidence of DGE and the change in postoperative nutritional status (body weight and serum albumin level during 12 months post-surgery) were compared. RESULTS: The incidence of DGE in the SSR group (13%) was significantly lower than that in the Non-SSR group (33%) (P = .018); further the significant DGE (grade B or C) was only 5%. Comparison of nutritional status showed that SSR facilitated a prompt recovery of body weight and serum albumin level at 6 months after PD. At 12 months after surgery, body weight gain was significantly better in the SSR group than in the Non-SSR group (P = .006), and albumin level tended to be higher in the SSR group (P = .071). CONCLUSION: Straight stomach reconstruction is able to reduce DGE in patients after PD and also improves their postoperative nutritional recovery.

Incisional surgical site infections by subcutaneous soaking of wound with aqueous 0.05% chlorhexidine gluconate in gastroenterological surgery: A randomized controlled trial.

BACKGROUND: Chlorhexidine gluconate solution is superior to povidone-iodine for prevention of surgical site infection. However, the overall efficacy of chlorhexidine gluconate for surgical site infection prevention in various types of gastroenterological surgery, as well as the optimal concentration of chlorhexidine gluconate, remain unclear. The aim of the present study was to clarify whether subcutaneous wound soaking with chlorhexidine gluconate would reduce the incidence of surgical site infection associated with gastroenterological surgery in patients with wound classes Ⅱ to Ⅳ. METHODS: Patients were randomly assigned (1:1) to either wound soaking with chlorhexidine gluconate (chlorhexidine gluconate group) or no chlorhexidine gluconate soaking (control group). After closure of the abdominal fascia, gentle subcutaneous soaking of the wound was performed using gauze fully soaked in aqueous 0.05% chlorhexidine gluconate before skin closure. Incisional surgical site infection was diagnosed using the Centers for Disease Control and Prevention criteria. The primary end point was the occurrence of incisional surgical site infection. RESULTS: Among 363 patients, 245 (67%) underwent laparoscopic surgery. All 363 patients were included-181 in the chlorhexidine gluconate group (49.9%) and 182 (50.1%) in the control group. There were no significant inter-group differences in patient background, the type of procedure, or wound classification. The incidence proportion of incisional surgical site infection was significantly lower in the chlorhexidine gluconate group than in the control group (9.4% vs 19.2%; P = .008). CONCLUSION: Subcutaneous wound soaking with chlorhexidine gluconate reduces the incidence of incisional surgical site infection in patients undergoing gastroenterological surgery.

Secondary Publication: Proposal for Points of Consideration for Pluripotent Stem Cell Culture.

Human pluripotent stem cells, such as human embryonic stem cells and human induced pluripotent stem cells, are used in basic research and various applied fields, including drug discovery and regenerative medicine. Stem cell technologies have developed rapidly in recent years, and the supply of culture materials has improved. This has facilitated the culture of human pluripotent stem cells and has enabled an increasing number of researchers and bioengineers to access this technology. At the same time, it is a challenge to share the basic concepts and techniques of this technology among researchers and technicians to ensure the reproducibility of research results. Human pluripotent stem cells differ from conventional somatic cells in many aspects, and many points need to be considered in their handling, even for those experienced in cell culture. Therefore, we have prepared this proposal, "Points of Consideration for Pluripotent Stem Cell Culture," to promote the effective use of human pluripotent stem cells. This proposal includes seven items to be considered and practices to be confirmed before using human pluripotent stem cells. These are laws/guidelines and consent/material transfer agreements, diversity of pluripotent stem cells, culture materials, thawing procedure, media exchange and cell passaging, freezing procedure, and culture management. We aim for the concept of these points of consideration to be shared by researchers and technicians involved in the cell culture of pluripotent stem cells. In this way, we hope the reliability of research using pluripotent stem cells can be improved, and cell culture technology will advance.

rBC2LCN, a new probe for live cell imaging of human pluripotent stem cells.

Cell surface biomarkers have been applied to discriminate pluripotent human embryonic stem cells and induced pluripotent stem cells from differentiated cells. Here, we demonstrate that a recombinant lectin probe, rBC2LCN, a new tool for fluorescence-based imaging and flow cytometry analysis of pluripotent stem cells, is an alternative to conventional pluripotent maker antibodies. Live or fixed colonies of both human embryonic stem cells and induced pluripotent stem cells were visualized in culture medium containing fluorescent dye-labeled rBC2LCN. Fluorescent dye-labeled rBC2LCN was also successfully used to separate live pluripotent stem cells from a mixed cell population by flow cytometry.

Vasculature cells control neuroglial co-localization and synaptic connection in a central nervous system tissue mimic system.

Despite the development of neural tissue differentiation methods using a wide variety of stem cells and compartments, there is no standardized strategy for establishing synapses. As the neuronal network is developed in parallel with blood vessel angiogenesis in the central nervous system (CNS) from the embryonic period, we examined neuron-astrocyte-vasculature interactions to understand the effect of the vasculature on the development and stabilization of neurological morphogenesis. We generated a cellular co-culture module targeting the CNS that was embedded in a collagen-based extracellular matrix (ECM) gel. Our neuron-astrocyte-vascular complex module identified the neurological co-localization effect by endothelial cells, as well as the pericyte-induced improvement of synaptic connections. Furthermore, it was suggested that the PDGF, BDNF, IGF, and WNT/BMP pathways were upregulated in synaptic connections enhanced conditions, which are composed of neurexin. These results suggest that the integrity of the vasculature cells in the CNS is important for the establishment of neuronal networks and for synapse connection.

Effects of switching from liraglutide to semaglutide or dulaglutide in patients with type 2 diabetes: A randomized controlled trial.

INTRODUCTION: Few studies have examined the effects of glucagon-like peptide-1 receptor agonist switching, particularly in Japanese patients. Therefore, we aimed to investigate the effects of switching from liraglutide to semaglutide or dulaglutide on blood glucose, body weight, and the occurrence of adverse effects in clinical practice. MATERIALS AND METHODS: This was an open-label, prospective, randomized, parallel-group controlled trial. Patients with type 2 diabetes treated with liraglutide (0.6 or 0.9 mg) at Yokosuka Kyosai Hospital in Japan were recruited from September 2020 to March 2022 and, after obtaining informed consent, randomly assigned to the semaglutide or dulaglutide group (1:1). Changes in the glycated hemoglobin level from baseline to weeks 8, 16, and 26 were evaluated post-treatment. RESULTS: Initially, 32 participants were enrolled, of whom 30 completed the study. Glycemic control was significantly better in the semaglutide group than in the dulaglutide group (-0.42 ± 0.49% vs -0.00 ± 0.34%, P = 0.0120). Body weight significantly decreased in the semaglutide group (-2.6 ± 3.6 kg, P = 0.0153), whereas no change was observed in the dulaglutide group (-0.1 ± 2.7 kg, P = 0.8432). We found a significant difference in body weight between the groups (P = 0.0469). The proportion of participants who reported adverse events was 75.0% and 18.8% in the semaglutide and dulaglutide groups, respectively. One patient in the semaglutide group had difficulty continuing treatment due to severe vomiting and weight loss. CONCLUSIONS: Switching from once-daily liraglutide to once-weekly semaglutide 0.5 mg significantly improved glycemic control and body weight compared with switching to once-weekly dulaglutide 0.75 mg.

Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased ß cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes.

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces ß cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged ß cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed ß cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the ß cell mass and ß cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against ß cell apoptosis, restored the ß cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced ß cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated ß cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.