Publications by authors named "Yuichiro Yamada"

205 Publications

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial.

Front Aging Neurosci 2021 12;13:680341. Epub 2021 Jul 12.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial. Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers. This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan. UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.680341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312849PMC
July 2021

Electronic monitoring of adherence to once-daily and twice-daily direct oral anticoagulants in patients with atrial fibrillation: Baseline data from the SMAAP-AF trial.

J Arrhythm 2021 Jun 30;37(3):616-625. Epub 2021 Mar 30.

Department of Cardiology Tokyo Women's Medical University Tokyo Japan.

Background: Nonadherence diminishes the efficacy of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF). This report presents the baseline survey results regarding medication adherence among NVAF patients who were treated with once-daily edoxaban or twice-daily apixaban from a randomized control trial of the effect of an educational intervention on DOAC adherence.

Methods: We prospectively studied 301 NVAF patients who were treated with edoxaban (n = 175) or apixaban (n = 126) during the 12-week observation period. Adherence was measured with an electronic monitoring system and is expressed as the percentage of days with the correct doses in the measurement period (days). Adherence to DOAC therapy was defined based on the standard threshold (≥80%) or a strict threshold (≥90%).

Results: Of the 301 patients, 33 had incomplete data or protocol deviations, leaving 268 patients (edoxaban 158 and apixaban 110) for the per-protocol baseline analysis. There was no difference in adherence (threshold ≥80%) between the groups (edoxaban 95% vs apixaban 91%,  = .2), but there was a lower proportion of patients with strict adherence (threshold ≥90%) among apixaban users than among edoxaban users (edoxaban 87% vs apixaban 76%,  = .02). Multivariate analysis showed a negative relationship between apixaban use and an adherence rate ≥90% (odds ratio 0.49, 95% confidence interval [CI]: 0.25-0.94).

Conclusions: Our study showed that the proportion of DOAC users with adherence (≥80%) did not differ between the groups, but the proportion of patients with strict adherence (≥90%) was lower among those using apixaban than among those using edoxaban.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/joa3.12532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207342PMC
June 2021

The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice.

Front Endocrinol (Lausanne) 2021 27;12:665537. Epub 2021 May 27.

Kansai Electric Power Hospital, Osaka, Japan.

A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.665537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190331PMC
May 2021

Effects of physician's diabetes self-management education using Japan Association of Diabetes Education and Care Diabetes Education Card System Program and a self-monitoring of blood glucose readings analyzer in individuals with type 2 diabetes: An exploratory, open-labeled, prospective randomized clinical trial.

J Diabetes Investig 2021 Jun 4. Epub 2021 Jun 4.

Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.

Aims/introduction: This 6-month, single-center, prospective, open-labeled, randomized trial was designed to investigate whether physicians' diabetes self-management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self-monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG.

Materials And Methods: Participants were randomized into intervention (I) and control (C) groups. Both groups received physicians' diabetes self-management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment-related quality of life form and an original questionnaire on SMBG use with five questions (Q1-Q5) before and after the study period.

Results: A total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment-related quality of life total score was not changed in either group. Interestingly, the score of Q1 ("How important is SMBG to you?") in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score.

Conclusion: Greater HbA1c-lowering by physicians' diabetes self-management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13607DOI Listing
June 2021

Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta- Mice with Progressive Diabetic Nephropathy.

Int J Mol Sci 2021 May 23;22(11). Epub 2021 May 23.

Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6- and DN-prone KK/Ta- mice. Here, we report that KK/Ta- mice, but not C57BL/6- mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta- mice, but not C57BL/6- mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22115491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197123PMC
May 2021

Effects of glucagon-like peptide-1 receptor agonists on secretions of insulin and glucagon and gastric emptying in Japanese individuals with type 2 diabetes: A prospective, observational study.

J Diabetes Investig 2021 May 22. Epub 2021 May 22.

Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.

Aims/introduction: Differences in the glucose-lowering mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting.

Materials And Methods: A single-arm, prospective, observational study was conducted to evaluate the effects of various GLP-1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP-1RA initiation. Effects on postprandial secretions of glucose-dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated.

Results: Eighteen subjects with type 2 diabetes received one of three GLP-1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12-week administration of all of the GLP-1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP-1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP-1RAs.

Conclusions: All of the GLP-1RAs were found to improve HbA1c in a 12-week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose-lowering effects and body weight reduction were observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13598DOI Listing
May 2021

Effects of GLP-1 receptor agonist on changes in the gut bacterium and the underlying mechanisms.

Sci Rep 2021 Apr 28;11(1):9167. Epub 2021 Apr 28.

Departments of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

There is a close relationship between the gut microbiota and metabolic disorders. In this study, acute administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide to mice increased the cecal levels of caseinolytic protease B, a component of Escherichia coli, and of norepinephrine. Chemical sympathectomy blocked these events. Norepinephrine was found to pass into the intestinal lumen in vitro. c-Fos staining of the intermediolateral nucleus was identified as indirect evidence of sympathetic nervous system activation of the intestinal tract by GLP-1RA. Under normal conditions, the increase in E. coli did not affect the host. However, in mice with colitis, bacterial translocation was observed with attenuation of tight junction gene expression. This is the first study to investigate the unique underlying mechanisms related the effects of GLP-1RA on changes in the gut bacterium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88612-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080802PMC
April 2021

Glucagon Prevents Cytotoxicity Induced by Methylglyoxal in a Rat Neuronal Cell Line Model.

Biomolecules 2021 02 15;11(2). Epub 2021 Feb 15.

Department of Internal Medicine, Division of Diabetes, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.

Although diabetic polyneuropathy (DPN) is a frequent diabetic complication, no effective therapeutic approach has been established. Glucagon is a crucial hormone for glucose homeostasis but has pleiotropic effects, including neuroprotective effects in the central nervous system. However, the importance of glucagon in the peripheral nervous system (PNS) has not been clarified. Here, we hypothesized that glucagon might have a neuroprotective function in the PNS. The immortalized rat dorsal root ganglion (DRG) neuronal cell line 50B11 was treated with methylglyoxal (MG) to mimic an in vitro DPN model. The cells were cultured with or without glucagon or MG. Neurotoxicity, survival, apoptosis, neurite projection, cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) were examined. Glucagon had no cytotoxicity and rescued the cells from neurotoxicity. Cell survival was increased by glucagon. The ratio of apoptotic cells, which was increased by MG, was reduced by glucagon. Neurite outgrowth was accelerated in glucagon-treated cells. Cyclic AMP and PKA accumulated in the cells after glucagon stimulation. In conclusion, glucagon protected the DRG neuronal cells from MG-induced cellular stress. The cAMP/PKA pathway may have significant roles in those protective effects of glucagon. Glucagon may be a potential target for the treatment of DPN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom11020287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919475PMC
February 2021

Lifestyle changes as a result of COVID-19 containment measures: Bodyweight and glycemic control in patients with diabetes in the Japanese declaration of a state of emergency.

J Diabetes Investig 2021 Feb 18. Epub 2021 Feb 18.

Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.

To clarify the association between lifestyle changes as a result of coronavirus disease 2019 containment measures and changes in metabolic and glycemic status in patients with diabetes, a cross-sectional, single-center, observation study was carried out. A self-reported questionnaire was provided to ascertain the frequency of various lifestyle activities before and after the coronavirus disease 2019 containment measures in Japan. Among 463 patients, change in glycated hemoglobin was significantly associated with change in bodyweight. After stratification by age 65 years, binary logistic regression analysis showed that increased frequency of snack eating increased bodyweight (odds ratio 1.709, P = 0.007) and glycated hemoglobin (odds ratio 1.420, P = 0.025) in the younger group, whereas in the older patients, reduced walking activities resulted in weight gain (odds ratio 0.726, P = 0.010). In conclusion, changes in eating behavior and physical activity increased bodyweight and reduced glycemic control among diabetes patients, but by different processes depending on age under the coronavirus disease 2019 containment measures in Japan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014217PMC
February 2021

A Histological Comparison Between Anterior Cruciate Ligament Remnant Tissue, Anatomically Reconstructed Graft, and Non-Anatomically Reconstructed Graft.

Cureus 2021 Jan 30;13(1):e13016. Epub 2021 Jan 30.

Orthopaedic Surgery, Jichi Medical University, Shimotsuke, JPN.

Introduction: To our knowledge, no studies have investigated the histological comparison between primary injured anterior cruciate ligament (ACL), initially anatomically reconstructed grafts and non-anatomically reconstructed grafts at the time of revision ACL reconstruction. The purpose of this study was to histologically clarify the differences between ACL remnant tissue, reconstructed graft after anatomic double-bundle ACL reconstruction, and reconstructed graft after non-anatomic single-bundle ACL reconstruction.

Methods: This histological study included five patients after anatomic double-bundle ACL reconstruction, three patients after non-anatomic single-bundle ACL reconstruction performed who injured their operated knees again, and five patients who injured their ACL for the first time and agreed to participate. All of the grafts and ACL remnant tissue were harvested, stained with hematoxylin and eosin, S-100, and alpha smooth muscle actin and evaluated using light microscopy.

Results: There was no area of necrosis in the reconstructed graft after an anatomic double-bundle ACL reconstruction. However, there were obvious areas of necrosis in the reconstructed graft after non-anatomic single-bundle ACL reconstruction. Additionally, the collagen fibers were more longitudinally oriented, and most cells were spindle shaped like those in ACL remnant tissue after an anatomic double-bundle ACL reconstruction in contrast with the finding of the grafts after non-anatomic single-bundle ACL reconstruction.

Conclusion: Initially reconstructed graft after an anatomic double-bundle ACL reconstruction may be beneficial if preserved at the time of the revision surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.13016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847778PMC
January 2021

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry).

BMJ Open Diabetes Res Care 2021 01;9(1)

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Introduction: Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.

Research Design And Methods: We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.

Results: Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.

Conclusions: Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjdrc-2020-001787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812112PMC
January 2021

Surgical ablation of whitened interscapular brown fat ameliorates cardiac pathology in salt-loaded metabolic syndrome rats.

Ann N Y Acad Sci 2021 05 19;1492(1):11-26. Epub 2020 Dec 19.

Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Brown adipose tissue (BAT) is an endocrine organ that contributes to thermogenesis and energy consumption. We investigated the effects of salt loading and surgical removal of whitened interscapular BAT (iBAT) on cardiac and adipose tissue pathology in DahlS.Z-Lepr /Lepr (DS/obese) rats, an animal model of metabolic syndrome (MetS). DS/obese rats were subjected to surgical removal of iBAT or sham surgery at 8 weeks of age and were provided with drinking water containing or not containing 0.3% NaCl for 4 weeks beginning at 9 weeks of age. Removal of iBAT suppressed the salt-induced exacerbation of left ventricular inflammation, fibrosis, and diastolic dysfunction, but not that of hypertension development, in DS/obese rats. Salt loading attenuated adipocyte hypertrophy but enhanced inflammation in both visceral white adipose tissue (WAT) and iBAT. Although iBAT removal did not affect visceral WAT pathology in salt-loaded DS/obese rats, it attenuated the elevation of circulating interleukin-6 levels in these animals. Downregulation of uncoupling protein-1 expression in iBAT of DS/obese rats was not affected by salt loading. Our results suggest that the conversion of iBAT to WAT-like tissue contributes to a salt-induced elevation of circulating proinflammatory cytokine levels that leads to exacerbation of cardiac pathology in this model of MetS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.14546DOI Listing
May 2021

Taxon- and Growth Phase-Specific Antioxidant Production by Chlorophyte, Bacillariophyte, and Haptophyte Strains Isolated From Tropical Waters.

Front Bioeng Biotechnol 2020 23;8:581628. Epub 2020 Nov 23.

Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Antioxidants found in microalgae play an essential role in both animals and humans, against various diseases and aging processes by protecting cells from oxidative damage. In this study, 26 indigenous tropical marine microalgae were screened. Out of the 26 screened strains, 10 were selected and were further investigated for their natural antioxidant compounds which include carotenoids, phenolics, and fatty acids collected in their exponential and stationary phases. The antioxidant capacity was also evaluated by a total of four assays, which include ABTS, DPPH, superoxide radical (O ) scavenging capacity, and nitric oxide (•NO) scavenging capacity. This study revealed that the antioxidant capacity of the microalgae varied between divisions, strains, and growth phase and was also related to the content of antioxidant compounds present in the cells. Carotenoids and phenolics were found to be the major contributors to the antioxidant capacity, followed by polyunsaturated fatty acids linoleic acid (LA), eicosapentaenoic acid (EPA), arachidonic acid (ARA), and docosahexaenoic acid (DHA) compared to other fatty acids. The antioxidant capacity of the selected bacillariophytes and haptophytes was found to be positively correlated to phenolic ( -value = 0.623, 0.714, and 0.786 with ABTS, DPPH, and •NO) under exponential phase, and to carotenoid fucoxanthin and β-carotene (R value = 0.530, 0.581 with ABTS, and 0.710, 0.795 with O ) under stationary phase. Meanwhile, antioxidant capacity of chlorophyte strains was positively correlated with lutein, β-carotene and zeaxanthin under the exponential phase (R value = 0.615, 0.615, 0.507 with ABTS, and R value = 0.794, 0.659, and 0.509 with •NO). In the stationary phase, chlorophyte strains were positively correlated with violaxanthin (0.755 with •NO), neoxanthin (0.623 with DPPH, 0.610 with •NO), and lutein (0.582 with •NO). This study showed that antioxidant capacity and related antioxidant compound production of tropical microalgae strains are growth phase-dependent. The results can be used to improve the microalgal antioxidant compound production for application in pharmaceutical, nutraceutical, food, and feed industry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2020.581628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719757PMC
November 2020

Alterations of retinal thickness measured by optical coherence tomography correlate with neurophysiological measures in diabetic polyneuropathy.

J Diabetes Investig 2020 Dec 10. Epub 2020 Dec 10.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Diabetic polyneuropathy (DPN) and diabetic retinopathy (DR) are traditionally regarded as microvascular complications. However, these complications may share similar neurodegenerative pathologies. Here we evaluate the correlations in the severity of DPN and changes in the thickness of neuroretinal layers to elucidate whether these complications exist at similar stages of progression.

Materials And Methods: A total of 43 patients with type 2 diabetes underwent a nerve conduction study (NCS), a macular optical coherence tomography, and a carotid artery ultrasound scan. Diabetic polyneuropathy was classified according to Baba's classification using NCS. The retina was automatically segmented into four layers; ganglion cell complex (GCC), inner nuclear layer/outer plexiform layer (INL/OPL), outer nuclear layer/photoreceptor inner and outer segments, and retinal pigment epithelium (RPE). The thickness of each retinal layer was separately analyzed for the fovea and the parafovea.

Results: Fourteen patients were classified as having moderate to severe diabetic polyneuropathy. The thicknesses of the foveal and parafoveal INL/OPL increased in patients with diabetic polyneuropathy compared with patients without. The thickness of the parafoveal retinal pigment epithelium decreased in patients with diabetic polyneuropathy. The thinning of parafoveal ganglion cell complex and foveal and parafoveal retinal pigment epithelium were positively correlated with deterioration of nerve functions in the nerve conduction study, but the thickening of INL/OPL was positively correlated with the nerve function deterioration. The thinning of parafoveal ganglion cell complex and foveal retinal pigment epithelium were positively correlated with the thickening of the carotid intima-media.

Conclusions: Depending on the progression of diabetic polyneuropathy, the ganglion cell complex and retinal pigment epithelium became thinner and the INL/OPL became thicker. These retinal changes might be noteworthy for pathological investigations and for the assessment of diabetic polyneuropathy and diabetic retinopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13476DOI Listing
December 2020

Neuroretinal dysfunction revealed by a flicker electroretinogram correlated with peripheral nerve dysfunction and parameters of atherosclerosis in patients with diabetes.

J Diabetes Investig 2021 Jul 18;12(7):1236-1243. Epub 2020 Dec 18.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Diabetic polyneuropathy (DPN) develops in the early stage of diabetes. However, no common diagnostic protocol has yet been established. Here, to verify that the flicker electroretinogram using a hand-held device can detect the early dysfunction of the peripheral nervous system in patients with diabetes, we investigated the correlation between the progression of DPN and neuroretinal dysfunction.

Materials And Methods: In total, 184 participants with type 1 or 2 diabetes underwent a flicker electroretinogram (ERG) using a hand-held device RETeval™ and nerve conduction study. Participants were also evaluated for intima-media thickness, ankle-brachial index, toe brachial index and brachial-ankle pulse wave velocity. Parameters of the nerve conduction study were used to diagnose the severity according to Baba's classification. A multiple regression analysis was used to examine the associations of ERG parameters with the severity of DPN categorized by Baba's classification. Diagnostic properties of the device in DPN were evaluated using a receiver operating characteristic curve.

Results: A multiple regression model to predict the severity of DPN was generated using ERG. In the model, moderate-to-severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.692, sensitivity 56.5%, specificity 78.3%, positive predictive value 70.6%, negative predictive value 66.1%, positive likelihood ratio 2.60, negative likelihood ratio 0.56). In the patients without diabetic retinopathy, the implicit time and amplitude in ERG significantly correlated with the parameters of the nerve conduction study, brachial-ankle pulse wave velocity and intima-media thickness.

Conclusions: Electroretinogram parameters obtained by the hand-held device successfully predict the severity of DPN. The device might be useful to evaluate DPN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264400PMC
July 2021

The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice.

Peptides 2021 01 24;135:170434. Epub 2020 Oct 24.

Kansai Electric Power Hospital, Osaka, Japan.

To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.peptides.2020.170434DOI Listing
January 2021

Secreted Factors from Stem Cells of Human Exfoliated Deciduous Teeth Directly Activate Endothelial Cells to Promote All Processes of Angiogenesis.

Cells 2020 10 31;9(11). Epub 2020 Oct 31.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.

Diabetes is a major risk factor for atherosclerosis and ischemic vascular diseases. Recently, regenerative medicine is expected to be a novel therapy for ischemic diseases. Our previous studies have reported that transplantation of stem cells promoted therapeutic angiogenesis for diabetic neuropathy and ischemic vascular disease in a paracrine manner, but the precise mechanism is unclear. Therefore, we examined whether secreted factors from stem cells had direct beneficial effects on endothelial cells to promote angiogenesis. The soluble factors were collected as conditioned medium (CM) 48 h after culturing stem cells from human exfoliated deciduous teeth (SHED) in serum-free DMEM. SHED-CM significantly increased cell viability of human umbilical vein endothelial cells (HUVECs) in MTT assays and accelerated HUVECs migration in wound healing and Boyden chamber assays. In a Matrigel plug assay of mice, the migrated number of primary endothelial cells was markedly increased in the plug containing SHED-CM or SHED suspension. SHED-CM induced complex tubular structures of HUVECs in a tube formation assay. Furthermore, SHED-CM significantly increased neovascularization from the primary rat aorta, indicating that SHED-CM stimulated primary endothelial cells to promote comprehensive angiogenesis processes. The angiogenic effects of SHED-CM were the same or greater than the effective concentration of VEGF. In conclusion, SHED-CM directly stimulates vascular endothelial cells to promote angiogenesis and is promising for future clinical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9112385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693657PMC
October 2020

GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice.

Endocrinology 2020 12;161(12)

Department of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

A number of disease states, including type 2 diabetes (T2D), are associated with an increased risk of pulmonary infection. Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat T2D and exert anti-inflammatory actions through a single, well-defined GLP-1 receptor (GLP-1R). Although highly expressed in the lung, little is known about the role of the GLP-1R in the context of pulmonary inflammation. Here we examined the consequences of gain or loss of GLP-1R activity in infectious and noninfectious lung inflammation. We studied wild-type mice treated with a GLP-1R agonist, and Glp1r-/- mice, in the setting of bleomycin-induced noninfectious lung injury and influenza virus infection. Loss of the GLP-1R attenuated the severity of bleomycin-induced lung injury, whereas activation of GLP-1R signaling increased pulmonary inflammation via the sympathetic nervous system. In contrast, GLP-1R agonism reduced the pathogen load in mice with experimental influenza virus infection in association with increased expression of intracellular interferon-inducible GTPases. Notably, the GLP-1 receptor agonist liraglutide improved the survival rate after influenza virus infection. Our results reveal context-dependent roles for the GLP-1 system in the response to lung injury. Notably, the therapeutic response of GLP-1R agonism in the setting of experimental influenza virus infection may have relevance for ongoing studies of GLP-1R agonism in people with T2D susceptible to viral lung injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/endocr/bqaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678414PMC
December 2020

Sodium-glucose cotransporter 2 inhibition attenuates protein overload in renal proximal tubule via suppression of megalin O-GlcNacylation in progressive diabetic nephropathy.

Metabolism 2020 12 16;113:154405. Epub 2020 Oct 16.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Electronic address:

Aims: The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload.

Materials And Method: We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2 (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers.

Results: The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis.

Conclusions: The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2020.154405DOI Listing
December 2020

Point-of-care nerve conduction device predicts the severity of diabetic polyneuropathy: A quantitative, but easy-to-use, prediction model.

J Diabetes Investig 2021 Apr 14;12(4):583-591. Epub 2020 Sep 14.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: A gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well-trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point-of-care nerve conduction device as an alternative way of diagnosis using a standard electromyography system.

Materials And Methods: We used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve.

Results: A multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) - 0.033 × (nerve conduction velocity [m/s]) - 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut-off value of 1.3065 in the model, moderate-to-severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34).

Conclusions: Nerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015817PMC
April 2021

Bioprospecting of indigenous marine microalgae with ammonium tolerance from aquaculture ponds for microalgae cultivation with ammonium-rich wastewaters.

J Biotechnol 2020 Nov 6;323:113-120. Epub 2020 Aug 6.

Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030, Kuala Terengganu, Malaysia; School of Fundamental Science, Universiti Malaysia Terengganu, 21030, Kuala Terengganu, Malaysia.

We isolated fifty-two strains from the marine aquaculture ponds in Malaysia that were evaluated for their lipid production and ammonium tolerance and four isolates were selected as new ammonium tolerant microalgae with high-lipid production: TRG10-p102 Oocystis heteromucosa (Chlorophyceae); TRG10-p103 and TRG10-p105 Thalassiosira weissflogii (Bacillariophyceae); and TRG10-p201 Amphora coffeiformis (Bacillariophyceae). Eicosapentenoic acid (EPA) in three diatom strain was between 2.6 and 18.6 % of total fatty acids, which were higher than in O. heteromucosa. Only A. coffeiformi possessed arachidonic acid. Oocystis heteromucosa naturally grew at high ammonium concentrations (1.4-10 mM), whereas the growth of the other strains, T. weissflogii and A. coffeiformi, were visibly inhibited at high ammonium concentrations (>1.4 mM-NH). However, two strains of T. weissflogii were able to grow at up to 10 mM-NH by gradually acclimating to higher ammonium concentrations. The ammonium tolerant strains, especially T. weissflogii which have high EPA contents, were identified as a valuable candidate for biomass production utilizing NH-N media, such as ammonium-rich wastewater.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbiotec.2020.08.001DOI Listing
November 2020

Arthroscopic superior capsule reconstruction with Teflon felt synthetic graft for irreparable massive rotator cuff tears: clinical and radiographic results at minimum 2-year follow-up.

J Shoulder Elbow Surg 2021 Mar 7;30(3):625-634. Epub 2020 Jul 7.

Department of Orthopedic Surgery, Osaka Medical College, Takatsuki, Osaka, Japan. Electronic address:

Background: Superior capsule reconstruction (SCR) was developed to improve shoulder function and relieve pain in patients with irreparable rotator cuff tears. Here, we investigated the clinical and radiographic outcomes and postoperative complications of SCR using a Teflon graft for reconstruction.

Methods: Thirty-five consecutive patients with irreparable rotator cuff tears underwent SCR with Teflon grafts. The American Shoulder and Elbow Surgeons score, active shoulder elevation, shoulder muscle strength, visual analog scale pain scores, acromiohumeral distance, and postoperative complications were investigated. Data obtained before and after surgery were compared by using a paired t-test, χ test, and 1-way analysis of variance, and data from 1-layer-graft SCR (15 patients; mean age, 75.1 years) and 3-layer-graft SCR (20 patients; mean age, 76.6 years) were compared by using an unpaired t-test. The average time to final follow-up was 42 months (range, 24-69 months).

Results: SCR using Teflon grafts of either 1 or 3 layers significantly improved the American Shoulder and Elbow Surgeons score (by 20.8, P = .001 for a 1-layer graft; and by 31.1, P < .0001 for a 3-layer graft), visual analog scale score for motion pain (by 3.2, P = .001; and by 3.0, P < .0001), and muscle strength in shoulder abduction (by 11.9 N, P = .02; and by 10.9 N, P = .008). Active elevation at final follow-up was significantly greater in the 3-layer-graft group (142° ± 27°) than in the 1-layer-graft group (107° ± 42°) (P = .006). One year after SCR, acromiohumeral distance in the 3-layer-graft group was significantly greater than preoperatively (P = .04), whereas in the 1-layer-graft group, it was not. On postoperative magnetic resonance imaging, none of the patients in the 3-layer-graft group had graft tears, whereas 2 patients had graft tears and 1 patient had severe synovitis after 1-layer-graft SCR.

Conclusion: SCR using a Teflon graft-especially a 3-layer graft-significantly improved shoulder function and shoulder abduction strength, with pain relief and a low rate of postoperative complications. SCR using a Teflon graft can be a viable option for irreparable rotator cuff tears, especially when an autograft or allograft is not available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jse.2020.06.022DOI Listing
March 2021

Vertebral mobility is a valuable indicator for predicting and determining bone union in osteoporotic vertebral fractures: a conventional observation study.

J Orthop Surg Res 2020 May 5;15(1):166. Epub 2020 May 5.

Department of Orthopaedic Science, Iwate Prefectural Central Hospital, 1-4-1, Ueda, Morioka, Iwate, 020-0066, Japan.

Background: Conservative treatments for osteoporotic vertebral fractures (OVFs) have not been standardized, and criteria for determining bone union have not been established. To determine bone union, we have adopted a cutoff value of 1.0 mm for vertebral mobility (V-mobility), defined as the difference in anterior vertebral height (Ha) between lateral radiographs taken in weight-bearing and non-weight-bearing positions. The present study aimed to investigate the usefulness of V-mobility for determining bone union and predicting bone union at 6 months after OVF onset.

Methods: The study included 54 acute OVFs from T11 to L3 in 53 patients (12 males, 41 females; mean age 82 years; age range 55-97 years) who were hospitalized at ≤ 3 weeks after OVF onset. Vertebral deformity (V-deformity) and V-mobility were evaluated in accordance with Ha on lateral radiographs taken in the sitting position (SIT), lateral decubitus position (DEC), and supine position (SUP). OVFs showing V-mobility of ≤ 1.0 mm between SIT and DEC radiographs and no intravertebral cleft on DEC radiograph were defined as semi-union, while those showing V-mobility of ≤ 1.0 mm between SIT and SUP radiographs and no intravertebral cleft on SUP radiograph were defined as bone union. We calculated the bone union rates including semi-unions associated with V-mobility cutoff values of 1.0 mm, 1.5 mm, and 2.0 mm and estimated cutoff values for V-mobility at 5 weeks after OVF onset to predict bone union at 6 months after OVF onset.

Results: The cumulative number of bone unions including semi-unions was more influenced by the different V-mobility cutoff values in Ha for determining bone union in the earlier period compared with the later period in the time course of OVF. Receiver-operating characteristic curve analyses revealed that V-mobility cutoff value of 2.1 mm in Ha between SIT and DEC radiographs at 5 weeks after OVF had moderate accuracy for predicting bone union including semi-union at 6 months after OVF. The mean V-deformity value on SIT radiographs did not progress significantly.

Conclusion: V-mobility in the early stage after OVF can predict bone union at 6 months after OVF and is a useful quantitative indicator for determining bone union.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13018-020-01649-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201770PMC
May 2020

Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial.

Lancet Diabetes Endocrinol 2020 05;8(5):377-391

Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.

Background: Given the unique phenotype of type 2 diabetes in Japanese patients, novel therapies such as oral semaglutide require evaluation in this population. PIONEER 9 aimed to assess the dose-response of oral semaglutide and to compare the efficacy and safety of oral semaglutide with placebo and a subcutaneous GLP-1 receptor agonist in a Japanese population.

Methods: PIONEER 9 was a 52-week, phase 2/3a, randomised, controlled trial done at 16 sites (clinics and university hospitals) in Japan. Japanese patients aged 20 years or older with uncontrolled type 2 diabetes managed by diet or exercise or with oral glucose-lowering drug monotherapy (washed out) were randomly assigned (1:1:1:1:1) to receive double-blind once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or placebo, or open-label subcutaneous once-daily liraglutide 0·9 mg. The primary endpoint was change in HbA from baseline to week 26 with the trial product (primary) estimand (which assumes all patients remained on trial product without rescue medication use) in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, NCT03018028.

Findings: Between Jan 10, and July 11, 2017, 243 patients were randomly assigned to oral semaglutide 3 mg (n=49), 7 mg (n=49), or 14 mg (n=48), or placebo (n=49), or to liraglutide 0·9 mg (n=48). Changes in HbA from baseline (mean 8·2%) to week 26 were dose-dependent with oral semaglutide (mean change -1·1% [SE 0·1] for oral semaglutide 3 mg, -1·5% [0·1] for 7 mg, and -1·7% [0·1] for 14 mg), -0·1% (0·1) with placebo, and -1·4% (0·1) with liraglutide 0·9 mg. Estimated treatment differences for change in HbA compared with placebo were -1·1 percentage points (95% CI -1·4 to -0·8; p<0·0001) for oral semaglutide 3 mg, -1·5 percentage points (-1·7 to -1·2; p<0·0001) for oral semaglutide 7 mg, and -1·7 percentage points (-2·0 to -1·4; p<0·0001) for oral semaglutide 14 mg. Estimated treatment differences for change in HbA compared with liraglutide 0·9 mg were 0·3 percentage points (95% CI -0·0 to 0·6; p=0·0799) for oral semaglutide 3 mg, -0·1 percentage points (-0·4 to 0·2; p=0·3942) for oral semaglutide 7 mg, and -0·3 percentage points (-0·6 to -0·0; p=0·0272) for oral semaglutide 14 mg. Gastrointestinal events, predominantly of mild or moderate severity, were the most frequently reported class of adverse event with oral semaglutide: constipation was most common, occurring in five to six (10-13%) patients with oral semaglutide, three (6%) with placebo, and nine (19%) with liraglutide 0·9 mg.

Interpretation: This study showed that oral semaglutide provides significant reductions in HbA compared with placebo in a dose-dependent manner in Japanese patients with type 2 diabetes, and has a safety profile consistent with that of GLP-1 receptor agonists.

Funding: Novo Nordisk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-8587(20)30075-9DOI Listing
May 2020

The Incretin Effect in Female Mice With Double Deletion of GLP-1 and GIP Receptors.

J Endocr Soc 2020 Feb 23;4(2):bvz036. Epub 2019 Dec 23.

Kansai Electric Power Hospital, Osaka, Japan.

To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUC) correlated linearly with suprabasal AUC both in WT (r = 0.942,  = .017) and DIRKO mice (r = 0.972,  = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose,  = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvz036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984998PMC
February 2020

Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?

Endocr Rev 2020 01;41(1)

Department of Cardiometabolic Disorders, Amgen Research, Thousand Oaks, California.

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the 2 approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity, and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/endrev/bnz002DOI Listing
January 2020

Magnitude of slowing gastric emptying by glucagon-like peptide-1 receptor agonists determines the amelioration of postprandial glucose excursion in Japanese patients with type 2 diabetes.

J Diabetes Investig 2020 Mar 25;11(2):389-399. Epub 2019 Jul 25.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Aims/introduction: Pharmacological levels of glucagon-like peptide-1 (GLP-1) can decelerate gastric emptying (GE) and reduce postprandial glucose levels. Most previous studies have used liquid meals to evaluate GE. We evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs) on GE and postprandial glucose excursion in Japanese type 2 diabetes mellitus patients using a combination of solid and liquid meals.

Materials And Methods: In this single-center, prospective, open-label study, nine healthy individuals and 17 patients with type 2 diabetes mellitus consumed a 460-kcal combination of a solid and liquid meal labeled with C-acetic acid. GE was measured from t = 0 to 150 min in a continuous C breath test. Eight participants with type 2 diabetes mellitus were administered GLP-1 RAs, and we examined the relationship between GE and blood glucose excursion.

Results: There were no differences in the average GE coefficient (GEC) and lag time between the healthy and type 2 diabetes mellitus groups. However, the type 2 diabetes mellitus group showed larger GEC variations (P < 0.05). The coefficient of variation of R-R intervals was a significant predictor of GEC in type 2 diabetes mellitus patients (P < 0.01). The short-acting GLP-1 RA reduced the GEC at 1 month (P = 0.012), whereas the long-acting GLP-1 RA did not significantly change the GEC after treatment. A positive relationship was observed between postprandial glucose excursion from T to T and the GEC (r  = 0.75; P < 0.01).

Conclusions: The reduction in GE rate by the administration of GLP-1 RAs can predict the improvement in postprandial glucose excursion in type 2 diabetes mellitus patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078094PMC
March 2020

An autopsy case of giant cell myocarditis showing shared pathology in the myocardium and skeletal muscles.

Cardiovasc Pathol 2019 Sep - Oct;42:10-14. Epub 2019 May 23.

Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2019.05.003DOI Listing
November 2019

Secreted factors from cultured dental pulp stem cells promoted neurite outgrowth of dorsal root ganglion neurons and ameliorated neural functions in streptozotocin-induced diabetic mice.

J Diabetes Investig 2020 Jan 21;11(1):28-38. Epub 2019 Jun 21.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Transplantation of stem cells promotes axonal regeneration and angiogenesis in a paracrine manner. In the present study, we examined whether the secreted factors in conditioned medium of stem cells from human exfoliated deciduous teeth (SHED-CM) had beneficial effects on diabetic polyneuropathy in mice.

Materials And Methods: Conditioned medium of stem cells from human exfoliated deciduous teeth was collected 48 h after culturing in serum-free Dulbecco's modified Eagle's medium (DMEM), and separated into four fractions according to molecular weight. Dorsal root ganglion neurons from C57BL/6J mice were cultured with SHED-CM or DMEM to evaluate the effect on neurite outgrowth. Streptozotocin-induced diabetic mice were injected with 100 μL of SHED-CM or DMEM into the unilateral hindlimb muscles twice a week over a period of 4 weeks. Peripheral nerve functions were evaluated by the plantar test, and motor and sensory nerve conduction velocities. Intraepidermal nerve fiber densities, capillary number-to-muscle fiber ratio, capillary blood flow and morphometry of sural nerves were also evaluated.

Results: Conditioned medium of stem cells from human exfoliated deciduous teeth significantly promoted neurite outgrowth of dorsal root ganglion neurons compared with DMEM. Among four fractions of SHED-CM, the only fraction of <6 kDa promoted the neurite outgrowth of dorsal root ganglion neurons. In addition, SHED-CM significantly prevented decline in sensory nerve conduction velocities compared with DMEM in diabetic mice. Although SHED-CM did not improve intraepidermal nerve fiber densities or morphometry of sural nerves, SHED-CM ameliorated the capillary number-to-muscle fiber ratio and capillary blood flow.

Conclusions: These results suggested that SHED-CM might have a therapeutic effect on diabetic polyneuropathy through promoting neurite outgrowth, and the increase in capillaries might contribute to the improvement of neural function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944849PMC
January 2020

Inhibition of GIP signaling extends lifespan without caloric restriction.

Biochem Biophys Res Commun 2019 06 17;513(4):974-982. Epub 2019 Apr 17.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Japan. Electronic address:

Aims/introduction: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue.

Materials And Methods: Gipr and Gipr mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid.

Results: We observed that GIP receptor-knockout (Gipr) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes.

Conclusions: Although maintenance of CR is difficult, food intake and muscle endurance of Gipr mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.04.036DOI Listing
June 2019
-->