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Aims: We aimed to identify patients who would benefit from basal insulin-supported oral therapy (BOT) with a glinide and an α-glucosidase inhibitor (a fixed-dose combination tablet of mitiglinide 10 mg and voglibose 0.2 mg) in Japanese type 2 diabetic patients., Methods: Patients who were hospitalized to improve hyperglycemia received basal-bolus insulin therapy. After the reduction of glucose toxicity, a 75 g oral glucose tolerance test and a glucagon test were performed. Thereafter, the basal-bolus insulin therapy was switched to BOT with mitiglinide, followed by further addition of voglibose. Interstitial glucose levels were continuously monitored throughout the study period. Diurnal glucose profile was recorded and analyzed. Patients were divided into two groups according to whether their percentage of time in range (TIR, 70-180 mg/dL) under BOT with mitiglinide/voglibose was higher than 70% or not, and the differences in clinical characteristics between the groups were analyzed., Results: Twenty patients were enrolled, and 19 of them completed the study. BOT with mitiglinide/voglibose achieved ≥ 70% of TIR in thirteen patients. The area under the curve of serum C-peptide levels during the oral glucose tolerance test was significantly higher in the patients with ≥ 70% of TIR. The daily insulin dosages and blood glucose profiles were comparable between the two groups., Conclusions: The efficacy of BOT with mitiglinide/voglibose depended on residual insulin secretory abilities. This therapy would be a useful therapeutic option for patients with type 2 diabetes., Competing Interests: Conflict of interestHideki Kamiya: lecture fees: Novo Nordisk Pharma, Sanofi, Sumitomo Pharma, Nippon Boehringer Ingelheim, Eli Lilly Japan, Daiichi Sankyo, Ono Pharmaceutical, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa, Novartis Pharma, MSD, Sanwa Kagaku Kenkyusho, Otsuka Pharmaceutical, Ltd., Terumo, Taisho Pharmaceutical. Research funding: Ono Pharmaceutical, Eli Lilly Japan, Kissei Pharmaceutical. Subsidies or donations: Ono Pharmaceutical, Taisho Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Japan Tobacco, Novo Nordisk Pharma. Endowed departments by commercial entities: Ono Pharmaceutical, Abbott Japan, Sanwa Kagaku Kenkyusho, Kowa, Terumo. Jiro Nakamura: lecture fees: Novo Nordisk Pharma, Sanofi, Daiichi Sankyo, Ono Pharmaceutical, Novartis Pharma, MSD, Taisho Pharmaceutical, Takeda Pharmaceutical, Terumo. Research funding: Eli Lilly Japan, Ono Pharmaceutical, Kissei Pharmaceutical. Subsidies or donations: MSD, Ono Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Japan Tobacco, Novo Nordisk Pharma, Taisho Pharmaceutical. Endowed departments by commercial entities: Ono Pharmaceutical, Abbott Japan, Sanwa Kagaku Kenkyusho, Kowa, Terumo. The other authors declare no conflict of interest., (© The Japan Diabetes Society 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

This study investigates whether the measurement of glucocorticoid metabolites (GCMs) in feces is a useful method for the noninvasive evaluation of stress in the endangered Tsushima leopard cats ( Prionailurus bengalensis euptilurus ). Feces were collected from six seemingly healthy and five diseased (renal dysfunction, adrenal tumor, hernia, feline immunodeficiency virus (FIV), feline leukemia virus (FeLV)) Tsushima leopard cats in captivity. Fecal GCMs were measured by enzyme immunoassay (EIA) for cortisol. Individuals that experienced a physical examination under anesthesia showed increased fecal GCMs 1-2 days after the event. An individual diagnosed with disk herniation showed decreased fecal GCMs after medical administration. The mean fecal GCM concentrations for six healthy animals and five diseased animals were 0.66 ± 0.08 and 2.65 ± 0.76 μg/g, respectively, which was significantly different. Cortisol and corticosterone were not clearly detected in the feces examined by the use of the HPLC-EIA analysis. GCMs may be excreted in the feces; however, the exact identification of these substances is not achieved. The results suggest that the measurement of fecal GCMs is useful for the husbandry and health management of this species.

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., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Peristomal pyoderma gangrenosum (PPG) presents multiple challenges for healthcare providers. The diagnosis of PPG may be delayed, and it may be mistaken for an irritant dermatitis or an infection. Patients with ostomies secondary to inflammatory bowel disease (IBD) may experience PPG. Issues related to PPG include difficulty maintaining a seal of the ostomy pouching system and preventing contamination of the painful, necrotic ulcerations characteristic of this condition. Treatment focuses on the appropriate assessment of the ulcers, successful pouch application, and proper management of IBD through a collaborative effort of both dermatologists and certified WOC nurses (CWOCN)., Cases: We treated 3 patients diagnosed with Crohn's disease (CD) who developed refractory PPG. All 3 were treated with a topical steroid lotion, prednisone, and adalimumab or a combination of these agents. Ostomy products and application were tailored to prevent leakage and protect areas of ulceration. All ulcers were healed within 6 months of our initial consultation., Conclusion: We successfully managed 3 patients with CD and PPG with appropriate ostomy care, including revision of the ostomy pouching techniques, topical steroid treatment, and treatment based on assessment of ulcer status by the dermatologist and the WOC nurse., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 by the Wound, Ostomy and Continence Nurses Society.)

Predicting drug-induced liver injury is important in early stage drug discovery; however, an accurate prediction with existing hepatotoxicity evaluation tools is difficult. Conventional monolayer (2D) cultures have short viabilities and are therefore inappropriate for performing long-term toxicity tests. Conventionally used 200-μm spheroids also have toxicity detection limits. The goal of this study was to develop a humanized liver tissue capable of evaluating long-term toxicity with high sensitivity. Spheroids consisting of co-cultured cryopreserved primary human hepatocytes and human hepatic stellate cells were developed using a 3D bio-printer. The "3D bio-printed liver tissue", of ∼1 mm, was then used for long-term viability assessments (over 25 days) based on ATP, albumin, and urea levels. Hepatotoxicity evaluation was performed by analyzing the expression of genes involved in drug metabolism and transport over a 2-week drug exposure period. The 3D bio-printed liver tissue showed improved viability and enhanced gene expression of enzymes related to drug metabolism and transport, as compared to the controls. Additionally, the 3D bio-printed liver tissue demonstrated a high sensitivity for hepatotoxicity evaluation when combined with pathological evaluation and measurements for ATP production, and secretion of albumin and urea. In conclusion, the 3D bio-printed liver tissue was able to detect the toxicity of compounds that was, otherwise, undetected by 2D culture and conventionally used spheroids. These findings demonstrate a 3D bio-printed liver tissue with increased accuracy of hepatotoxicity prediction in the early stages of drug discovery, as compared to currently available methods.

The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.