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Insulin secretion is regulated in multiple steps, and one of the main steps is in the endoplasmic reticulum (ER). Here, we show that UDP-glucose induces proinsulin ubiquitination by cereblon, and uridine binds and competes for proinsulin degradation and behaves as sustainable insulin secretagogue. Using insulin mutagenesis of neonatal diabetes variant-C43G and maturity-onset diabetes of the young 10 (MODY10) variant-R46Q, UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) protects cereblon-dependent proinsulin ubiquitination in the ER. Cereblon is a ligand-inducible E3 ubiquitin ligase, and we found that UDP-glucose is the first identified endogenous proinsulin protein degrader. Uridine-containing compounds, such as uridine, UMP, UTP, and UDP-galactose, inhibit cereblon-dependent proinsulin degradation and stimulate insulin secretion from 3 to 24 h after administration in β-cell lines as well as mice. This late and long-term insulin secretion stimulation is designated a day sustainable insulin secretion stimulation. Uridine-containing compounds are designated as proinsulin degradation regulators.

We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and UDP-glucose bind to cereblon in a similar way to thalidomide. From these results, UDP-glucose was identified as a molecular glue between cereblon and glucokinase. Glucokinase produces glucose-6-phosphate in the pancreas and liver. Especially in β-cells, glucokinase is the main target of glucose for glucose-induced insulin secretion. UDP-glucose administration ubiquitinated and degraded glucokinase, lowered glucose-6-phosphate production, and then reduced insulin secretion in β-cell lines and mice. Maturity-onset diabetes of the young type 2 (MODY2) glucokinaseE256K mutant protein was resistant to UDP-glucose induced ubiquitination and degradation. Taken together, glucokinase ubiquitination and degradation signaling might be impaired in MODY2 patients.

Pig skeletal muscle-derived stem cells (SK-MSCs) were transplanted onto the common peroneal nerve with a collagen tube as a preclinical large animal experiment designed to address long nerve gaps. In terms of therapeutic usefulness, a human family case was simulated by adjusting the major histocompatibility complex to 50% and 100% correspondences. Swine leukocyte antigen (SLA) class I haplotypes were analyzed and clarified, as well as cell transplantation. Skeletal muscle-derived CD34+/45− (Sk-34) cells were injected into bridged tubes in two groups (50% and 100%) and with non-cell groups. Therapeutic effects were evaluated using sedentary/general behavior-based functional recovery score, muscle atrophy ratio, and immunohistochemistry. The results indicated that a two-Sk-34-cell-transplantation group showed clearly and significantly favorable functional recovery compared to a non-cell bridging-only group. Supporting functional recovery, the morphological reconstitution of the axons, endoneurium, and perineurium was predominantly evident in the transplanted groups. Thus, Sk-34 cell transplantation is effective for the regeneration of peripheral nerve gap injury. Additionally, 50% and 100% SLA correspondences were therapeutically similar and not problematic, and no adverse reaction was found in the 50% group. Therefore, the immunological response to Sk-MSCs is considered relatively low. The possibility of the Sk-MSC transplantation therapy may extend to the family members beyond the autologous transplantation. [ABSTRACT FROM AUTHOR]

Objectives: Neuromyelitis optica spectrum disorder (NMOSD) can cause severe disability after a single attack. This study aimed to investigate the reduction of oral medications, including steroids, in patients using biologics within 1 year after the onset or relapse of NMOSD. Methods: Patients with NMOSD who were using biologics and attending the Department of Neurology at St. Marianna University School of Medicine from November 2019 to February 2023 were enrolled. The patients were introduced to biologics within 1 year of their last relapses. The study examined whether these patients experienced clinical relapse, changes in prednisolone dosage of 5 mg/day or less and changes in the number of oral medications. Results: A total of 14 patients were included. The mean prednisolone dosage was 17.5 ± 5.8 mg/day, and the mean number of medications was 6.2 ± 4.2. No relapse was reported in any patient after the introduction of biologics. The prednisolone dosage gradually decreased to 5.3 ± 2.9 mg/day and 3.1 ± 1.7 mg/day at 6 and 12 months, respectively, and the rates of achieving a prednisolone dosage of ≤5 mg/day at 6 and 12 months were 61.5% and 100%, respectively. The total number of medications decreased to 4.4 ± 4.6. Conclusions: Biologics can be introduced early after NMOSD relapse to reduce prednisolone dosage and counteract polypharmacy. The high relapse prevention rate of biologics makes them a valuable option for preventing relapse in patients with NMOSD. [ABSTRACT FROM AUTHOR]