Tracking insulin- and glucagon-expressing cells in vitro and in vivo using a double reporter human embryonic stem cell line.

Human embryonic stem cell (hESC)-derived pancreatic alpha and beta cells can be used to develop cell replacement therapies to treat diabetes. However, recent published differentiation protocols yield varying amounts of alpha and beta cells amidst heterogeneous cell populations. To visualize and isolate hESC-derived alpha and beta cells, we generated a GLUCAGON-2AmScarlet and INSULIN-2A-EGFP dual fluorescent reporter (INSEGFPGCGmScarlet) hESC line using CRISPR/Cas9.

ARMC5 selectively degrades SCAP-free SREBF1 and is essential for fatty acid desaturation in adipocytes.

SREBF1 plays the central role in lipid metabolism. It has been known that full-length SREBF1 that did not associate with SCAP (SCAP-free SREBF1) is actively degraded, but its molecular mechanism and its biological meaning remain unclear. ARMC5-CUL3 complex was recently identified as E3 ubiquitin ligase of full-length SREBF.

Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.

Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid.

HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.

Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.

Unlabelled: Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. Here, we define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. While islets from the majority of donors exhibited the expected relative response magnitudes, with glucose being highest, amino acid moderate, and fatty acid small, 9% of islets stimulated with amino acid and 8% of islets stimulated with fatty acids had larger responses compared with high glucose.

Effect of sodium-glucose cotransporter 2 inhibitors on serum low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus.

Aims/introduction: We aimed to evaluate factors that influence changes in blood low-density lipoprotein cholesterol (LDL-C) levels after treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors in Japanese patients with type 2 diabetes.

Materials And Methods: We retrospectively analyzed clinical data of outpatients newly initiated on SGLT2 inhibitors (n = 176) and other oral antidiabetic drugs (n = 227). The patients were classified into four subgroups according to statin administration and baseline LDL-C levels (<120 or ≥120 mg/dL).

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation.

Aims/hypothesis: Glucagon-expressing pancreatic alpha cells have attracted much attention for their plasticity to transdifferentiate into insulin-producing beta cells; however, it remains unclear precisely when, and from where, alpha cells emerge and what regulates alpha cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha cell differentiation using a novel time-resolved reporter system.

Methods: We established the mouse model, 'Gcg-Timer', in which newly generated alpha cells can be distinguished from more-differentiated cells by their fluorescence.

Human A2-CAR T Cells Reject HLA-A2 + Human Islets Transplanted Into Mice Without Inducing Graft-versus-host Disease.

Background: Type 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include the use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD).

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5.

Restoring functional β cell mass is a potential therapy for those with diabetes. However, the pathways regulating β cell mass are not fully understood. Previously, we demonstrated that Sox4 is required for β cell proliferation during prediabetes.

Effect of a mobile app chatbot and an interactive small-group webinar on COVID-19 vaccine intention and confidence in Japan: a randomised controlled trial.

Introduction: We investigated the effect of social media-based interventions on COVID-19 vaccine intention (VI) and confidence in Japan.

Methods: We conducted a three-arm randomised controlled trial between 5 November 2021 and 9 January 2022 during a low incidence (<1000/day) of COVID-19 in Japan in the midst of the second and the third waves. Japanese citizens aged ≥20 who had not received any COVID-19 vaccine and did not intend to be vaccinated were randomly assigned to one of the following three groups: (1) a control group, (2) a group using a mobile app chatbot providing information on COVID-19 vaccines and (3) a group using interactive webinars with health professionals.

Newly discovered knowledge pertaining to glucagon and its clinical applications.

Glucagon has been defined as an 'insulin counteracting hormone', which raises blood glucose levels. Recent progress in basic research has shown that glucagon is closely involved in glucose and amino acid metabolism. Additionally, its secretion is intricately, but precisely, regulated by various mechanisms involving molecules in addition to glucose, thus showing its critical role in systemic nutrient metabolism.

In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm.

Improving methods for human embryonic stem cell differentiation represents a challenge in modern regenerative medicine research. Using drug repurposing approaches, we discover small molecules that regulate the formation of definitive endoderm. Among them are inhibitors of known processes involved in endoderm differentiation (mTOR, PI3K, and JNK pathways) and a new compound, with an unknown mechanism of action, capable of inducing endoderm formation in the absence of growth factors in the media.

Heterogeneity of Islet Cells during Embryogenesis and Differentiation.

Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial.

Corowa-kun: A messenger app chatbot delivers COVID-19 vaccine information, Japan 2021.

Background: There is a long history in Japan of public concerns about vaccine adverse events. Few studies have assessed how mobile messenger apps affect COVID-19 vaccine hesitancy.

Methods: Corowa-kun, a free chatbot, was created on February 6, 2021 in LINE, the most popular messenger app in Japan.

Calcium-dependent transcriptional changes in human pancreatic islet cells reveal functional diversity in islet cell subtypes.

Aims/hypothesis: Pancreatic islets depend on cytosolic calcium (Ca) to trigger the secretion of glucoregulatory hormones and trigger transcriptional regulation of genes important for islet response to stimuli. To date, there has not been an attempt to profile Ca-regulated gene expression in all islet cell types. Our aim was to construct a large single-cell transcriptomic dataset from human islets exposed to conditions that would acutely induce or inhibit intracellular Ca signalling, while preserving biological heterogeneity.

Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system.

Aims/hypothesis: While pancreatic beta cells have been shown to originate from endocrine progenitors in ductal regions, it remains unclear precisely where beta cells emerge from and which transcripts define newborn beta cells. We therefore investigated characteristics of newborn beta cells extracted by a time-resolved reporter system.

Methods: We established a mouse model, 'Ins1-GFP; Timer', which provides spatial information during beta cell neogenesis with high temporal resolution.

Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.

The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present LUXendin645, a far-red fluorescent GLP1R antagonistic peptide label.

Cellular Autophagy in Cells Plays a Role in the Maintenance of Islet Architecture.

Autophagy is known to play a pivotal role in intracellular quality control through the degradation of subcellular damaged organelles and components. Whereas autophagy is essential for maintaining -cell function in pancreatic islets, it remains unclear as to how the cellular autophagy affects the homeostasis and function of glucagon-secreting cells. To investigate the role of autophagy in cells, we generated a mutant mouse model lacking , a key molecule for autophagosome formation, specifically in cells.

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors.

Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β cells for diabetes treatment. A greater understanding of how β cells form during embryonic development will improve current hESC differentiation protocols. All pancreatic endocrine cells, including β cells, are derived from Neurog3-expressing endocrine progenitors.

Cytomegalovirus meningitis in a patient with relapsed acute myeloid leukemia.

Cytomegalovirus meningitis/meningoencephalitis is a potentially fatal complication following hematopoietic stem cell transplantation that causes significant morbidity and mortality. In the pre-transplant setting, a few cases involving lymphoid malignancies have been reported. However, there have been no reports of patients with myeloid malignancies.