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).

Protocol development to further differentiate and transition stem cell-derived pancreatic progenitors from a monolayer into endocrine cells in suspension culture.

The generation of functional β-cells from human pluripotent stem cells (hPSCs) for cell replacement therapy and disease modeling of diabetes is being investigated by many groups. We have developed a protocol to harvest and aggregate hPSC-derived pancreatic progenitors generated using a commercially available kit into near uniform spheroids and to further differentiate the cells toward an endocrine cell fate in suspension culture. Using a static suspension culture platform, we could generate a high percentage of insulin-expressing, glucose-responsive cells.

-linked -acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding.

Adipose tissues accumulate excess energy as fat and heavily influence metabolic homeostasis. -linked -acetylglucosamine (-GlcNAc) modification (-GlcNAcylation), which involves the addition of -acetylglucosamine to proteins by -GlcNAc transferase (Ogt), modulates multiple cellular processes. However, little is known about the role of -GlcNAcylation in adipose tissues during body weight gain due to overnutrition.

Human A2-CAR T cells reject HLA-A2+ human islets transplanted into mice without inducing graft versus host disease.

Background: Type 1 diabetes (T1D) is an autoimmune disease characterised 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 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- -host disease (xGVHD).

A Century-long Journey From the Discovery of Insulin to the Implantation of Stem Cell-derived Islets.

For the past century, insulin injections have saved millions of lives, but glycemic instability is still a persistent challenge for people with diabetes, leading to tremendous morbidity and premature mortality. Research in the field of islet transplantation has demonstrated that replacing insulin-producing β cells can restore euglycemia comparable to individuals without diabetes. However, a short supply of cadaveric islet donors, the technically challenging process of isolating islets, and the requirement for chronic immune suppression have impeded widespread clinical adoption.

Glycaemia and body weight are regulated by sodium-glucose cotransporter 1 (SGLT1) expression via O-GlcNAcylation in the intestine.

Objective: The intestine is an important organ for nutrient metabolism via absorption and endocrine systems. Nutrients regulate O-GlcNAcylation, a post-translational modification of various proteins by O-GlcNAc transferase (OGT). We have previously shown that general OGT knockout induced severe weight loss and hypoglycaemia in mice, but little is known about how O-GlcNAcylation in the intestine modulates nutrient metabolism, especially glucose metabolism, through absorption.

Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces bodyweight and fat mass, but not muscle mass, in Japanese type 2 diabetes patients treated with insulin: A randomized clinical trial.

Aims/introduction: Sodium-glucose cotransporter 2 inhibitors reduce bodyweight (BW) by creating a negative energy balance. Previous reports have suggested that this BW reduction is mainly loss of body fat and that ~20% of the reduction is lean mass. However, the effects of sodium-glucose cotransporter 2 inhibitors on BW and body composition remain unclear.

MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1-α signalling in beige adipocytes.

Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and β3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown.

Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle.

O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated.

Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice.

Aims/hypothesis: O-GlcNAcylation is characterised by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O-GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O-GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions.

Pivotal Role of -GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis.

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. -linked -acetylglucosamine (-GlcNAc) modification is characterized by the addition of -acetylglucosamine to various proteins by -GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of -GlcNAc modification in adipose tissues.