Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin.

Heterogeneity of human pancreatic β-cells.

Background: Human pancreatic β-cells are heterogeneous. This has been known for a long time and is based on various functional and morphological readouts. β-Cell heterogeneity could reflect fixed subpopulations with distinct functions.

Increased SLC38A4 Amino Acid Transporter Expression in Human Pancreatic α-Cells After Glucagon Receptor Inhibition.

Plasma amino acids and their transporters constitute an important part of the feedback loop between the liver and pancreatic α-cell function, and glucagon regulates hepatic amino acid turnover. Disruption of hepatic glucagon receptor action activates the loop and results in high plasma amino acids and hypersecretion of glucagon associated with α-cell hyperplasia. In the present study, we report a technique to rescue implanted human pancreatic islets from the mouse kidney capsule.

Gene Signature of the Human Pancreatic ε Cell.

The ghrelin-producing ε cell represents the fifth endocrine cell type in human pancreatic islets. The abundance of ε cells in adult pancreas is extremely low, which has hampered the investigation on the molecular pathways regulating the development and the function of this cell type. In this study, we explored the molecular features defining the function of pancreatic ε cells isolated from adult nondiabetic donors using single-cell RNA sequencing technology.

Mice harboring the human R138X loss-of-function mutation have increased insulin secretory capacity.

encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in protect against type 2 diabetes in humans.

Gene Signature of Proliferating Human Pancreatic α Cells.

Pancreatic α cells proliferate at a low rate, and little is known about the control of this process. Here we report the characterization of human α cells by large-scale, single-cell RNA sequencing coupled with pseudotime ordering. We identified two large subpopulations and a smaller cluster of proliferating α cells with increased expression of genes involved in cell-cycle regulation.

Pseudotime Ordering of Single Human β-Cells Reveals States of Insulin Production and Unfolded Protein Response.

Proinsulin is a misfolding-prone protein, making its biosynthesis in the endoplasmic reticulum (ER) a stressful event. Pancreatic β-cells overcome ER stress by activating the unfolded protein response (UPR) and reducing insulin production. This suggests that β-cells transition between periods of high insulin biosynthesis and UPR-mediated recovery from cellular stress.

Heterogeneity of the Pancreatic Beta Cell.

The pancreatic beta cell functions as a key regulator of blood glucose levels by integrating a variety of signals in response to changing metabolic demands. Variations in beta cell identity that translate into functionally different subpopulations represent an interesting mechanism to allow beta cells to efficiently respond to diverse physiological and pathophysiological conditions. Recently, there is emerging evidence that morphological and functional differences between beta cells exist.

Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development.

Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used a allele to ablate , one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3 endocrine progenitor lineage (). Remarkably, many essential components of the β cell transcriptional network that were down-regulated in the mice, were maintained in the mice - yet the mice displayed defective β cell differentiation and recapitulated the phenotype.

Pancreatic β cell identity requires continual repression of non-β cell programs.

Loss of β cell identity, the presence of polyhormonal cells, and reprogramming are emerging as important features of β cell dysfunction in patients with type 1 and type 2 diabetes. In this study, we have demonstrated that the transcription factor NKX2.2 is essential for the active maintenance of adult β cell identity as well as function.

An "exacerbate-reverse" strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease.

Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1Δ strains grown under viable aerobic conditions.