title: Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting.
abstract: The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing β-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. At present, however, the effects of betatrophin on human β-cells are not known. Here we use administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate β-cell replication in mice, to test its effect on human β-cells. Although mouse β-cells, in their normal location in the pancreas or when transplanted under the kidney capsule, respond with a dramatic increase in β-cell DNA replication, human β-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic approach for treating human diabetes.
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: John
authors.initials: J
authors.lastname: Le Lay
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000293:Adolescent; D000328:Adult; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D036361:Peptide Hormones / Q000096:biosynthesis*; D010455:Peptides / Q000494:pharmacology; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous
chemical_list: C000595899:ANGPTL8 protein, mouse; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D036361:Peptide Hormones; D010455:Peptides; C532752:S961 peptide; D011972:Receptor, Insulin