title: Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice.
abstract: The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kuznetsova
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Section of Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Opare-Addo
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Rozzo
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sadagurski
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Norquay
authors.affiliation: Housey Pharmaceutical Research Laboratories, Southfield, Michigan, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Reed
authors.affiliation: Section of Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ilham
authors.initials: I
authors.lastname: El Khattabi
authors.affiliation: Section of Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.affiliation: Section of Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.affiliation: Section of Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Morris F
authors.initials: MF
authors.lastname: White