Highly Enantioselective Catalytic Alkynylation of Quinolones: Substrate Scope, Mechanistic Studies, and Applications in the Syntheses of Chiral -Heterocyclic Alkaloids and Diamines.

The alkynylation of 4-siloxyquinolinium triflates has been achieved under the influence of copper bis(oxazoline) catalysis. The identification of the optimal bis(oxazoline) ligand was informed through a computational approach that enabled the dihydroquinoline products to be produced with up to 96% enantiomeric excess. The conversions of the dihydroquinoline products to biologically relevant and diverse targets are reported.

Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.

Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing β-cells is the primary means of β-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human β-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human β-cell proliferation in vitro and in vivo.

Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling.

Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic β-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote β-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK.

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.

High-throughput luminescent reporter of insulin secretion for discovering regulators of pancreatic Beta-cell function.

Defects in insulin secretion play a central role in the pathogenesis of type 2 diabetes, yet the mechanisms driving beta-cell dysfunction remain poorly understood, and therapies to preserve glucose-dependent insulin release are inadequate. We report a luminescent insulin secretion assay that enables large-scale investigations of beta-cell function, created by inserting Gaussia luciferase into the C-peptide portion of proinsulin. Beta-cell lines expressing this construct cosecrete luciferase and insulin in close correlation, under both standard conditions or when stressed by cytokines, fatty acids, or ER toxins.

Targeting the pancreatic β-cell to treat diabetes.

Diabetes is a leading cause of morbidity and mortality worldwide, and predicted to affect over 500 million people by 2030. However, this growing burden of disease has not been met with a comparable expansion in therapeutic options. The appreciation of the pancreatic β-cell as a central player in the pathogenesis of both type 1 and type 2 diabetes has renewed focus on ways to improve glucose homeostasis by preserving, expanding and improving the function of this key cell type.

Effectiveness of a computerized insulin order template in general medical inpatients with type 2 diabetes: a cluster randomized trial.

Objective: To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes.

Research Design And Methods: We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians.

Exaggerated postsurgical inflammation in a patient with insufficiently treated Addison disease.

A patient with Addison disease developed fever, pain, and marked orbital inflammation 3 days after evisceration in the setting of perforated corneal ulcer. He was treated for presumed orbital cellulitis without improvement. Increasing the corticosteroid dose for his Addison disease resulted in complete resolution of the inflammation.