Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts.

The present study was conducted to assess the role of activin(s) in the regulatory mechanism to maintain constant liver mass. To this end, we infused follistatin, an activin antagonist, into the portal vein of the rat. Follistatin induced DNA synthesis, as assessed by bromodeoxy uridine labeling, in intact livers. Small peaks of bromodeoxy uridine labeling were observed after 3 and 18 hours of infusion, and a large peak was observed after 48 hours. In follistatin-treated rats, the DNA content of the liver was significantly elevated after 72 hours and returned to the basal value within 120 hours. Likewise, liver weight increased significantly after 60 and 72 hours, but returned to the control value within 120 hours. Apoptosis of hepatocytes, assessed by the Tdt-mediated, dUTP-biotin nick end labeling method was observed after 72 hours or later. Messenger RNA (mRNA) expression of hepatocyte growth factor, transforming growth factor-␣ ␣, tumor necrosis factor-␣, and interleukin-6 did not increase after the addition of follistatin. The mRNA expression and immunoreativity of transforming growth factor-␤ ␤ increased after the administration of follistatin. These results suggest that the blockade of activin action leads to the initiation of DNA synthesis in the intact liver. Activins may tonically inhibit hepatocyte growth in the intact liver. Transforming growth factor-␤ ␤ may also act to maintain constant liver mass when activin action is blocked. (HEPATOLOGY 2000;31: 916-921.)Liver mass is carefully regulated in mammals, 1 and the ratio of liver mass and body weight is maintained within a narrow range under normal conditions. When the effective liver mass is reduced by partial hepatectomy, the remnant liver tissue, comprising parenchymal and nonparenchymal cells, starts growing. 2-4 Parenchymal cells eventually initiate DNA replication, which is followed by DNA replication of nonparenchymal cells. Within a few days after hepatectomy, the liver mass is restored, and liver regeneration stops when the liver mass reaches the optimal level for body size.

Autoimmune deficiency and destruction in either βcell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucosepotentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

Activin A produced in MDCK cells tonically inhibits branching tubulogenesis, and HGF induced branching tubulogenesis mainly by blocking the production of activin A.

Abstract-Furin, a yeast Kex2-family endoprotease, converts many vasoregulatory propeptides, including protransforming growth factor (TGF)-␤ to their mature forms. We examined whether furin expression is regulated by shear stress in vivo and in vitro. When an arteriovenous shunt was placed between the carotid artery and external jugular vein in rabbits, furin and TGF-␤ were highly expressed in shear stress-loaded endothelial cells. Exposure of bovine aortic endothelial cells in culture to shear stress induced furin and TGF-␤ expression in a similar manner. Molecular analysis of furin expression in bovine aortic endothelial cells revealed that shear stress increases the furin gene expression at transcriptional levels. Furthermore, TGF-␤ itself increased the furin mRNA levels. Shear-mediated furin expression was partly mediated by TGF-␤ because shear-induced furin mRNA levels were considerably decreased by overexpression of the truncated form of the TGF-␤ type II receptor. Likewise, blockade of furin activity by a furin inhibitor significantly decreased the endothelial production of mature TGF-␤. Taken