SerpinB1 Promotes Pancreatic β Cell Proliferation

Abstract

Summary Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β-cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model which manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β-cell proliferation in humans, mice and zebrafish. Small molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β-cells, and mice lacking serpinB1 exhibit attenuated β-cell compensation in response to insulin resistance. Finally, SerpinB1-treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β-cell mass in patients with diabetes.

A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

“…PDGF-AA has a potent effect to stimulate juvenile human islet ␤-cell proliferation but is inactive in adult human islets apparently due to loss of PDGF signaling as a function of islet age (45). The current study joins another recent report showing human islet cell proliferative effects of serpin B1 (46) as evidence for the existence of peptidic factors capable of enhancing functional ␤-cell mass. Future efforts will be focused on identification of other Pdx-1-induced factors that may complement the human islet cell proliferative effects of Inhbb overexpression or activin B addition.…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…Consistent with findings by Gromada and colleagues (127), ANGPTL8 also failed to exert a pro-proliferative effect on transplanted human β cells (128). More promising are recent findings on osteocalcin (120) and SERPINB1 (122), which indicate that these hormones could be effective in stimulating human β cell proliferation. Proliferation of β cells was increased after treatment of human islets with decarboxylated osteocalcin or small molecules mimicking SERPINB1 activity both ex vivo and after transplantation into mice (122).…”

“…More promising are recent findings on osteocalcin (120) and SERPINB1 (122), which indicate that these hormones could be effective in stimulating human β cell proliferation. Proliferation of β cells was increased after treatment of human islets with decarboxylated osteocalcin or small molecules mimicking SERPINB1 activity both ex vivo and after transplantation into mice (122). Preliminary analysis of mice treated with small-molecule mimics of SERPINB1 suggests that the effects on proliferation of extrapancreatic tissues are limited, which raises hope that it might be possible to identify growthstimulating agents that are selective for β cells.…”

SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction

“…The MAPK pathway is closely related to the cell protective effects of SERPINB1 28 and involved in STAT3 activation during lung injury 29 . We then used specific inhibitors to respectively inhibit ERK1/2, p38 MAPK, and JNK, the three major kinases in MAPK family in our OALT model to explore whether MAPK plays a role in SERPINB1-mediated HO-1 and STAT3 activation to confer pulmonary protective effects against ALI.…”