Pleiotrophin Expression and Actions in Pancreatic β-Cells

Abstract

Pleiotrophin (PTN) is a heparin-binding cytokine that is widely expressed during early development and increases in maternal circulation during pregnancy.Aged PTN-deficient mice exhibit insulin resistance, suggesting a role in metabolic control. The objectives of this study were to determine if PTN is expressed in mouse pancreatic β-cells in young vs. adult animals, and its effects on DNA synthesis, β-cell gene expression and glucose-stimulated insulin secretion (GSIS). The Ptn gene was expressed in isolated fractions of young mouse β-cells, especially within immature β-cells with low glucose transporter 2 expression. Expression was retained in the adult pancreas but did not significantly change during pregnancy. PTN and its receptor, phosphotyrosine phosphatase-β/ζ, were also expressed in the proliferative INS1E β-cell line. Fluorescence immunohistochemistry showed that PTN peptide was present in islets of Langerhans in adult mice, associated predominantly with β-cells. The percentage of β-cells staining for PTN did not alter during mouse pregnancy, but intense staining was seen during β-cell regeneration in young mice following depletion of β-cells with streptozotocin. Incubation of INS1E cells with PTN resulted in an increased DNA synthesis as measured by Ki67 localization and increased expression of Pdx1 and insulin. However, both DNA synthesis and GSIS were not altered by PTN in isolated adult mouse islets. The findings show that Ptn is expressed in mouse β-cells in young and adult life and could potentially contribute to adaptive increases in β-cell mass during early life or pregnancy.

Pleiotrophin and metabolic disorders: insights into its role in metabolism

“…In humans, circulating PTN levels are significantly associated with advancing chronological age, what confirms a retention of pleiotrophin expression in adult tissues (8). In particular, a residual expression of pleiotrophin has been found in the adult liver, brain, adipose tissue, testis, and pancreas (9)(10)(11).…”

“…Pancreatic b cells share with neurons that are excitable cells (95) and that retain high levels of Ptn expression in the adult. In fact, PTN maintains a high level of expression in the b cells of pancreatic islets of adult rats [10], mice [10] and humans [10]. The expression of Ptn in b cells could potentially contribute to adaptive increases in b cell mass as PTN is prominently expressed in Ins + Glut LO 2 cells, the immature pancreatic b cells that have multipotential islet endocrine cell lineage potentiality, and retain the proliferative capacity (10).…”

“…Although avb3 integrin is a PTN receptor that is expressed in the pancreatic islets (96), RPTP b/z is the most probable target for PTN in pancreatic islets (10). Treatment with rPTN increased DNA synthesis and upregulated the expression of Pdx-1 and insulin genes in the INS1E rat insulinoma cells suggesting that PTN modulates b cell expansion through RPTP b/z and/or other surface binding proteins (10).…”

High-Density Lipoprotein Is Located Alongside Insulin in the Islets of Langerhans of Normal and Rodent Models of Diabetes

“…The study also showed that, in contrast to the effect of LDL and VLDL, HDL prevents the release and invigoration of proapoptotic molecules in the beta cells of the pancreas. In addition, several peptides, including but not limited to apelin, pleiotrophin, ghrelin and urocortin have also been detected in the beta cells of the pancreas [ 27 , 46 , 47 , 48 ].…”

Ghrelin deletion and conditional ghrelin cell ablation increase pancreatic islet size in mice

“…Resp18 is upregulated in islets by exposure to high glucose and in islets of diabetic NOD mice, and it shares a partial sequence homology with IA-2, which is a dense-core secretory vesicle protein that helps facilitate insulin secretion ( 64 ). The Ptn gene product pleiotrophin is a secreted heparin-binding cytokine that is of interest because of its capacity to promote angiogenesis, act as a protooncogene, stimulate cell differentiation, and induce proliferation of several cell types, including β cell–derived cell lines ( 66 , 67 ). Intense pleiotrophin expression is observed during β cell regeneration following STZ-induced β cell depletion in mice ( 67 ).…”