Hepatocyte growth factor (HGF) is produced in pancreatic mesenchyme-derived cells and islet cells. <i>In vitro</i>, HGF increases the insulin content proliferation of islets. To study role <i>in vivo</i>, we have developed three lines transgenic mice overexpressing mHGF using rat II promoter (RIP). Each RIP-HGF line displays clear expression mRNA protein islet. RIP-mHGF are relatively hypoglycemic post-prandial fasting states compared with their normal littermates. They display inappropriate...

Parathyroid hormone-related protein (PTHrP) is a prohormone that posttranslationally processed to family of mature secretory forms, each which has its own cognate receptor(s) on the cell surface mediate actions PTHrP. In addition being secreted via classical pathway and interacting with receptors in paracrine/autocrine fashion, PTHrP appears be able enter nucleus directly following translation influence cellular events an "intracrine" fashion. this report, we demonstrate can targeted...

The factors that regulate pancreatic beta cell proliferation are not well defined. In order to explore the role of murine placental lactogen (PL)-I (mPL-I) in islet mass regulation<i>in vivo</i>, we developed transgenic mice which mPL-I is targeted using rat insulin II promoter. Rat II-mPL-I displayed both fasting and postprandial hypoglycemia (71 105 mg/dl, respectively) as compared with normal (92 129 mg/dl; <i>p</i> < 0.00005 for both). Plasma concentrations were inappropriately elevated,...

OBJECTIVE The objectives of the study were to determine whether cell cycle transcription factor, FoxM1, is required for glucose homeostasis and β-cell mass expansion in maternal islets during pregnancy FoxM1 essential placental lactogen (PL)-induced proliferation. RESEARCH DESIGN AND METHODS β-Cell mass, proliferation, assessed virgin, pregnant, postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1Δpanc). Wild-type cultured or without PL examined induction. Transgenic overexpressing...

Glucose stimulates rodent and human β-cell replication, but the intracellular signaling mechanisms are poorly understood. Carbohydrate response element-binding protein (ChREBP) is a lipogenic glucose-sensing transcription factor with unknown functions in pancreatic β-cells. We tested hypothesis that ChREBP required for glucose-stimulated proliferation. The relative expression of was determined liver β-cells using quantitative RT-PCR (qRT-PCR), immunoblotting, immunohistochemistry. Loss-...

Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the β-cell. However, whether HGF/c-Met has role in maternal β-cell adaptation during pregnancy unknown. To address this issue, we characterized glucose homeostasis pregnant mice lacking c-Met pancreas (PancMet KO mice). Circulating HGF islet expression were increased mice. Importantly, PancMet displayed decreased replication apoptosis at gestational day (GD)15. The was associated with reductions prolactin receptor...

Recent advances in human islet transplantation have highlighted the need for expanding pool of β-cells available transplantation. We developed three transgenic models which growth factors (hepatocyte factor [HGF], placental lactogen, or parathyroid hormone-related protein) been targeted to β-cell using rat insulin promoter (RIP). Each displays an increase size and number, each insulin-mediated hypoglycemia. Of these models, RIP-HGF mouse least impressive phenotype under basal conditions. In...

Parathyroid hormone-related protein (PTHrP) is initially translated as a preprohormone which posttranslationally processed to yield family of mature secretory forms. Most attention has focused on the amino-terminal portion molecule homologous parathyroid hormone. It clear, however, that mid-region species PTHrP cleaved from highly conserved PTHrP, and amino terminus this peptide Ala38. The purposes current study were three: 1) confirm Arg37 immediately preceding Ala38 serves...

Parathyroid hormone-related protein (PTHrP) is produced by the pancreatic islet. It also has receptors on islet cells, suggesting that it may serve a paracrine or autocrine role within We have developed transgenic mice, which overexpress PTHrP in through use of rat insulin II promoter (RIP). Glucose homeostasis these mice markedly abnormal; RIP-PTHrP are hypoglycemic post-prandial and fasting states display inappropriate hyperinsulinemia. At end 24-hour fast, blood glucose values 49 mg/dl as...

To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions vivo and response to cytokines vitro.We generated pancreas-specific c-Met-null (PancMet KO) mice characterized their diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed effect HGF/c-Met signaling vitro cytokine-induced death mouse human islets, specifically examining nuclear (NF)-κB.Islets exposed or from MLDS-treated displayed significantly...

Hepatocyte growth factor (HGF) increases beta cell proliferation and function in rat insulin promoter (RIP)-targeted transgenic mice. RIP-HGF mouse islets also superiorly to normal a transplant setting. Here, we aimed determine whether viral gene transfer of the HGF into ex vivo could enhance performance streptozotocin-diabetic severe combined immunodeficient marginal islet mass model which 300 uninfected or adenovirus (Adv) LacZ-transduced equivalents were insufficient correct...

PTH and PTH-related peptides (PTHrPs) interact with a common PTH/PTHrP receptor (type I), which is expressed in many tissues, including bone kidney. Amino-terminal PTHrPs also recognize receptors several nonclassical target some of these, the signaling mechanisms differ qualitatively from those classical type I receptor. In normal keratinocytes squamous carcinoma cell lines, PTHrP stimulate rise intracellular calcium, but not cAMP, suggesting existence an alternate, II SqCC/Y1 cells stably...

One of the goals in treatment for diabetes is to enhance pancreatic beta cell function, proliferation, and survival. This study explores role lactogenic hormones, prolactin (PRL) placental lactogen (PL), We have previously shown that transgenic mice expressing mouse lactogen-1 (mPL1) cells under rat insulin II promoter (RIP) are resistant diabetogenic cytotoxic effects streptozotocin (STZ) vivo. The current demonstrates lactogens protect insulinoma (INS-1) primary against two distinct death...

Overexpression of hepatocyte growth factor (HGF) in the β-cell transgenic mice enhances proliferation, survival, and function. In current studies, we have used conditional ablation c-met gene to uncover physiological role HGF Mice which is inactivated (MetCKO mice) display normal body weight, blood glucose, plasma insulin compared with control littermates. contrast, MetCKO displayed significantly diminished glucose tolerance reduced after a challenge vivo. This impaired was not caused by...

Diabetes results from a deficiency of functional beta-cells. Previous studies have identified hepatocyte growth factor (HGF) and parathyroid hormone-related protein (PTHrP) as two potent beta-cell mitogens. The objective this study is to determine 1) whether HGF PTHrP additive/synergistic effects on proliferation; 2) the signaling pathways through which these factors mediate mitogenesis; 3) activation this/these pathway(s) enhances human replication.We generated phenotypically analyzed...

Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models reduced mass and regeneration: multiple low-dose streptozotocin (MLDS) partial pancreatectomy (Ppx). We also analyzed administration could accelerate regeneration wild-type (WT) after Ppx. Mouse islets obtained 7 days post-Ppx displayed...

Loss of functional β-cell mass is a major cause diabetes. Thus, identifying regulators health crucial for treating this disease. The We evaluated Lgr4 expression in mouse and human islets response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db aging) stress. To determine the role LGR4 we employed vitro loss gain function primary rodent β-cells examined its mechanism action INS1 cell line. Using was reduced by multiple stressors. In vitro, knockdown decreased...

OBJECTIVE Inducing human β-cell growth while enhancing function is a major goal in the treatment of diabetes. Parathyroid hormone–related protein (PTHrP) enhances rodent and through parathyroid hormone-1 receptor (PTH1R). Based on this, we hypothesized that PTH1R expressed β-cells PTHrP has potential to enhance proliferation and/or function. RESEARCH DESIGN AND METHODS expression, proliferation, glucose-stimulated insulin secretion (GSIS), expression differentiation cell-cycle genes were...

Adaptive β-cell replication occurs in response to increased metabolic demand during insulin resistance. The intracellular mediators of this compensatory are poorly defined and their identification could provide significant targets for regeneration therapies. Here we show that glucose vitro resistance vivo activate protein kinase C ζ (PKCζ) pancreatic islets β-cells. PKCζ is required glucose- glucokinase activator–induced proliferation rodent human β-cells vitro. Furthermore, either...