Targeted Inactivation of Hepatocyte Growth Factor Receptor c-met in β-Cells Leads to Defective Insulin Secretion and GLUT-2 Downregulation Without Alteration of β-Cell Mass

Abstract

Overexpression of hepatocyte growth factor (HGF) in the ␤-cell of transgenic mice enhances ␤-cell proliferation, survival, and function. In the current studies, we have used conditional ablation of the c-met gene to uncover the physiological role of HGF in ␤-cell growth and function. Mice in which c-met is inactivated in the ␤-cell (MetCKO mice) display normal body weight, blood glucose, and plasma insulin compared with control littermates. In contrast, MetCKO mice displayed significantly diminished glucose tolerance and reduced plasma insulin after a glucose challenge in vivo. This impaired glucose tolerance in MetCKO mice was not caused by insulin resistance because sensitivity to exogenous insulin was similar in both groups. Importantly, in vitro glucose-stimulated insulin secretion in MetCKO islets was decreased by ϳ50% at high glucose concentrations compared with control islets. Furthermore, whereas insulin and glucokinase expression in MetCKO islets were normal, GLUT-2 expression was decreased by ϳ50%. These changes in ␤-cell function in MetCKO mice were not accompanied by changes in total ␤-cell mass, islet morphology, islet cell composition, and ␤-cell proliferation. Interestingly, however, MetCKO mice display an increased number of small islets, mainly single and doublet ␤-cells. We conclude that HGF/c-met signaling in the ␤-cell is not essential for ␤-cell growth, but it is essential for normal glucose-dependent insulin secretion. Diabetes 54:2090 -2102, 2005 M any factors have been identified that are capable of stimulating ␤-cell hyperplasia in vitro or in vivo: glucose, reg (regenerationassociated gene), growth hormone, insulin, IGFs, islet neogenesis-associated peptide, glucagon-like peptide 1 (GLP-1), ␤-cellulin, transforming growth factor-␣ (TGF-␣), gastrin, prolactin, parathyroid hormone-related protein, placental lactogen, and hepatocyte growth factor (HGF) (1). The fundamental importance of several islet growth factors as physiological regulators of islet growth and function has also been highlighted in studies using generalized knockout mice or transgenic mice overexpressing dominant-negative forms of their receptors in the ␤-cell (2-5). More recently, conditional disruption strategies using the Cre-LoxP system have allowed the direct deletion of growth factor receptor signaling in the pancreatic ␤-cell (6 -8). ␤-Cell-specific knockout of the insulin receptor or IGF-1 receptor leads to altered glucose sensing and glucose intolerance in adult mice (7,8). In addition, mice with ␤-cell-specific knockout of the insulin receptor show an age-dependent decrease in islet size and ␤-cell mass (7). These studies indicate that insulin and IGF-1 are important for differentiated function, but they do not seem to play a major role in early growth/development of the pancreatic ␤-cell.HGF is a mesenchyme-derived protein originally identified as a circulating factor in liver regeneration (9). To accomplish its actions, HGF binds with high affinity to, and induces the dimerization of, a transmembrane receptor ...

Stromal Cell–Derived Factor-1 (SDF-1)/CXCL12 Attenuates Diabetes in Mice and Promotes Pancreatic β-Cell Survival by Activation of the Prosurvival Kinase Akt

“…Islet endothelial cells have unique protein expression patterns (37) and produce several growth factors (36). Hepatocyte growth factor-containing conditioned medium prepared from islet-derived endothelial cells stimulates pancreatic endocrine cell proliferation, and additional paracrine factors produced by the endothelial cells also may regulate ␤-cell mass (38,39). We also observed the expression of SDF-1 throughout the pancreas in cells residing within the periductal and perivascular interstitium.…”

Tissue-Specific Deletion of the Retinoblastoma Protein in the Pancreatic β-Cell Has Limited Effects on β-Cell Replication, Mass, and Function

“…Both the Jacks exon 3 and Berns exon 19 pRb knockouts, when homozygous, have previously been reported to result in embryonic lethality. RIP-Cre mice (33) were generously provided by Dr. Mark Magnuson, Vanderbilt University, and had previously been bred onto a CD-1 background (34). The pRb ϩ/Ϫ heterozygous mice were propagated by crossing with wild-type C57Bl56 mice.…”

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

“…To examine the essential roles of the HGF-Met system in β-cells, Met was deleted using rat insulin II promoter (RIP)-driven Cre expression (52,53). β-cell-specific Met -/-mice exhibited normal body weight, blood glucose and plasma insulin levels (52,53). However, the mice exhibited reduced glucose tolerance and reduced plasma insulin levels following glucose challenge; thus, the HGF-Met signaling pathway may be essential for normal glucose-dependent insulin secretion.…”