The Reg Family Member INGAP Is a Marker of Endocrine Patterning in the Embryonic Pancreas

Department of Internal Medicine, The Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, VA 23510, USA.
Pancreas (Impact Factor: 2.96). 02/2008; 36(1):1-9. DOI: 10.1097/MPA.0b013r318148c8e6
Source: PubMed


Adult islet neogenesis is believed to recapitulate elements of pancreatic endocrine development. Identifying factors that regulate islet neogenesis-associated protein (INGAP) gene activity could provide links to pancreas development.
Predicted transcriptional regulators of INGAP were screened in an INGAP-promoter-reporter assay. Based upon their temporal expression, the occurrence of INGAP-positive cells during pancreas embryonic development were studied.
Pancreatic transcription factors, PDX-1, Ngn3, NeuroD, and Isl-1, activated the INGAP promoter, but PAX4, PAX6, and Nkx2.2 did not. The INGAP-positive cells were present in the developing pancreatic bud of the mouse embryo. Emerging clusters of unorganized endocrine cells were INGAP positive. These cells coexpressed insulin or somatostatin, but glucagon-expressing cells remained distinct. The INGAP-positive cells were also detected in the maturing neonatal endocrine cells organized into islets. In direct contrast to the embryo, glucagon localized with most INGAP-positive cells in the postnatal endocrine cells. The INGAP-positive cells juxtaposed pancreatic duct cells. A subset of 5-bromo-2'-deoxyuridine-positive/INGAP-positive cells was detected in the neonatal pancreas.
These data implicate INGAP and/or Reg family proteins in endocrine cell patterning during embryonic development and suggest that INGAP immunoreactivity is a key marker associated with early endocrine cells.

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    • "studies suggest that combinations of inflammation-modulating agents with islet trophic factors may be one approach in the treatment or reversal of T1DM. Islet neogenesis associated protein (INGAP) is a member of the Reg3 family of pancreatic proteins and regulated by transcriptional factors involved in neuroendocrine lineage commitment [7]. In studies of normal hamsters, administration of an INGAP-derived peptide (corresponding to amino acids 104 -118 of INGAP) appeared to stimulate islet neogenesis, as evidenced by small foci of insulin-positive islet-like clusters budding from intralobular and terminal ductules [8]. "
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    ABSTRACT: Type 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.
    Journal of Diabetes Mellitus 01/2012; 02(02). DOI:10.4236/jdm.2012.22040
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    • "INGAP was a compound originally identified as part of a protein complex (ilotropin), isolated from pancreata of normal adult hamsters previously wrapped in cellophane [2], and thereafter cloned and sequenced [3]. Lately however, the presence of INGAP was found at the embryonic mouse pancreas commitment period, thus providing evidence of its early normal presence and possible role in pancreas development and patterning [4]. INGAP gene encodes a 19,940 Da transcript [3], only produced in different subsectors of the pancreas (islets, duct and exocrine cells) [5]. "
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    ABSTRACT: We have studied the structural and dynamical properties of the biologically active pentadecapeptide of the islet neogenesis associated protein (INGAP-PP) and of two other pentadecapeptides with the same amino acid composition but randomly scrambled primary sequences, using molecular dynamic simulations. Our data demonstrates that whilst the peptides with scrambled sequences show no definite prevalent structure in solution, INGAP-PP maintains a notably stable tertiary fold, namely, a conformer with a central beta-sheet and closed C-terminal. Such structure resembles the one corresponding to the amino acid sequence of human pancreatitis associated protein-1 (PAP-1), which presents 85% sequence homology with INGAP. These results could reasonably explain why the two scrambled sequences tested showed no biological activity, while INGAP-PP significantly increases beta-cells function and mass both in vitro and in vivo conditions. The capability of INGAP-PP to temporarily adopt other closely related conformations offers also a plausible explanation for the 50 fold experimental difference in potency between the active pentadecapeptide and the whole protein. They also suggest that the C-terminal region of INGAP-PP may plausibly be the locus for its interaction with the cell receptor. Consequently, the knowledge gathered through our data can help to obtain more potent INGAP-PP analogs, suitable for the prevention and treatment of diabetes.
    Journal of Molecular Graphics and Modelling 12/2008; 27(6):701-5. DOI:10.1016/j.jmgm.2008.11.001 · 1.72 Impact Factor
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    ABSTRACT: BackgroundWe previously demonstrated that somatostatin receptor type 5 (SSTR5) gene ablation results in alterations in insulin secretion and glucose metabolism, accompanied by morphologic alterations in the islets of Langerhans. The underlying mechanism(s) by which SSTR5 exerts its cellular functions remain(s) unknown. We hypothesized that SSTR5 mediates the inhibitory effect of somatostatin (SST) on insulin secretion and islet proliferation by regulating a specific set of pancreatic genes. MethodsTo identify SSTR5-regulated pancreatic genes, gene expression microarray analysis was performed on the whole pancreas of 1- and 3-month-old wild-type (WT) and SSTR5 knockout (SSTR5 −/−) male mice. Real-time RT-PCR and immunofluorescence were performed to validate selected differentially expressed genes. ResultsA set of 143 probes were identified to be differentially expressed in the pancreas of 1-month-old SSTR5 −/− mice, 72 of which were downregulated and 71 upregulated. At 3months of age, SSTR5 gene ablation resulted in downregulation of a set of 30 probes and upregulation of a set of 37 probes. Among these differentially expressed genes, there were 15 and 5 genes that were upregulated and downregulated, respectively, in mice at both 1 and 3months of age. Three genes, PAP/INGAP, ANG, and TDE1, were selected to be validated by real-time RT-PCR and immunofluorescence. ConclusionsA specific set of genes linked to a wide range of cellular functions such as islet proliferation, apoptosis, angiogenesis, and tumorigenesis were either upregulated or downregulated in SSTR5-deficient male mice compared with their expression in wild-type mice. Therefore, these genes are potential SSTR5-regulated genes during normal pancreatic development and functional maintenance.
    World Journal of Surgery 04/2009; 33(4):630-637. DOI:10.1007/s00268-008-9893-1 · 2.64 Impact Factor
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