A Pentadecapeptide Fragment of Islet Neogenesis-Associated Protein Increases Beta-Cell Mass and Reverses Diabetes in C57BL/6J Mice

Rosenberg, Lawrence; Lipsett, Mark; Yoon, Ji‐Won; Prentki, Marc; Wang, Rennian; Lee, Youn-Jung; Pittenger, Gary L.; Taylor‐Fishwick, David A.; Vinik, Aaron I.

doi:10.1097/01.sla.0000143270.99191.10

Cited by 140 publications

(151 citation statements)

References 40 publications

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“…Islet size analysis showed that the increase in ␤-cell mass resulted predominantly from an increase in the numbers of smaller islets, suggesting that AT possibly potentiated the appearance of new islets by neogenesis. Studies by Brand et al (6) and Rosenberg et al (32) indicate that, in the STZ rat model, islet neogenesis is a significant contributor to ␤-cell mass expansion. The use of a higher dose of AT, 40 mg/kg, also resulted in increased ␤-cell mass at PD 44 following STZ treatment.…”

Section: Discussionmentioning

confidence: 99%

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Marchand

Arany

Hill

2010

American Journal of Physiology-Endocrinology and Metabolism

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Marchand KC, Arany EJ, Hill DJ. Effects of atorvastatin on the regeneration of pancreatic ␤-cells after streptozotocin treatment in the neonatal rodent. Am J Physiol Endocrinol Metab 299: E92-E100, 2010. First published April 13, 2010; doi:10.1152/ajpendo.00132.2010.-To investigate the role of statins in ␤-cell regeneration a model of streptozotocin (STZ)-induced ␤-cell injury was used in the neonatal rat. We hypothesized that ␤-cell growth and regeneration would increase following treatment with atorvastatin and that this would be associated with intraislet vasculogenesis. Pregnant Wistar rats were gavaged with 20 or 40 mg/kg atorvastatin for 21 days commencing on gestation day 15. Atorvastatin was detected in the circulation of the offspring. On postnatal day 4, the pups were given either a control or STZ (70 mg/kg ip) injection. ␤-Cell mass had partially recovered by postnatal day 44 following STZ treatment, and atorvastatin (20 mg/ kg) significantly increased ␤-cell mass in both STZ-treated and control animals. An increase in the numbers of small islets at postnatal day 44 was seen in STZ-treated animals following atorvastatin, suggestive of neogenesis, and glucose tolerance was improved. Treatment with atorvastatin caused an increase in the numbers of intraislet endothelial cells at postnatal day 14 and the percentage of endothelial cells undergoing DNA synthesis, suggesting that angiogenesis had preceded the increase in ␤-cell mass. The results indicate that functional ␤-cell mass was expanded with atorvastatin in both control and STZ-treated neonatal rats and suggests a novel effect of a statin in promoting islet plasticity.

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Section: Discussionmentioning

confidence: 99%

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Marchand

Arany

Hill

2010

American Journal of Physiology-Endocrinology and Metabolism

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“…The organization of INGAP's 175 amino acids classifies it as a member of the group 2 superfamily of reg-related proteins (Okamoto 1999). In addition to the biological efficacy of INGAP, a pentadecapeptide derived from the INGAP holoprotein retains biological activity (Rosenberg et al 2004). INGAP or INGAP-peptide administered to rodents (Rosenberg et al , 2004 or dogs (G Pittenger & D TaylorFishwick, unpublished observations) stimulates new islet growth as evidenced by elevated b-cell mass identified in quantitative histological and molecular analyses of insulin.…”

Section: Introductionmentioning

confidence: 99%

Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin

Taylor‐Fishwick¹,

Bowman²,

Hamblet³

et al. 2006

Journal of Endocrinology

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Islet neogenesis associated protein (INGAP) is a protein factor that can stimulate new islet mass from adult pancreatic progenitor cells. In models of islet neogenesis, INGAP expression is elevated in pancreatic acinar cells. Using a transgenic model to drive a sustained expression of INGAP in pancreatic acinar cells, we have identified a protection to chemical-induced hyperglycemia. A sustained expression of INGAP during development did not perturb islet development or basal blood glucose homeostasis, although b-cell mass and pancreatic insulin content were significantly increased in the INGAP transgenic mice. When challenged with a diabetogenic dose of streptozotocin (STZ), mice carrying the INGAP transgene did not become hyperglycemic. In contrast, wild-type mice became and remained hyperglycemic, blood glucoseO 550 mg/dl. The serum insulin levels and islet morphology were preserved in the transgenic mice after STZ treatment. These data suggest that the sustained expression of INGAP in the acinar pancreas confers resistance to a diabetogenic insult. The INGAP transgenic mouse provides a new model to uncover factors that are protective to diabetes onset and biomarkers to track b-cell pathology.

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“…Gene expression profiling has identified the Reg3 gene family as potentially involved in the stimulatory effect of RKIP1 ablation on pancreatic growth at P28. Interestingly, the Reg3 genes have been previously associated to pancreatic regeneration and islet cell neogenesis [37][38][39][40][41]. Further supporting a role for Reg3 genes in pancreatic postnatal development, a recent study has described the upregulation of Reg3 genes in the mouse pancreas between P7 and P30 followed by their subsequent downregulation in adulthood [42].…”

Section: Discussionmentioning

confidence: 83%

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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A Pentadecapeptide Fragment of Islet Neogenesis-Associated Protein Increases Beta-Cell Mass and Reverses Diabetes in C57BL/6J Mice

Abstract: Because there is a deficiency of beta-cell mass in both type-1 and type-2 diabetes, INGAP peptide stimulation of fully functional neoislet differentiation may provide a novel approach for diabetes therapy.

Cited by 140 publications

References 40 publications

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

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