Pancreatic-Specific Inactivation of IGF-I Gene Causes Enlarged Pancreatic Islets and Significant Resistance to Diabetes

Lu, Yue; Herrera, Pedro Luis; Guo, Yunlong; Sun, David C. H.; Tang, Zhengyi; LeRoith, Derek; Liu, Jun Li

doi:10.2337/diabetes.53.12.3131

Cited by 68 publications

(74 citation statements)

References 60 publications

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“…The down-regulation of Igf1 expression detected in our mouse Men1 insulinoma model seems to be consistent with the observation that Igf1 pancreas-specific disruption led to b-cell hypertrophy and increased cell survival (Lu et al 2004). IGFbp3 overexpression has been previously reported in pancreatic endocrine neoplasm and in other cancers, particularly in metastatic pancreatic endocrine neoplasm (Maitra et al 2003, Hansel et al 2004.…”

Section: Discussionsupporting

confidence: 72%

Gene expression profiling in insulinomas of Men1 β-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic β-cell tumorigenesis

Fontanière¹,

Tost²,

Wierinckx³

et al. 2006

Endocr Relat Cancer

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Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic b-cells. In these mice, we observed full penetrance of insulinoma with defined histological characteristics of tumorigenesis. To identify the genetic factors taking part in the tumour development, we performed gene expression profiling analysis of these insulinomas at different stages. Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 are down-regulated more than fourfold compared with normal pancreatic islets. Clustering analysis reveals the deregulation of Hox gene family and the genes involved in cell proliferation and cell cycle control. The altered expression of Igf2, Igfbp3 and Igfbp6 as well as cyclin A2, B2 and D2 are confirmed by quantitative RT-PCR, with the overexpression of all the three cyclins found in early stage insulinomas. Moreover, an increased proportion of cyclin A2-and D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) protein are detected in mouse Men1 insulinomas by immunostaining. Interestingly, the analysis of DNA methylation patterns by quantitative serial pyrosequencing reveals that four specific CpGs in the intragenic differentially methylated region 2 (DMR2) region of the Igf2 gene known to augment transcription through methylation are significantly hypermethylated in insulinomas of Men1 b-cell mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be detected. Thus, our data indicate the involvement of both genetic and epigenetic mechanisms in early tumorigenesis of b-cells related to MEN1 inactivation.

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Section: Discussionsupporting

confidence: 72%

Gene expression profiling in insulinomas of Men1 β-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic β-cell tumorigenesis

Fontanière¹,

Tost²,

Wierinckx³

et al. 2006

Endocr Relat Cancer

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“…Other studies, in contrast, did not favour this role for IGFs. Pancreas-specific Igf1 gene deficiency mice exhibited enlarged islets and resistance to diabetes induced by streptozotocin [29]. Beta-cell-specific knockout of Igf1r in mice did not affect beta cell mass, but resulted in agedependent impairment of glucose tolerance and defective glucose-stimulated insulin secretion [30,31].…”

Section: Discussionmentioning

confidence: 98%

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

et al. 2007

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Aims/hypothesis The Goto-Kakizaki (GK) rat is a spontaneous model of type 2 diabetes. Defective beta cell mass detectable in late fetal age precedes the onset of hyperglycaemia. Our hypothesis was that an embryonic IGF production deficiency might be involved in beta cell mass anomaly in the diabetic GK rat. To test this, we evaluated during pancreatic organogenesis: (1) the beta cell development in GK rats on embryonic day (E) 13.5 and E18.5; (2) IGF2 and IGF1 receptor (IGF1R) pancreatic protein production on E13.5 and E18.5; (3) the in vitro development of GK pancreatic rudiment on E13.5; and (4) the in vitro effect of IGF2 addition on beta cell mass. Materials and methods Beta cell quantitative analyses were determined by immunohistochemistry and morphometry. IGF2 and IGF1R pancreatic protein production was evaluated using western blot analyses. Dorsal pancreatic rudiments were dissected on E13.5, separated from surrounding mesenchyme and cultured for 7 days without or with recombinant IGF2. Results While beta cell mass was already decreased on E18.5, the differentiation of the first beta cells was in fact normal in E13.5 GK pancreas. Moreover, defective IGF2 and IGF1R protein production was detected in GK pancreatic rudiment as early as E13.5. The isolated GK pancreatic rudiment as maintained in vitro mimics the GK beta cell deficiency observed in vivo. This last approach enabled us to show that GK beta cells were fully responsive to IGF2 as far as their net growth is concerned. Conclusions/interpretation In diabetic GK rat, defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly. IGF2 supplementation expands the pool of beta cells.

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“…However, several reports challenge a critical role of the IGF-1/IGF1R system for islet proliferation or protection. On one side, pancreasspecific deletion of IGF-1 results in enlarged islet mass and enhanced protection from chemically or dietary experimental diabetic state (15). On the other hand, b-cell-specific deletion of IGF1R does not alter total islet mass and only causes mild hyperinsulinemia (16).…”

Section: Introductionmentioning

confidence: 99%

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

Zumsteg

Caviezel²,

Pisarsky³

et al. 2012

Molecular Cancer Research

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NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic b-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared with Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-2, a high-affinity ligand for IGF1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials neither did affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, that is, the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-2 and of the IGF-2-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-2.

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Pancreatic-Specific Inactivation of IGF-I Gene Causes Enlarged Pancreatic Islets and Significant Resistance to Diabetes

Cited by 68 publications

References 60 publications

Gene expression profiling in insulinomas of Men1 β-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic β-cell tumorigenesis

Gene expression profiling in insulinomas of Men1 β-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic β-cell tumorigenesis

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

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