β cell expression of IGF-I leads to recovery from type 1 diabetes

George, Mónica; Ayuso, Eduard; Casellas, Alba; Costa, Cristina; Devedjian, Jean Christophe; Bosch, Fátima

doi:10.1172/jci200212969

Cited by 41 publications

(34 citation statements)

References 59 publications

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“…These mice are normoglycemic and normoinsulinemic and have body weight similar to that of control mice (31). Surprisingly, ocular alterations such as cataracts and megaloglobus or buphthalmos appeared in old (more than 6 months) transgenic mice.…”

Section: Igf-1 Is Overexpressed In Eyes Of Transgenic Micementioning

confidence: 89%

“…Transgenic mice overexpressing IGF-1 under the control of the RIP-I show increased IGF-1 in β cells (31). These mice are normoglycemic and normoinsulinemic and have body weight similar to that of control mice (31).…”

Section: Igf-1 Is Overexpressed In Eyes Of Transgenic Micementioning

confidence: 95%

“…Male transgenic mice overexpressing IGF-1 under the control of the rat insulin promoter-I (RIP-I) in both the C57BL/6-SJL and CD1 mouse genetic background (31), which showed similar phenotype, were used. The expression of IGF-1 in β cells of transgenic mice counteracts cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin (STZ), increases β cell mass through neogenesis and β cell replication, and leads to recovery from type 1 diabetes (31).…”

Section: Animalsmentioning

confidence: 99%

“…RT-PCR analysis of RNA from the whole eye was carried out by standard methods. The RIP-I/IGF-1 chimeric gene contained partial rabbit β-globin sequences that were used to design specific primers (31). The forward primer was in exon 2 of β globin (5′-GGATC-CTGAGAACTTCAG-3′) and the reverse primer was inside the IGF-1 cDNA (5′-TTCCTGCACTTCCTCTAC-3′).…”

Section: Animalsmentioning

confidence: 99%

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Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Ruberte

Ayuso²,

Navarro³

et al. 2004

J. Clin. Invest.

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150

115

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IGF-1 has been associated with the pathogenesis of diabetic retinopathy, although its role is not fully understood. Here we show that normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 in the retina developed most alterations seen in human diabetic eye disease. A paracrine effect of IGF-1 in the retina initiated vascular alterations that progressed from nonproliferative to proliferative retinopathy and retinal detachment. Eyes from 2-month-old transgenic mice showed loss of pericytes and thickening of basement membrane of retinal capillaries. In mice 6 months and older, venule dilatation, intraretinal microvascular abnormalities, and neovascularization of the retina and vitreous cavity were observed. Neovascularization was consistent with increased IGF-1 induction of VEGF expression in retinal glial cells. In addition, IGF-1 accumulated in aqueous humor, which may have caused rubeosis iridis and subsequently adhesions between the cornea and iris that hampered aqueous humor drainage and led to neovascular glaucoma. Furthermore, all transgenic mice developed cataracts. These findings suggest a role of IGF-1 in the development of ocular complications in long-term diabetes. Thus, these transgenic mice may be used to study the mechanisms that lead to diabetes eye disease and constitute an appropriate model in which to assay new therapies.Nonstandard abbreviations used: glial fibrillar acidic protein (GFAP); intraocular pressure (IOP); intraretinal microvascular abnormalities (IRMAs); rat insulin promoter-I (RIP-I); streptozotocin (STZ); von Willebrand factor (vWF).

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Section: Igf-1 Is Overexpressed In Eyes Of Transgenic Micementioning

confidence: 89%

Section: Igf-1 Is Overexpressed In Eyes Of Transgenic Micementioning

confidence: 95%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

See 2 more Smart Citations

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Ruberte

Ayuso²,

Navarro³

et al. 2004

J. Clin. Invest.

Self Cite

150

115

View full text Add to dashboard Cite

show abstract

“…It is unclear whether proliferation or neogenesis governs β cell hyperplasia in insulin-resistant states and what drives expansion of β cell mass. Many growth factors can increase β cell proliferation (8)(9)(10), but there is no evidence that the metabolic syndrome increases systemic growth factor levels. Similarly, although both glucose (11) and free fatty acids (12) can promote β cell proliferation, the increase of β cell mass in mouse models of insulin resistance precedes the onset of these metabolic changes.…”

Section: Introductionmentioning

confidence: 99%

Role of the forkhead protein FoxO1 in cell compensation to insulin resistance

Okamoto

Hribal²,

Lin³

et al. 2006

Journal of Clinical Investigation

118

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Diabetes is associated with defective β cell function and altered β cell mass. The mechanisms regulating β cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory β cell hyperplasia is achieved via proliferation of existing β cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine β cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents β cell replication in 2 models of β cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal β cells. We propose that β cell compensation to insulin resistance is a proliferative response of existing β cells to growth factor signaling and requires FoxO1 nuclear exclusion.

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The Antidiabetic Effect of Mesenchymal Stem Cells Is Unrelated to Their Transdifferentiation Potential But to Their Capability to Restore Th1/Th2 Balance and to Modify the Pancreatic Microenvironment

et al. 2012

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Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmune destruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemic administration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells (MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorly understood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic b-cells and (b) modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administration of 5 3 10 5 syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia and presented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation, MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reduction in the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, in the pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift from proinflammatory to antinflammatory. MSC transplantation did not reduce pancreatic cell apoptosis but recovered local expression and increased the circulating levels of epidermal growth factor, a pancreatic trophic factor. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to their transdifferentiation potential but to their capability to restore the balance between Th1 and Th2 immunological responses along with the modification of the pancreatic microenvironment. Our data should be taken into account when designing clinical trials aimed to evaluate MSC transplantation in patients with T1DM since the presence of endogenous precursors seems to be critical in order to restore glycemic control.

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β cell expression of IGF-I leads to recovery from type 1 diabetes

Cited by 41 publications

References 59 publications

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Role of the forkhead protein FoxO1 in cell compensation to insulin resistance

The Antidiabetic Effect of Mesenchymal Stem Cells Is Unrelated to Their Transdifferentiation Potential But to Their Capability to Restore Th1/Th2 Balance and to Modify the Pancreatic Microenvironment

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