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

Caldérari, Sophie; Gangnerau, M. N.; Thibault, M. C.; Meile, Marie‐José; Kassis, Nadim; Álvarez, Carmen; Portha, Bernard; Serradas, Patricia

doi:10.1007/s00125-007-0676-2

Cited by 67 publications

(60 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 and Table 1). These data confirm and extend our earlier reports of decreased transcript levels of Pdx1, Neurog3 (also known as Ngn3) and Igf2 [16,18] and reduction in pancreatic IGF2 and IGF1R protein levels [16] in E18.5 GK stock fetuses.…”

Section: Resultssupporting

confidence: 92%

See 1 more Smart Citation

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

Chavey¹,

Bailbé²,

Maulny³

et al. 2012

Diabetologia

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis We used the GK/Par rat, a spontaneous model of type 2 diabetes with early defective beta cell neogenesis, to determine whether the development of GK/Par offspring in a non-diabetic intrauterine/postnatal environment would prevent the alteration of fetal beta cell mass (BCM) and ultimately decrease the risk of diabetes later in adult life. Methods We used an embryo-transfer approach, with fertilised GK/Par ovocytes (oGK) being transferred into pregnant Wistar (W) or GK/Par females (pW and pGK). Offspring were phenotyped at fetal age E18.5 and at 10 weeks of age, for BCM, expression of genes of pancreatic progenitor cell regulators (Igf2, Igf1r, Sox9, Pdx1 and Ngn3), glucose tolerance and insulin secretion. Results (1) Alterations in neogenesis markers/regulators and BCM were as severe in the oGK/pW E18.5 fetuses as in the oGK/pGK group. (2) Adult offspring from oGK transfers into GK (oGK/pGK/sGK) had the expected diabetic phenotype compared with unmanipulated GK rats. (3) Adult offspring from oGK reared in pW mothers and milked by GK foster mothers had reduced BCM, basal hyperglycaemia, glucose intolerance and low insulin, to an extent similar to that of oGK/pGK/sGK offspring. (4) In adult offspring from oGK transferred into pW mothers and milked by their W mothers (oGK/pW/sW), the phenotype was similar to that in oGK/pGK/sGK or oGK/pW/sGK offspring. Conclusions/interpretation These data support the conclusion that early BCM alteration and subsequent diabetes risk in the GK/Par model are not removed despite normalisation of the prenatal and postnatal environments, either isolated or combined.

show abstract

Section: Resultssupporting

confidence: 92%

“…Western blot analysis Gel electrophoresis and immunoblotting for the detection of IGF2 and IGF1 receptor (IGF1R) were performed as previously described [16] and detailed in ESM Methods.…”

Section: Methodsmentioning

confidence: 99%

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

Chavey¹,

Bailbé²,

Maulny³

et al. 2012

Diabetologia

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, genes coding for transcription factors crucial to the pancreatic beta cell-such as Neurog3, Nkx6.1, NeuroD2, and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA)-were found to be putative binding targets for ZBED6 in myoblast cells (1). ZBED6-mediated control of IGF2 may be relevant to beta cells because it has been observed that aberrant IGF2 production in embryonic pancreas preceded the subsequent beta cell mass anomaly that develops in diabetic Goto-Kakizaki rats (3). Furthermore, the human insulin gene is clustered closely together with IGF2 (4), pointing to the possibility that not only IGF2, but also insulin might be controlled by a common ZBED6-dependent regulatory mechanism.…”

mentioning

confidence: 99%

Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Wang

Jiang

Wallerman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have investigated whether the recently discovered transcription factor, zinc finger BED domain-containing protein 6 (ZBED6), is expressed in insulin-producing cells and, if so, to what extent it affects beta cell function. ZBED6 was translated from a ZC3H11A transcript in which the ZBED6-containing intron was retained. ZBED6 was present in mouse βTC-6 cells and human islets as a double nuclear band at 115/120 kDa and as a single cytoplasmic band at 95-100 kDa, which lacked N-terminal nuclear localization signals. We propose that ZBED6 supports proliferation and survival of beta cells, possibly at the expense of specialized beta cell function-i.e., insulin production-because (i) the nuclear ZBED6 were the predominant forms in rapidly proliferating βTC-6 cells, but not in human islet cells; (ii) down-regulation of ZBED6 in βTC-6 cells resulted in altered morphology, decreased proliferation, a partial S/G2 cell-cycle arrest, increased expression of beta cell-specific genes, and higher rates of apoptosis; (iii) silencing of ZBED6 in the human PANC-1 duct cell line reduced proliferation rates; and (iv) ZBED6 binding was preferentially to genes that control transcription, macromolecule biosynthesis, and apoptosis. Furthermore, it is possible that beta cells, by switching from full length to a truncated form of ZBED6, can decide the subcellular localization of ZBED6, thereby achieving differential ZBED6-mediated transcriptional regulation.Z inc finger BED domain-containing protein 6 (ZBED6) is a recently discovered transcription factor restricted to and highly conserved among placental mammals (1). The intron-less ZBED6 has evolved from a domesticated DNA transposon and is located in one of the first introns of another gene, zinc finger CCCH-type containing 11A (ZC3H11A), with which it has no sequence homology. ZBED6 belongs to the CCCH zinc-finger BEAT and DREF (BED) domain-containing family and contains two DNA-binding BED domains and one hobo-Ac-Tam3 (hATC) dimerization domain. ZBED6 has a broad tissue distribution in mammals (1). In muscle tissue of pigs, it has been observed that ZBED6 negatively regulates insulin-like growth factor-2 (IGF2) transcription (1). A G-to-A transition in intron 3 of IGF2 abrogates the binding site for ZBED6 and leads to a threefold upregulation of IGF2 mRNA expression in skeletal muscle. Mutant pigs lacking the ZBED6 binding site display increased muscle mass, bigger hearts, and less fat deposition (2). Silencing of ZBED6 in mouse C2C12 myoblast cells was associated with elevated IGF2 expression, increased cell proliferation, and a faster wound-healing process. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified >2,000 ZBED6 binding sites in the genome. Genes associated with ZBED6 binding sites show a highly significant enrichment for certain Gene Ontology (GO) classifications, including development and transcriptional regulation (1).It is possible that ZBED6 controls not only IGF2 expression in muscle, but also the function of insulin-producing beta cells. ...

show abstract

“…In addition, as GK rats exhibit more than a 50% decrease in beta cell mass from fetal life onwards [10,11], we hypothesise that defective pancreatic vascularisation is associated with perinatal beta cell mass deficit. Indeed, vessel development, a major component of pancreatic islet development and function, is particularly active around birth [12][13][14] and altered programming of vascularisation has been shown to affect the development and function of various organs [15][16][17].…”

Section: Introductionmentioning

confidence: 94%

“…GK rats were bred in our own colony at the University Paris-Diderot, together with Wistar control rats from the GK strain derived after backcrossing of animals selected at the upper limit of normal distribution for glucose tolerance [19]. Characteristics of GK rats have been previously described [1,[4][5][6]10,11,[18][19][20][21]. At the indicated age, rats were weighed, bled at time of decapitation and blood, liver and pancreas collected for analysis.…”

Section: Animalsmentioning

confidence: 99%

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto–Kakizaki (GK) rat

Lacraz

et al. 2011

Diabetologia

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis The adult non-obese Goto-Kakizaki (GK) rat model of type 2 diabetes, particularly females, carries in addition to hyperglycaemia a genetic predisposition towards dyslipidaemia, including hypercholesterolaemia. As cholesterol-induced atherosclerosis may be programmed in utero, we looked for signs of perinatal lipid alterations and islet microangiopathy. We hypothesise that such alterations contribute towards defective pancreas/islet vascularisation that might, in turn, lead to decreased beta cell mass. Accordingly, we also evaluated islet inflammation and endothelial activation in both prediabetic and diabetic animals.Methods Blood, liver and pancreas were collected from embryonic day (E)21 fetuses, 7 dayold prediabetic neonates and 2.5 month-old diabetic GK rats and Wistar controls for analysis/quantification of: (1) Results Systemic and hepatic cholesterol anomalies already exist in GK fetuses and neonates.Hyperglycaemic GK fetuses exhibit a similar percentage decrease in total pancreas and islet vascularisation and beta cell mass. Normoglycaemic GK neonates show systemic inflammation, signs of islet pre-microangiopathy, disturbed angiogenesis, collapsed vascularisation and altered pancreas development. Concomitantly, GK neonates exhibit elevated defence mechanisms.Conclusions/interpretation These data suggest an autoinflammatory disease, triggered by in utero programming of cholesterol-induced islet microangiopathy interacting with chronic hyperglycaemia in GK rats. During the perinatal period, GK rats show also a marked deficient islet vascularisation in conjunction with decreased beta cell mass.

show abstract

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

Cited by 67 publications

References 49 publications

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto–Kakizaki (GK) rat

Contact Info

Product

Resources

About