Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

Liu, Jingxuan; Walp, Erik R.; May, Catherine Lee

doi:10.4161/isl.19982

Cited by 16 publications

(12 citation statements)

References 49 publications

(86 reference statements)

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“…AFAM is involved in vitamin E transport and has been associated with insulin secretion in islet cells (38). However, because these measurements represent a small, yet well-controlled group of individuals, the global scope of these markers on a wider scale are not clear and need to be analyzed in other cohorts.…”

Section: Discussionmentioning

confidence: 99%

Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility

et al. 2015

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We determined longitudinal serum proteomics profiles from children with HLA-conferred diabetes susceptibility to identify changes that could be detected before seroconversion and positivity for disease-associated autoantibodies. Comparisons were made between children who seroconverted and progressed to type 1 diabetes (progressors) and those who remained autoantibody negative, matched by age, sex, sample periodicity, and risk group. The samples represented the prediabetic period and ranged from the age of 3 months to 12 years. After immunoaffinity depletion of the most abundant serum proteins, isobaric tags for relative and absolute quantification were used for sample labeling. Quantitative proteomic profiles were then measured for 13 case-control pairs by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, a label-free LC-MS/MS approach was used to analyze depleted sera from six case-control pairs. Importantly, differences in abundance of a set of proteins were consistently detected before the appearance of autoantibodies in the progressors. Based on top-scoring pairs analysis, classification of such progressors was observed with a high success rate. Overall, the data provide a reference of temporal changes in the serum proteome in healthy children and children progressing to type 1 diabetes, including new protein candidates, the levels of which change before clinical diagnosis.

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Section: Discussionmentioning

confidence: 99%

Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility

et al. 2015

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“…Total RNA was extracted from pancreatic islets isolated by the standard collagenase P (Roche, 11 213 873 001) protocol ( 31 ) or whole pancreata. Total RNA preparation and cDNA synthesis were performed as described ( 23 ). Quantitative PCR (qPCR) reactions were performed using SYBR Green JumpStart Taq ReadyMix (Sigma-Aldrich, S4438) and a Stratagene Mx3005P qPCR system.…”

Section: Methodsmentioning

confidence: 99%

“…In adult mouse β-cells, Isl-1 was identified as a key downstream target of leptin-induced Janus kinase signal transducer and activator of transcription 3 signaling ( 22 ). Recently, a transgenic mouse with islet-specific overexpression of Isl-1 displayed improved β-cell function ( 23 ). Interest in the mechanisms whereby Isl-1 regulates postnatal β-cell function is further raised by type 2 diabetes linkage and genome-wide association studies that identified genetic markers in the chromosomal region encompassing the ISL-1 locus ( 24 – 27 ).…”

Section: Introductionmentioning

confidence: 99%

Islet-1 Is Essential for Pancreatic β-Cell Function

Ediger

Liu

et al. 2014

Diabetes

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Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal β-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, β-cell–specific Isl-1 loss-of-function mouse: Isl-1L/L; Pdx1-CreERTm. Ablating Isl-1 in postnatal β-cells reduced glucose tolerance without significantly reducing β-cell mass or increasing β-cell apoptosis. Rather, islets from Isl-1L/L; Pdx1-CreERTm mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1L/L; Pdx1-CreERTm mice and βTC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the β-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using chromatin immunoprecipitation sequencing and luciferase reporter assays, we found that Isl-1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus Isl-1 is essential for postnatal β-cell function, directly regulates Pdx1 and Slc2a2, and has a mature β-cell cistrome distinct from that of pancreatic endocrine progenitors.

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“…Expression studies in mice suggest that the different responsiveness of albumin gene family members is crucial for their liver expression [11]. More recently, a microarray study showed increased expression of transcription factor islet-1 levels (which is associated with increased β-cell function) to increase afamin expression 35-fold [12].…”

Section: Gene Regulation Of Afaminmentioning

confidence: 98%

Afamin — A pleiotropic glycoprotein involved in various disease states

Dieplinger

2015

Clinica Chimica Acta

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The human glycoprotein afamin was discovered as the fourth member of the albumin gene family. Despite intense research over the last 20 years, our knowledge of afamin's physiological or pathophysiological functions is still very limited. Circulating afamin is primarily of hepatic origin and abundant concentrations are found in plasma, cerebrospinal, ovarian follicular and seminal fluids. In vitro binding studies revealed specific binding properties for vitamin E. A previously performed analytical characterization and clinical evaluation study of an enzyme-linked immunosorbent assay for quantitative measurement of afamin in human plasma demonstrated that the afamin assay meets the quality specifications for laboratory medicine. Comparative proteomics has identified afamin as a potential biomarker for ovarian cancer and these findings were confirmed by quantitative immunoassay of afamin and validated in independent cohorts of patients with ovarian cancer. Afamin has also been investigated in other types of carcinoma. Most of these studies await further evaluation with validated quantitative afamin assays and require validation in larger patient cohorts. Transgenic mice overexpressing the human afamin gene revealed increased body weight and increased blood concentrations of lipids and glucose. These transgenic mouse data were in line with three large human population-based studies showing that afamin is strongly associated with the prevalence and development of the metabolic syndrome. This review summarizes and discusses the molecular, biochemical and analytical characterization of afamin as well as possible clinical applications of afamin measurement.

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Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

Cited by 16 publications

References 49 publications

Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility

Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility

Islet-1 Is Essential for Pancreatic β-Cell Function

Afamin — A pleiotropic glycoprotein involved in various disease states

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