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?-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

ABSTRACT: The presence of insulin receptor (IR) on ?-cells suggests that insulin has an autocrine/paracrine role in the regulation of ?-cell function. It has previously been reported that the ?-cell specific loss of IR (?IRKO) leads to the development of impaired glycemic regulation and ?-cell death in mice. However, temporally controlled ?IRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on ?-cells during the 2nd transition phase of the fetal murine pancreas is required for maintaining normal islet development.We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase IR knockout (MIP-?IRKO) mouse model to investigate the loss of ?-cell IR during pancreatic development at embryonic day (e) 13, a phase of endocrine proliferation and ?-cell fate determination. Fetal pancreata examined at e19-20 showed significantly reduced IR levels in the ?-cells of MIP-?IRKO mice. Morphologically, MIP-?IRKO pancreata exhibited significantly enlarged islet size with increased ?-cell area and proliferation. MIP-?IRKO pancreata also displayed significantly increased Igf-2 protein level and Akt activity with a reduction in phospho-p53 when compared to control littermates. Islet vascular formation and Vegf-a protein level was significantly increased in MIP-?IRKO pancreata.Our results demonstrate a developmental role for the ?-cell IR, whereby its loss leads to an islet compensatory overgrowth, and contributes further information towards elucidating the temporally sensitive signaling during ?-cell commitment.

SUBMITTER: Trinder M

PROVIDER: S-EPMC5216695 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

Trinder Mark M Zhou Liangyi L Oakie Amanda A Riopel Matthew M Wang Rennian R

Oncotarget 20160701 29

The presence of insulin receptor (IR) on β-cells suggests that insulin has an autocrine/paracrine role in the regulation of β-cell function. It has previously been reported that the β-cell specific loss of IR (βIRKO) leads to the development of impaired glycemic regulation and β-cell death in mice. However, temporally controlled βIRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on β-cells during the 2nd ...[more]

PMID: 27384998

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Project description:IntroductionAlthough much attention has been given to the global three-dimensional aspect of adolescent idiopathic scoliosis (AIS), the accurate three-dimensional morphology of the primary and compensatory curves, as well as the intervening junctional segments, in the scoliotic spine has not been described before.MethodsA unique series of 77 AIS patients with high-resolution CT scans of the spine, acquired for surgical planning purposes, were included and compared to 22 healthy controls. Non-idiopathic curves were excluded. Endplate segmentation and local longitudinal axis in endplate plane enabled semi-automatic geometric analysis of the complete three-dimensional morphology of the spine, taking inter-vertebral rotation, intra-vertebral torsion and coronal and sagittal tilt into account. Intraclass correlation coefficients for interobserver reliability were 0.98-1.00. Coronal deviation, axial rotation and the exact length discrepancies in the reconstructed sagittal plane, as defined per vertebra and disc, were analyzed for each primary and compensatory curve as well as for the junctional segments in-between.ResultsThe anterior-posterior difference of spinal length, based on "true" anterior and posterior points on endplates, was +3.8% for thoracic and +9.4% for (thoraco)lumbar curves, while the junctional segments were almost straight. This differed significantly from control group thoracic kyphosis (-4.1%; P<0.001) and lumbar lordosis (+7.8%; P<0.001). For all primary as well as compensatory curves, we observed linear correlations between the coronal Cobb angle, axial rotation and the anterior-posterior length difference (r?0.729 for thoracic curves; r?0.485 for (thoraco)lumbar curves).ConclusionsExcess anterior length of the spine in AIS has been described as a generalized growth disturbance, causing relative anterior spinal overgrowth. This study is the first to demonstrate that this anterior overgrowth is not a generalized phenomenon. It is confined to the primary as well as the compensatory curves, the junctional zones do not exhibit this growth discrepancy, however, they are straight.

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?-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

Publications

β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

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