New Insights into the Roles of Insulin/IGF-I in the Development and Maintenance of β-Cell Mass

Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Reviews in Endocrine and Metabolic Disorders (Impact Factor: 4.89). 09/2005; 6(3):199-210. DOI: 10.1007/s11154-005-3051-y
Source: PubMed
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    • "Increasing pancreatic b cell mass is of vital importance in response to relative insulin deficiency in physiology (e.g., pregnancy ) or in the pre-state of type 2 diabetes mellitus (T2DM) (e.g., obesity) including insulin resistance. Several factors have been shown to stimulate b cell proliferation, including innervation by the autonomous nervous system (Imai et al., 2008) as well as humoral factors such as glucose, incretins (GLP-1, GIP), adipokines (adiponectin, leptin), growth hormones (GHs; prolactin, placental lactogen), and insulin (for review, see Leibiger et al., 2008; Liu et al., 2009; Kulkarni, 2005; Vasavada et al., 2006; Yesil and Lammert, 2008). Interestingly, among these factors, insulin has also been shown to contribute to the differentiated b cell phenotype by, for example, regulating expression and nuclear activity of transcription factors Pdx-1/Ipf-1, FoxO1, and FoxA2 (Leibiger et al., 2008). "
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    ABSTRACT: Insulin resistance is a syndrome that affects multiple insulin target tissues, each having different biological functions regulated by insulin. A remaining question is to mechanistically explain how an insulin target cell/tissue can be insulin resistant in one biological function and insulin sensitive in another at the same time. Here, we provide evidence that in pancreatic β cells, knockdown of PI3K-C2α expression results in rerouting of the insulin signal from insulin receptor (IR)-B/PI3K-C2α/PKB-mediated metabolic signaling to IR-B/Shc/ERK-mediated mitogenic signaling, which allows the β cell to switch from a highly glucose-responsive, differentiated state to a proliferative state. Our data suggest the existence of IR-cascade-selective insulin resistance, which allows rerouting of the insulin signal within the same target cell. Hence, factors involved in the rerouting of the insulin signal represent tentative therapeutic targets in the treatment of insulin resistance.
    Cell Reports 09/2015; 13(1). DOI:10.1016/j.celrep.2015.08.058 · 8.36 Impact Factor
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    • "Pancreatic β-cells vigorously proliferate postnatally to increase insulin secretion capacity [2], which is implicated in adult β-cell mass [3]. Although the compensatory growth of β-cell mass in insulin resistance has been intensively investigated [4], the signaling pathway that regulates postnatal proliferation of β-cells is less well known [5]. Uncovering this mechanism will elucidate how β-cell mass is regulated during development and how the insulin-expressing cells that differentiate from stem cells acquire the capacity to proliferate. "
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    ABSTRACT: The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.
    PLoS ONE 08/2014; 9(8):e104184. DOI:10.1371/journal.pone.0104184 · 3.23 Impact Factor
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    • "The exact role of Igf2 expression in the fetal pancreas is unclear. In genetic models, decreased Igf2 expression in fetal pancreata led to lower INS cell proliferation rates and increased INS cell apoptosis (Kulkarni 2005). Overexpression of Igf2 in INS cells is associated with an increase in INS cell mass (Devedjian et al. 2000), while global overexpression of Igf2 causes islet GLU cell hyperplasia with an abnormal INS:GLU ratio (Petrik et al. 1999). "
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    ABSTRACT: Malnutrition in utero (IU) could alter pancreatic development. Reported here are the effects of high fat diet (HFD) during pregnancy on fetal growth and pancreatic morphology in an 'At Risk' animal model of metabolic disease, the glucose transporter 4 heterozygous mouse (G4+/-). Wild type (WT) female mice mated with G4+/- males were fed HFD or control (CD) diet for 2 weeks prior to mating and throughout pregnancy. At embryonic day18.5 fetuses were sacrificed and pancreata isolated for analysis of morphology and expression of genes involved in insulin-cell development, proliferation, apoptosis, glucose transport and function. Compared to WT CD, WT HFD fetal pancreata had a 2.4 fold increase in the number of glucagon cells (p=0.023). HFD also increased glucagon cell size by 18% in WT pancreata compared to WT CD. Compared to WT CD, G4+/- CD had an increased number of insulin cells, and decreased insulin and glucagon cell size. Compared to G4+/- CD, G4+/- HFD fetuses had increased pancreatic gene expression of Igf2, a mitogen and inhibitor of apoptosis. Expression of genes involved in proliferation, apoptosis, glucose transport and insulin secretion were not altered in WT HFD compared with G4+/- HFD pancreata. In contrast to WT HFD pancreata, HFD exposure did not alter pancreatic islet morphology in fetuses with GLUT4 haploinsufficiency; this may be mediated in part by increased Igf2 expression. Thus, interactions between IU diet and fetal genetics may play a critical role in the developmental origins of health and disease.
    Journal of Endocrinology 06/2014; 3(2). DOI:10.1530/JOE-14-0114 · 3.72 Impact Factor
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