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Okada, T. et al. Insulin receptors in cells are critical for islet compensatory growth response to insulin resistance. Proc. Natl Acad. Sci. USA 104, 8977-8982

Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2007; 104(21):8977-82. DOI: 10.1073/pnas.0608703104
Source: PubMed

ABSTRACT Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used liver-specific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in beta-cell mass. LIRKO mice, also lacking functional insulin receptors in beta-cells (beta IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to beta IRKO and beta-cell-specific IGF1 receptor knockout (beta IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, beta IRKO, but not beta IGFRKO, mice exhibited poor islet growth consistent with insulin-stimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance.

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Available from: Chong Wee Liew, Aug 28, 2015
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    • "In embryonic and postnatal development, IGF-1 and IGF-2 play either modest or supporting roles in the expansion and development of bcell mass (Kulkarni, 2005, Cantley et al., 2007, Otani et al., 2004), although b-cell mass appears to be mediated through the IR (Otani et al., 2004, Kulkarni et al., 2002, Okada et al., 2007). The IRmediated growth effects of b-cells are regulated by the PI3K/Akt/ FoxO1 and PI3K/mTORC1/P70S6K signaling pathways (Okada et al., 2007, Pende et al., 2000). As mentioned above, insulin acts via a paracrine secretion and response mechanism to increase the expression of insulin and glucokinase, and this action is IR/PI3K mediated, not involving ERK (Leibiger et al., 2001). "
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    • "We demonstrated that GKA upregulated IRS-2 via Ca2+-calcineurin but did not affect ATF3 levels in β-cells. The insulin receptor plays a crucial role in β-cell proliferation in response to insulin resistance (40). However, we noted that even if signals from insulin and IGF-1 receptors were canceled by OSI-906, GKA satisfactorily increased IRS-2 and regulated ER stress–related genes. "
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