title: Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance.
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.
authors.affiliation: Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Okada
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hinault
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.forename: Jan
authors.initials: J
authors.lastname: Krtzfeldt
authors.forename: Catherine
authors.initials: C
authors.lastname: Yin
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D021581:Active Transport, Cell Nucleus; D000821:Animal Feed; D000818:Animals; D049109:Cell Proliferation; D005223:Fats / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006965:Hyperplasia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D005223:Fats; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D011972:Receptor, Insulin; D005947:Glucose