title: Long- but not short-term adult-onset, isolated GH deficiency in male mice leads to deterioration of β-cell function, which cannot be accounted for by changes in β-cell mass.
abstract: Developmental models of GH deficiency (GHD) and excess indicate that GH is positively associated with β-cell mass. Therefore, the reduction in GH levels observed with age and weight gain may contribute to the age-related decline in β-cell function. To test this hypothesis, β-cell mass and function were assessed in a mouse model of adult-onset, isolated GHD (AOiGHD). β-Cell mass did not differ between low-fat (LF)-fed AOiGHD and controls. However, high fat-fed AOiGHD mice displayed impaired expansion of β-cell mass and a reduction of bromodeoxyuridine-labeled islet cells, whereas in vitro β-cell function (basal and glucose-stimulated insulin secretion [GSIS]) did not differ from controls. In contrast, duration of AOiGHD differentially altered in vitro β-cell function in LF-fed mice. Specifically, islets from young LF-fed AOiGHD mice showed significant reductions in insulin content and basal insulin secretion, but GSIS was similar to that of controls. A similar islet phenotype was observed in a developmental model of isolated GHD (GH-releasing hormone knockout). Given that LF- and high fat-fed AOiGHD mice, as well as GH-releasing hormone knockout mice, display improved insulin sensitivity, islet changes may be due to reduced insulin demand, rather than primary β-cell dysfunction. However, islets from older LF-fed AOiGHD mice exhibited impaired GSIS, associated with reduced expression of genes important to maintain glucose sensing, suggesting that factors secondary to AOiGHD can alter β-cell function with age. AOiGHD mice exhibited postprandial hypertriglyceridemia and increased pancreatic expression of lipid/inflammatory stress response genes (activating transcription factor 3 and peroxisome proliferator activator receptor β/δ). Therefore, we speculate that these changes may initially protect the AOiGHD β-cell, but with age, lipotoxicity may impair β-cell function.
authors.affiliation: Research and Development Division (J.C.-C., M.D.G., N.K.P., D.G., R.D.K.), Jesse Brown Veterans Affairs Medical Center, and Section of Endocrinology, Diabetes, and Metabolism (J.C.-C., M.D.G., N.K.P., D.G., R.D.K.), Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Department of Cell Biology, Physiology, and Immunology (M.D.G., R.M.L.), University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia and Centros de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutricion, Cordoba 14014, Spain; and Division of Endocrinology, Diabetes, and Metabolism (M.A., R.S.), School of Medicine, Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Jose
authors.initials: J
authors.lastname: Cordoba-Chacon
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Pokala
authors.forename: David
authors.initials: D
authors.lastname: Geldermann
authors.forename: Maria
authors.initials: M
authors.lastname: Alba
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvatori
authors.forename: Raul M
authors.initials: RM
authors.lastname: Luque
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Kineman
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000737:chemistry; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000172:deficiency*; D006706:Homeostasis; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048068:PPAR-beta / Q000378:metabolism; D010641:Phenotype; D019518:Postprandial Period; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism; D013997:Time Factors
chemical_list: D007328:Insulin; D008055:Lipids; D048068:PPAR-beta; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D001973:Bromodeoxyuridine; D005947:Glucose