Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in β-cell mass Jose Cordoba-Chacon a,b , Neena Majumdar a,b , Naveen K. Pokala a,b , Manuel D. Gahete a,b,c,d,e , Rhonda D. Kineman a,b, ⁎ a Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA b Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA c Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14014, Spain d Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Córdoba, 14014, Spain e CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, 14014, Spain abstract article info Article history: Received 11 September 2014 Received in revised form 11 March 2015 Accepted 12 April 2015 Available online 17 April 2015 Keywords: Growth hormone (GH) IGF-I Insulin β-cells In vivo mouse studies Insulin resistance It is clear that elevations in circulating GH can lead to an increase in insulin levels. This increase in insulin may be due to GH-mediated insulin resistance and enhanced lipolysis. However, there is also in vitro and in vivo evidence that GH acts directly to increase β-cell proliferation and insulin production. Our laboratory recently developed an animal model with elevated endogenous GH levels associated with a small (25%), but significant, increase in IGF-I (HiGH mice). As expected, insulin levels were elevated in HiGH mice; however, whole body insulin sensitivity was not altered and glucose tolerance was improved. This metabolic phenotype suggests that modest elevations in circulating GH and IGF-I may enhance β-cell mass and/or function, in the absence of systemic insulin resistance, thus improving glucose homeostasis. Objective: To determine if β-cell mass and/or function is altered in HiGH mice. Design: Male HiGH mice and their littermate controls were fed a low-fat or high-fat diet. Body composition and circulating metabolic endpoints were monitored overtime. The pancreas was recovered and processed for assessment of β-cell mass or in vitro basal and glucose-stimulated insulin secretion. Results: HiGH mice showed elevated circulating insulin and normal glucose levels, while non-esterified FFA levels and triglycerides were reduced or normal, depending on diet and age. β-cell mass did not differ between HiGH and control mice, within diet. However, islets from HiGH mice contained and released more insulin under basal conditions, as compared to control islets, while the relative glucose-stimulated insulin release did not differ. Conclusions: Taken together, these results suggest moderate elevations in circulating GH and IGF-I can directly increase basal insulin secretion without impacting β-cell mass, independent of changes in whole body insulin sensitivity and hyperlipidemia. Published by Elsevier Ltd. 1. Introduction Elevated circulating GH levels are associated with elevated insulin levels in patients with acromegaly [1], subjects treated with high dose GH [2,3], and in some rodent models with elevated endogenous or heterologous GH levels [4–8]. Since GH has been shown to antagonize the action of insulin [9–11], the increase in insulin is believed to be due in part to β-cell compensation to guard against the insulin resistant state. However, studies in mice with elevated endogenous GH (HiGH mouse; [8]) or young mice that express the bovine GH transgene (bGH Tg mouse), report hyperinsulinemia but normal insulin sensitivity (by ip ITT) and improved glucose tolerance (by ip GTT), when mice are maintained on a standard chow or low-fat (LF) diet [12,13]. It is also possible that elevated GH could act directly to increase insu- lin production. Multiple studies have reported GH can directly stimulate β-cell function or proliferation [15,16]. However the direct effects of GH on β-cell proliferation shown in the early studies were attributed to the use of human GH that can activate the prolactin receptor, while rodent GH does not bind/activate prolactin receptor [17]. Nonetheless, the GH receptor was shown to be required for diet-induced β-cell expansion [18]. Given a rise in GH is normally accompanied by a rise in IGF-I, studies have sought to determine if IGF-I has direct effects on β-cell pro- liferation or function, by knocking out the IGF-I receptor in β-cells. Growth Hormone & IGF Research 25 (2015) 189–195 ⁎ Corresponding author at: Jesse Brown VA Medical Center, Research and Development Division, 820 S. Damen Ave, Bldg. 11A, Suite 6215, MP151, Chicago, IL 60612, USA. Tel.: +1 312 569 6977; fax: +1 312 569 8114. E-mail address: kineman@uic.edu (R.D. Kineman). http://dx.doi.org/10.1016/j.ghir.2015.04.002 1096-6374/Published by Elsevier Ltd. Contents lists available at ScienceDirect Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir