Elevation in endogenous GH levels enhances insulin suppression of hepatic glucose output in mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 780-806-Determinants of Insulin Resistance & Associated Metabolic Disturbances
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-797
Manuel D. Gahete1, Jose Cordoba-Chacon2, Raul M. Luque3, Owen P. McGuinness4 and Rhonda D. Kineman*2
1University of Córdoba, Cordoba, Spain, 2University of Illinois at Chicago, Department of Medicine, Chicago, IL, 3University of Córdoba, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Cordoba, Spain, 4Vanderbilt University School of Medicine, Nashville, TN
Studies using mouse models with extreme elevations in GH levels, due to ectopic expression of GH transgenes or GH-producing pituitary tumors, have revealed GH can antagonize the actions of insulin and promote hyperglycemia. In order to determine if more modest elevations in GH have similar effects on glucose homeostasis, we have examined the metabolic phenotype of the HiGH mouse model, where endogenous GH levels are increased 2-3 fold due to somatotrope-specific loss of IGF-I and insulin negative feedback (1). Under low-fat fed conditions, HiGH mice display elevated insulin levels without significant changes in whole body insulin sensitivity, while glucose clearance is improved (1). In the current study, hyperinsulinemic/euglycemic clamps revealed that the soleus of HiGH mice had reduced glucose uptake, consistent with GH acting as an insulin antagonist. However, glucose uptake in the gastrocnemius, vastus lateralis or adipose tissue did not significantly differ from controls. Unexpectedly, hepatic glucose output was reduced in HiGH mice under clamp conditions, which may be due to a reduction in gluconeogenesis, as supported by pyruvate tolerance tests and reduced hepatic PEPCK mRNA levels under fed and fasted conditions. Of note, hepatic PEPCK expression is elevated in a mouse model of adult-onset, isolated GH deficiency (AOiGHD), which has reduced circulating insulin levels and improved whole body insulin sensitivity (2). These GH-associated changes in hepatic function might be indirectly due to chronic changes in insulin levels.  However, we have also observed that GH (100ng/ml, 6h) or insulin (100nM) could suppress PEPCK mRNA levels to ~50% of vehicle-treated controls in primary mouse hepatocytes maintained in serum free medium, containing a low level of insulin (3nM).  In contrast, high dose insulin, but not GH, could suppress PEPCK expression in the absence of low insulin. Taken together, these results suggest that raising endogenous GH levels within the physiological range does not lead to hepatic insulin resistance. In fact, GH appears to work in combination with insulin to control glucose production. Although further studies are required to better understand the interrelationship between GH and insulin on hepatic function, these results indicate that the ability of GH to antagonize the actions of insulin is not absolute, and is in fact, tissue- and dose-dependent.

(1) Gahete MD, et al., Endocrinology 2011; 152(12):4825. (2) Luque RM, et al., Plos One 2011; 6(1):e15767. doi:10.1371/journal.pone.0015767.

Nothing to Disclose: MDG, JC, RML, OPM, RDK

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Merit Award and NIH: R01DK088133 awarded to RDK; Fundacion Caja Madrid and “Sara Borrell” CD11/00276 awarded to MDG;Fundacion Alfonso Martin Escudero awarded to JC-C; Ministerios de Educacion y Ciencia e Innovación: RYC-2007-00186, JC2008-00220, BFU2008-01136/BFI awarded to RML.