Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

1 Fraser Laboratories, Department of Medicine, and 3 Department of Surgery, McGill University, Montreal, Quebec H3A 1A1, Canada; and 2 Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopapthic Medicine, Ohio University, Athens, Ohio 45701 Submitted 22 September 2003 ; accepted in final form 5 May 2004 Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR –/– ) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR –/– mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR –/– mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR –/– mice was only one-third of that in wild-type littermates. Total -cell mass was reduced 4.5-fold in GHR –/– mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR –/– mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis. glucose homeostasis; immunohistochemistry; Laron syndrome; insulin tolerance test Address for reprint requests and other correspondence: J.-L. Liu, Fraser Laboratories, M3–15, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada (E-mail: jun-li.liu{at}mcgill.ca ).