Liver-specific IGF-I gene deficient mice exhibit accelerated diabetes in response to streptozotocin, associated with early onset of insulin resistance Rong Yu a , Shoshana Yakar b , Ye Lauren Liu a , Yarong Lu a , Derek LeRoith b , Dengshun Miao a , Jun-Li Liu a, * a Fraser Laboratories, M3-15, Department of Medicine, McGill University Health Center, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 b Diabetes Branch, NIDDK, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1758, USA Received 2 January 2003; received in revised form 26 March 2003; accepted 31 March 2003 Abstract Liver-specific IGF-I gene deficient (LID) mice exhibit pancreatic islet hyperplasia and insulin resistance. To clarify their causal relationship, we studied age-dependent changes in these two aspects and the response to b-cell damage caused by streptozotocin in adult mice. As a result, the onset of insulin resistance in LID mice was detectable as early as 1-month of age, while hyperinsulinemia was developed after a significant delay at 2.5-month. Upon streptozotocin administration, control mice exhibited significant hyperglycemia after 9 days, and glucose levels continued to rise at 12  /15 days. LID mice developed diabetes much more rapidly, with hyperglycemia after 6 days and higher glucose levels up to 15 days. They also exhibited significant weight loss and 6/19 died. Serum insulin assay, insulin mRNA analysis and immunohistochemistry revealed that the more severe diabetes in LID mice was not due to more damage to their b-cells. Thus LID mice are more sensitive to streptozotocin-induced b-cell damage, due to a primary defect in insulin responsiveness. The pancreatic islet hyperplasia observed in these mice seems to represent a compensatory response to insulin resistance, therefore, offers no protection against b-cell damage. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cre/loxP; Insulin resistance; Pancreatic islets; Immunohistochemistry 1. Introduction Insulin-like growth factor I (IGF-I) belongs to a family of polypeptides that evolved from a common ancestor into IGF-I, IGF-II and proinsulin. IGF-I is essential for normal cell proliferation, differentiation, intrauterine development, and postnatal growth (LeR- oith, 1997; Liu et al., 1993; Powell-Braxton et al., 1993). Unlike insulin, both IGF-I and IGF-II are bound to high-affinity binding proteins in the circulation. The IGFs bind to a distinct IGF-I receptor (IGF-IR) on the surface of target cells. IGF-I has a much higher affinity for the IGF-IR than does insulin; similarly, insulin more selectively binds to the insulin receptor than to the IGF- IR. IGF-I is widely expressed during mammalian embryonic and postnatal development, as well as in adulthood. IGF-I promotes the postnatal somatic growth of bone, muscle, fat, and many other tissues. Although IGF-I can be synthesized by extrahepatic tissues, it has been well established that the liver is the primary source of circulating IGF-I (LeRoith, 1997; Yakar et al., 1999). Using Cre/loxP-mediated, liver- specific IGF-I gene deficient (LID) mice, we have previously suggested that liver-derived IGF-I is not required for normal growth, but is essential for main- taining normal carbohydrate metabolism (Yakar et al., 1999, 2001). Thus, adult LID mice exhibited significant hyperinsulinemia due to pancreatic islet hyperplasia, growth hormone hypersecretion, and insulin resistance in skeletal muscle, despite having normal blood glucose levels and clearance. * Corresponding author. Tel.:  /1-514-842-1231x35059; fax:  /1- 514-843-2819. E-mail address: jun-li.liu@mcgill.ca (J.-L. Liu). Molecular and Cellular Endocrinology 204 (2003) 31  /42 www.elsevier.com/locate/mce 0303-7207/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0303-7207(03)00145-X