The insulin-like growth factor binding protein-1 (IGFBP-1) is uniquely characterized among the family of IGF binding proteins by the characteristics that (1) circulating IGFBP-1 levels inversely correlate with fetal birthweights in multiple paradigms in both humans and rodents and (2) IGFBP-1 is tightly regulated by insulin and dramatically elevated under conditions of hypoinsulinemia such as occurs in insulin-dependent diabetes mellitus (IDDM). The exact in vivo functions of IGFBP-1 are unknown, however, considerable evidence supports the hypothesis that the family of six IGFBPs are major modulators of IGF-I and IGF-II, mitogenic peptides that mediate growth and metabolism. The proposed project will test the hypothesis that IGFBP-1 is a major regulator of IGF availability and has a critical role in fetal and postnatal growth and in glucose counterregulation. This hypothesis leads to the following testable predictions that: (1) IGFBP-1 will be present in embryonic circulation by mid-gestational ages, as early as IGFs are known to act in fetal growth. (2) IGFBP-1 deficiency during development will result in increased fetal and neonatal growth. (3) IGFBP-1 will attenuate growth and metabolic effects of chronic and acute IGF-1 challenge. (4) Chemical induction of IDDM in IGFBP-1 deficient mice will result in attenuation of secondary complications of diabetes that are the result of decreased IGF availability. (5) Either deficiency or overexpression of IGFBP-1 will alter the rate and amount of kidney hypertrophy associated with both uninephrectomy and chemically-induced IDDM. The proposed research will directly test these predictions using, in part, a powerful approach to establish a genetic mouse model that is deficient in IGFBP-1. These studies will provide a better understanding of the in vivo role of IGFBP- 1 in growth and metabolism during normal states and in specific pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK048103-03
Application #
2016827
Study Section
Endocrinology Study Section (END)
Program Officer
Smith, Philip F
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033