Dr. Freemark's work has focused on the roles of the lactogenic hormones in perinatal and postnatal insulin production. He has made the novel observation that PRLRs in the human fetus and fetal rat are expressed only in pancreatic exocrine tissue and ductal epithelial cells in early gestation, emerging in pancreatic beta cells near the time of birth. Since the emergence of PRLRs in pancreatic beta cells coincides with a surge of beta cell proliferation and insulin production, he hypothesized that lactogens might play roles in islet maturation. Subsequent studies lent strong support to this hypothesis.

The lactogenic and somatogenic hormones have overlapping actions in a number of metabolic systems. Consequently, some effects of lactogen resistance might be obscured by compensatory actions of growth hormone. To address this problem, his laboratory has recently generated a mouse with combined deficiencies in lactogen signaling and GH production. This mouse is unique among experimental models of somatolactogen production and action. The model was created by breeding prolactin receptor (PRLR)-deficient (knockout) males with GH-deficient ("little") females. In contrast to mice with isolated GH- or PRLR-deficiencies, double mutant (lactogen-resistant and GH-deficient) mice on day 7 of life had growth failure and hypoglycemia These findings suggest that lactogens and GH act in concert to facilitate weight gain and glucose homeostasis during the perinatal period. Plasma insulin, IGF-I and IGF-H concentrations were decreased in both GH-deficient and double-mutant neonates but were normal in PRLR-deficient mice. Body weights of the double mutants were decreased markedly during the first 3-4 months of age, and adults had striking reductions in femur length, plasma IGF-I and IGF binding protein-3 concentrations, and femoral bone mineral density. By age 6-12 months, however, the double mutant mice developed obesity, hyperleptinemia, fasting hyperglycemia, relative hypoinsulinemia, insulin resistance, and glucose intolerance; males were affected to a greater degree than females. The combination of perinatal growth failure and late-onset obesity and insulin resistance suggests that the lactogen resistant/GH­deficient mouse may serve as a model for the development of the metabolic syndrome.

Christopher Newgard, Ph.D., Professor of Pharmacology, Cancer Biology and Internal Medicine and Director of the Sarah Stedman Center for Nutritional Studies/Metabolics Center

Dr. Newgard's laboratory is interested in gaining a fundamental understanding of metabolic regulatory mechanisms, and in the application of this understanding to the development of new therapies for the epidemic diseases of diabetes and obesity. The work is organized around two ambitious practical goals that encompass smaller and more approachable basic science projects, summarized as follows: