Abstract

In light of the fact that patients with newly diagnosed Type I and Type II diabetes have significantly elevated basal and exercise- induced growth hormone (GH) levels despite their hyperglycemia, this proposal aims to continue the study of the effects of insulin on in vitro GH gene expression. Insulin action will be studied on the regulation of basal and stimulated GH gene transcription, mRNA levels and protein synthesis. Specific regulatory sites for insulin action will also be identified on the transfected GH gene. Insulin binding and receptor occupancy will be correlated with biologic action of insulin on GH gene expression. Increased GH levels have been implicated in development of diabetic macrovascular and microvascular complications. The elevations of GH have also been implicated in the pathophysiology of metabolic disorder in diabetes. The studies proposed here will provide further insight into the molecular mechanism of insulin action at the level of specific polypeptide hormone gene regulation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK034824-04
Application #
3233096
Study Section
Metabolism Study Section (MET)
Project Start
1985-06-01
Project End
1993-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048

  Publications

Webster, J; Prager, D; Melmed, S (1994) Insulin-like growth factor-1 activation of extracellular signal-related kinase-1 and -2 in growth hormone-secreting cells. Mol Endocrinol 8:539-44
Prager, D; Li, H L; Asa, S et al. (1994) Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant. Proc Natl Acad Sci U S A 91:2181-5
Prager, D; Li, H L; Yamasaki, H et al. (1994) Human insulin-like growth factor I receptor internalization. Role of the juxtamembrane domain. J Biol Chem 269:11934-7
Prager, D; Yamasaki, H; Weber, M M et al. (1994) Role of the insulin-like growth factors in regulating neuroendocrine function. Neurobiol Aging 15:569-72
Yamamoto, H; Prager, D; Yamasaki, H et al. (1993) Rat pituitary GC cell insulin-like growth factor-I receptor regulation. Endocrinology 133:1420-5
Prager, D; Weber, M M; Gebremedhin, S et al. (1993) Interaction between insulin and thyroid hormone in rat pituitary tumour cells: insulin attenuates tri-iodothyronine-induced growth hormone mRNA levels. J Endocrinol 137:107-14
Ezzat, S; Ezrin, C; Yamashita, S et al. (1993) Recurrent acromegaly resulting from ectopic growth hormone gene expression by a metastatic pancreatic tumor. Cancer 71:66-70
Yamasaki, H; Prager, D; Melmed, S (1993) Structure-function of the human insulin-like growth factor-I receptor: a discordance of somatotroph internalization and signaling. Mol Endocrinol 7:681-5
Prager, D; Yamasaki, H; Weber, M M et al. (1992) Human insulin-like growth factor I receptor function in pituitary cells is suppressed by a dominant negative mutant. J Clin Invest 90:2117-22
Ezzat, S; Ren, S G; Braunstein, G D et al. (1992) Octreotide stimulates insulin-like growth factor-binding protein-1: a potential pituitary-independent mechanism for drug action. J Clin Endocrinol Metab 75:1459-63

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