Recent studies have indicated that insulin is internalized into target cells and localizes in several intracellular organelles including the nucleus, nuclear membrane, and Golgi. Moreover, these organelles have specific binding sites for insulin. The proposed studies will probe both the nature of these intracellular insulin receptors and whether insulin has direct effects on the cell interior. Recent studies from our laboratory and others have demonstrated that insulin has direct effects on isolated nuclei and nuclear envelopes. In the first series of experiments, using 125I-insulin crosslinking studies and insulin-ferritin, we will probe the nature and location of the insulin receptors found on the nuclear envelope and on the endoplasmic reticulum. In the second series of experiments, we will probe the effects of insulin on nuclear mRNA efflux from isolated nuclei. We will investigate both the efflux of total nuclear mRNA as well as efflux of specific mRNAs for albumin and other proteins using cDNA probes. In addition, direct effects of insulin on nucleoside triphosphatase, the enzyme that regulates mRNA efflux, will be studied and compared both with insulin-like hormones such as the insulin-like growth factors and with epidermal growth factor. It has recently been reported that the interaction of insulin with the plasma membrane insulin receptor produces a small molecular weight protein peptide that may function as a second messenger for insulin. In addition, in studies with nuclear envelopes and isolated nuclei, we will test the effect of this putative second messenger for insulin and compare it to insulin itself. We believe that these types of studies should provide new information concerning the possible direct effects of insulin on nuclear functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK026667-08
Application #
3227982
Study Section
Metabolism Study Section (MET)
Project Start
1979-03-01
Project End
1988-06-30
Budget Start
1986-09-01
Budget End
1988-06-30
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Mount Zion Hospital and Medical Center
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94120
Blouet, Clémence; Schwartz, Gary J (2012) Duodenal lipid sensing activates vagal afferents to regulate non-shivering brown fat thermogenesis in rats. PLoS One 7:e51898
Blouet, Clemence; Liu, Shun-Mei; Jo, Young-Hwan et al. (2012) TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity. J Neurosci 32:9870-7
Brunetti, A; Brunetti, L; Foti, D et al. (1996) Human diabetes associated with defects in nuclear regulatory proteins for the insulin receptor gene. J Clin Invest 97:258-62
Hartmann, K K; Baier, T G; Papa, V et al. (1992) A monoclonal antibody to the T-cell receptor increases IGF-I receptor content in normal T-lymphocytes: comparison with phytohemagglutinin. J Cell Biochem 48:81-5
Mamula, P W; Goldfine, I D (1992) Cloning and characterization of the human insulin-like growth factor-I receptor gene 5'-flanking region. DNA Cell Biol 11:43-50
Rosenthal, S M; Brunetti, A; Brown, E J et al. (1991) Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II. J Clin Invest 87:1212-9
Rosenthal, S M; Brown, E J; Brunetti, A et al. (1991) Fibroblast growth factor inhibits insulin-like growth factor-II (IGF-II) gene expression and increases IGF-I receptor abundance in BC3H-1 muscle cells. Mol Endocrinol 5:678-84
Mamula, P W; McDonald, A R; Brunetti, A et al. (1990) Regulating insulin-receptor-gene expression by differentiation and hormones. Diabetes Care 13:288-301
Amacher, S L; Goodman, L J; Bravo, D A et al. (1989) Glucocorticoid-regulated and constitutive trafficking of proteolytically processed cell surface-associated glycoproteins in wild type and variant rat hepatoma cells. Mol Endocrinol 3:1634-42
Trischitta, V; Wong, K Y; Brunetti, A et al. (1989) Endocytosis, recycling, and degradation of the insulin receptor. Studies with monoclonal antireceptor antibodies that do not activate receptor kinase. J Biol Chem 264:5041-6

Showing the most recent 10 out of 19 publications