Preliminary data suggests there exists an autoregulatory feedback loop within the human islet: insulin stimulates somatostatin, and somatostatin inhibits insulin secretion. The purpose of this First Award project is to demonstrate that insulin and somatostatin are intraislet mediators of islet cell secretion. Hormonal infusions and immunoneutralization techniques with antibodies and Fab fragments of antibodies directed against insulin and somatostatin will be used in isolated perfused human and rat pancreas models. These models allow for in vitro studies of cell-to-cell communication with preservation of islet microvasculature. Insulin and somatostatin secretory responses will be measured using radio- immunoassay techniques. Somatostatin and insulin mRNA transcription will be characterized using Northern blot technique. Diffusion characteristics of FITC-antibody and FITC-Fab fragments can be examined utilizing an in vivo microscopy rat pancreas model. The experiments in this proposal have these specific aims: 1. To determine whether intraislet somatostatin is an inhibitory mediator of insulin secretion; 2. To determine whether intraislet insulin is a stimulatory mediatory of somatostatin secretion; 3. To determine whether intraislet insulin regulates the transcription of somatostatin mRNA; 4. To determine whether intraislet somatostatin regulates the transcription of insulin mRNA; 5. To determine whether the antibodies and Fab fragments of the antibodies leave the intravascular compartment and enter the interstitium of the islet. The significance of this study is in obtaining a better understanding of islet physiology. Furthermore, we anticipate that these techniques will be used to study the transplanted islet.

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 #
1R29DK046441-01
Application #
3464874
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1993-05-01
Project End
1998-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Liu, Shi-He; Patel, Sanjeet; Gingras, Marie-Claude et al. (2011) PDX-1: demonstration of oncogenic properties in pancreatic cancer. Cancer 117:723-33
Brunicardi, F C; Dyen, Y; Brostrom, L et al. (2000) The circulating hormonal milieu of the endocrine pancreas in healthy individuals, organ donors, and the isolated perfused human pancreas. Pancreas 21:203-11
Brunicardi, F C; Wen, D; Bradley, J C et al. (2000) The effect of intraislet somatostatin immunoneutralization on insulin secretion in the isolated perfused rat pancreas. Int J Surg Investig 1:381-8
Kleinman, R M; Fagan, S P; Ray, M K et al. (1999) Differential inhibition of insulin and islet amyloid polypeptide secretion by intraislet somatostatin in the isolated perfused human pancreas. Pancreas 19:346-52
Fagan, S P; Azizzadeh, A; Moldovan, S et al. (1998) Insulin secretion is inhibited by subtype five somatostatin receptor in the mouse. Surgery 124:254-8;discussion 258-9
Atiya, A W; Moldovan, S; Adrian, T E et al. (1997) Intraislet somatostatin inhibits insulin (via a subtype-2 somatostatin receptor) but not islet amyloid polypeptide secretion in the isolated perfused human pancreas. J Gastrointest Surg 1:251-6; discussion 256
Atiya, A; Malik, M; Une, S et al. (1997) Immunomodulatory activities of the somatostatin receptor subtype analogues on human peripheral blood lymphocytes. Transplant Proc 29:2151
Kleinman, R M; Gingerich, R; Ohning, G et al. (1997) Intraislet regulation of pancreatic polypeptide secretion in the isolated perfused rat pancreas. Pancreas 15:384-91
Ren, J; Bell, G; Coy, D H et al. (1997) Activation of human somatostatin receptor type 2 causes inhibition of cell growth in transfected HEK293 but not in transfected CHO cells. J Surg Res 71:13-8
Brunicardi, F C; Stagner, J; Bonner-Weir, S et al. (1996) Microcirculation of the islets of Langerhans. Long Beach Veterans Administration Regional Medical Education Center Symposium. Diabetes 45:385-92

Showing the most recent 10 out of 16 publications